thromboembolism
diagnosaurus
Thrombotic thrombocytopenic purpura
DDx
Disseminated intravascular coagulation Hemolytic uremic syndrome Preeclampsia-eclampsia Meningitis Evans syndrome (idiopathic thrombocytopenic purpura with autoimmune hemolytic anemia)
See related DDx Microangiopathic hemolytic anemia Thrombocytopenia Hemolytic anemia Altered mental status
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thromboembolism Hemoglobinuria Acute renal failure Fever and rash
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thromboembolism
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thromboembolism
Deep-vein thrombosis
Etiology Risk factors
Bed rest or immobility Hypercoagulable state, eg, malignancy, nephrotic syndrome, inherited defect Advanced age Oral contraceptive use Systemic lupus erythematosus or antiphospholipid antibody syndrome
DDx Muscular strain Baker’s cyst (rupture or obstruction of popliteal [= ιγνυακή ] vein)
Achilles tendon rupture Cellulitis Superficial thrombophlebitis Lymphatic obstruction, eg, obstruction by pelvic tumor
Reflex sympathetic dystrophy Tumor or fibrosis obstructing iliac vein
May-Thurner syndrome (left iliac vein compressed by right common iliac artery)
See related DDx Calf pain Hypercoagulable state Unilateral edema Pulmonary thromboembolism
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thromboembolism
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thromboembolism
Hypercoagulable state
Etiology Acquired Immobility or postoperative state Cancer Inflammatory disorders, eg, ulcerative colitis Myeloproliferative disorder, eg, polycythemia vera, essential thrombocytosis Estrogens, pregnancy Heparin-induced thrombocytopenia Lupus anticoagulant Anticardiolipin antibodies Nephrotic syndrome Paroxysmal nocturnal hemoglobinuria Disseminated intravascular coagulation Congestive heart failure
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thromboembolism
Congenital Activated protein C resistance, eg, Factor V Leiden Prothrombin 20210 mutation Antithrombin III deficiency Protein C deficiency Protein S deficiency Hyperhomocysteinemia Dysfibrinogenemia Abnormal plasminogen
See related DDx
Deep-vein thrombosis Pulmonary thromboembolism
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thromboembolism
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thromboembolism
Superficial thrombophlebitis DDx Deep-vein thrombosis Cellulitis Lymphangitis Erythema nodosum Erythema induratum (associated with tuberculosis) Panniculitis
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thromboembolism
Associated conditions Varicose veins Pregnancy or postpartum state Trauma Thromboangiitis obliterans (Buerger's disease) Migratory thrombophlebitis with pancreatic cancer (Trousseau's syndrome) Behçet's syndrome See related DDx Unilateral edema Deep-vein thrombosis
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thromboembolism
Thromboangiitis obliterans
(Buerger's disease) DDx
Limb ischemia due to emboli or atherosclerosis Autoimmune:
1. 2. 3. 4. 5.
Raynaud’s disease, polyarteritis nodosa, systemic lupus erythematosus, antiphospholipid antibody syndrome, Takayasu’s arteritis Rare:
1. ergotamine intoxication, 2. cannabis arteritis,
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thromboembolism 3. hypothenar hammer (jackhammer) syndrome
See related DDx Acute limb ischemia Claudication Foot pain Hand pain Vasculitis syndromes Livedo reticularis
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thromboembolism
quick answears
1-12 of 12 Results
Pemphigus
| GO |
Pulmonary Embolism
| GO |
Symptoms and Signs >
Clinical findings depend on the size of the embolus and the patient's preexisting cardiopulmonary status
Dyspnea occurs in 75–85% and chest pain in 65–75% of patients Tachypnea is
the only sign reliably found in more than 50%
of patients
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thromboembolism 97% of patients in the PIOPED study had at least one of the following
– Dyspnea – Tachypnea – Chest pain with breathing
Table 9-15.
and signs
Frequency of specific symptoms
in patients at risk for pulmonary thromboembolism.
PIOPED2
UPET1
PIOPED2
PE+ (n
PE+ (n = PE– (n =
= 327)
117)
248)
84%
73%
72%
74%
66%
59%
53%
37%
36%
Leg pain
nr
26%
24%
Hemoptysis
30%
13%
8%
Palpitations
nr
10%
18%
Wheezing
nr
9%
11%
Anginal pain
14%
4%
6%
92%
70%
68%
Crackles (rales)
58%
51%
40%3
Heart rate 100/min
44%
30%
24%
24%
13%3
23%
13%3
7%
12%
Symptoms Dyspnea Respirophasic chest pain Cough
Signs Respiratory rate 16 UPET, 20 PIOPED
Fourth heart sound (S4) nr
Accentuated pulmonary
53%
component of second heart sound (S2P) T 37.5 °C UPET, 38.5 °C 43% PIOPED Homans' sign
nr
4%
2%
Pleural friction rub
nr
3%
2%
Third heart sound (S3)
nr
3%
4%
Cyanosis 19%
1%
2%
1Data from the Urokinase-Streptokinase Pulmonary Embolism Trial, as reported in Bell WR, Simon TL, DeMets DL. The clinical features of submassive and massive pulmonary emboli. Am J Med. 1977;62:355. 2Data from patients enrolled in the PIOPED I study, as reported in Stein PD et al. Clinical, laboratory, roentgenographic, and electrocardiographic findings in patients with acute pulmonary embolism and no preexisting cardiac or pulmonary disease. Chest. 1991;100:598. 3P < .05 comparing patients in the PIOPED I study. PE+, confirmed diagnosis of pulmonary embolism; PE–, diagnosis of pulmonary embolism ruled out; nr, not reported.
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thromboembolism
Differential Diagnosis
:
Myocardial infarction (heart attack) Pneumonia Pericarditis Congestive heart failure Pleuritis (pleurisy) Pneumothorax Pericardial tamponade
Laboratory Tests ECG is
:
abnormal in 70% of patients
– Sinus tachycardia and nonspecific ST-T changes are the most common findings Acute respiratory alkalosis, hypoxemia, and widened arterial–alveolar O2 gradient (A–a Do2),
but these
findings are not diagnostic Using a
D-dimer threshold between 300 and 500 ng/mL ,
a rapid ELISA has shown a sensitivity for venous thromboembolism of 95–97% and a
imaging
specificity of 45%
:
Figure 9-5.
D-dimer and helical CT-PA based diagnostic algorithm for PE. CT-PA, CT pulmonary angiogram; PE,
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thromboembolism pulmonary embolism; ELISA, enzyme-linked immunosorbent assay; VTE, venous thromboembolic disease; LE US, lower extremity venous ultrasound for deep venous thrombosis; PA, pulmonary angiogram. (Reproduced, with permission, from van Belle A et al: Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA 2006;295:172.)
Copyright © The McGraw-Hill Companies. All rights reserved.
Chest radiograph—most common findings
– Atelectasis – Infiltrates – Pleural effusions – Westermark sign is focal oligemia with a prominent central pulmonary artery | go | – Hampton hump is a pleural-based area of increased intensity from intraparenchymal hemorrhage | go |
Lung scanning (V/Q scan)
– A normal scan can exclude PE – A high-probability scan is sufficient to make the diagnosis in most cases – Indeterminate scans are common and do not further refine clinical pretest probabilities
study
Helical CT arteriography is supplanting V/Q scanning as the initial diagnostic
– It requires administration of intravenous radiocontrast dye but is otherwise noninvasive – It is very
sensitive for the detection of thrombus in the proximal pulmonary arteries
but less so in the segmental and subsegmental arteries
Venous thrombosis studies – Venous ultrasonography is the test of choice in most centers – Diagnosing DVT establishes the need for treatment and may preclude invasive testing in patients in whom there is a high suspicion for PE
In the setting of a nondiagnostic V/Q scan, negative serial DVT studies over 2 weeks predict a low risk (< 2%) of subsequent DVT over the next 6 weeks
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Pulmonary angiography is the reference standard for the diagnosis of PE – Invasive, but safe—minor complications in < 5% – Role in the diagnosis of PE controversial , but generally used when
there is a high clinical probability and negative noninvasive studies
MRI is a research tool for the diagnosis of PE
Treatment > Medications >
Table 14–13. Initial anticoagulation for VTE.1
Anticoagulant Dose/Frequency Clinical Scenario DVT,
DVT,
lower
upper
Comment PE VTE, with
VTE,
concomitant cancersevere renal related
extremity extremity
impairment2 x
x
x
x
Bolus may
Unfractionated
80 units/kg IV
heparin
bolus then
be omitted
continuous IV
if risk of
infusion of 18
bleeding is
units/kg/h
perceived to be elevated. Maximum bolus, 10,000 units. Requires aPTT monitoring. Most patients: begin warfarin at time of initiation of heparin
17,500 units SC
x
aPTT
q12h (initial dose)
monitoring required with dose adjustment
330 units/kg SC x x
Fixed-
1 then 250
dose; no
units/kg SC q12h
aPTT monitoring required
Enoxaparin 3
1 mg/kg SC q12h
x
x
x
Most patients:
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thromboembolism begin warfarin at time of initiation of LMWH 1.5 mg/kg SC
x
once daily Tinzaparin 3
175 units/kg SC
x
x
x
x
once daily
Cancer: administer LMWH for 3–6 months
Dalteparin 3
200 units/kg SC
x
x
x
x
once daily
Cancer: administer LMWH for 3–6 months; reduce dose to 150 units/kg after first month of treatment
Fondaparinux
5–10mg SC once
x
x
x
Use, 7.5
daily (see
mg for
Comment)
body weight 50– 100 kg, 10 mg for body weight > 100 kg
Note: An "x" denotes appropriate use of the anticoagulant. 1Obtain baseline hemoglobin, platelet count, aPTT PT/INR, creatinine, urinalysis, and hemoccult prior to initiation of anticoagulation. Anticoagulation is contraindicated in the setting of active bleeding. 1Obtain baseline hemoglobin, platelet count, aPTT PT/INR, creatinine, urinalysis, and hemoccult prior to initiation of anticoagulation. Anticoagulation is contraindicated in the setting of active bleeding. 2Defined as creatinine clearance < 30 mL/min. 3Body weight < 50 kg: reduce dose and monitor anti-Xa levels. DVT, deep venous thrombosis; IV, intravenously; PE, pulmonary embolism; SC, subcutaneously; VTE, venous thromboembolic disease (includes DVT and PE).
Full anticoagulation with heparin should begin with the diagnostic evaluation in patients with a moderate to high clinical likelihood of PE and no contraindications Once the diagnosis of proximal DVT or PE is established, it is critical to ensure adequate therapy LMWHs are as effective as unfractionated heparin – Administered in dosages determined by body weight once or twice daily without the need for coagulation monitoring – Subcutaneous administration appears to be as effective as the intravenous route
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Warfarin
:
– Initial dose: 2.5–10 mg/day – Usually requires 5–7 days to become therapeutic; therefore, heparin is generally continued for 5 days
– Maintenance therapy usually requires 2–15 mg/day – Contraindicated in pregnancy; LMWHs are safe alternatives
Guidelines for the duration of full anticoagulation
:
– 6 months for an initial episode with a reversible risk factor – 12 months after an initial, idiopathic episode – 6–12 months to indefinitely in patients with irreversible risk factors or recurrent disease
Thrombolytic therapy accelerates resolution of thrombi when compared with heparin, but does not improve mortality
2.1%)
– Carries 10-fold greater risk of intracranial hemorrhage compared with heparin (0.2– – Indicated in patients who are hemodynamically unstable while on heparin
Venal caval interruption (IVC filters) may be indicated when a significant contraindication to anticoagulation exists or when recurrence occurs despite adequate anticoagulation
IVC filters decrease the short-term incidence of PE, but increase the rate of recurrent DVT
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thromboembolism
Surgery
:
Pulmonary embolectomy is an emergency procedure with a high mortality rate performed at few centers
Therapeutic Procedures
:
Catheter devices that fragment and extract thrombus have been used on small numbers of patients Platelet counts should be monitored for the first 14 days of UFH due to the risk of immune-mediated thrombocytopenia Warfarin has interactions with many drugs
Complications
:
Immune-mediated thrombocytopenia occurs in 3% of patients taking UFH
Hemorrhage is the major complication of anticoagulation with heparin: risk of any hemorrhage is 0–7%; risk of fatal hemorrhage is 0–2%
Risk of hemorrhage with warfarin therapy is 3–4% per patient year, but correlates with INR
Chronic thromboembolic pulmonary hypertension occurs in about 1% of patients; selected patients may benefit from pulmonary endarterectomy
prevntion
:
Table 14–12. Pharmacologic prophylaxis of VTE in selected clinical scenarios.1
Anticoagulant Dose
Frequency Clinical
Comment
Scenario Enoxaparin
40 mg
Once daily
Most medical
—
inpatients and
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thromboembolism critical care patients Surgical patients — (moderate risk for VTE) Abdominal/pelvic Continue for 4 cancer surgery
weeks total duration
Twice daily Bariatric surgery Higher doses may be required 30 mg
Twice daily Orthopedic surgery2
Give for at least 10 days. For THR, TKA, or HFS, continue up to 35 days after surgery
Major trauma
Not applicable to patients with isolated lower extremity trauma
Acute spinal
—
cord injury — Dalteparin
2500
Once daily
units
Most medical
—
inpatients Abdominal
Give for 5–10
surgery
days
(moderate risk for VTE) 5000
Once daily
units
Orthopedic
First dose =
surgery2
2500 units. Give for at least 10 days. For THR, TKA, or HFS, continue up to 35 days after surgery
Abdominal
Give for 5–10
surgery (higher- days risk for VTE) Medical
—
inpatients Fondaparinux
2.5 mg
Once daily
Orthopedic
Give for at
surgery2
least 10 days. For THR, TKA, or HFS, continue up to 35 days after surgery
Unfractionated
5000
Three
heparin
units
times daily severe renal
Patients with
LMWHs contraindicated
insufficiency3 Patients with
LMWHs
epidural
contraindicated
catheters Surgical patients Includes (higher risk for
gynecologic
VTE)
surgery for
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thromboembolism malignancy and urologic surgery, neurosurgery in high-risk patients 5000
Twice daily Surgical patients Includes
units
(moderate risk)
gynecologic surgery (moderate risk)
Warfarin
(variable) Once daily
Orthopedic
Titrate to goal
surgery2
INR = 2.5. Give for at least 10 days. For THR, TKA or HFS, continue up to 35 days after surgery
1All regimens administered subcutaneously, except for warfarin. 2Includes TKA, THR, and HFS. 3Defined as creatinine clearance < 30 mL/min. HFS, hip fracture surgery; LMWH, low-molecular-weight heparin; THR, total hip replacement;.TKA, total knee arthroplasty; VTE, venous thromboembolic disease.
Prognosis
:
Overall prognosis depends on the underlying disease rather the thromboembolic event
than
Death from recurrent PE occurs in only 3% of cases; 6 months of anticoagulation therapy reduces the risk of recurrent thrombosis and death by 80–90% Perfusion defects resolve in most survivors
When to Refer
:
All patients evaluated for or diagnosed with a PE should be evaluated by an expert (typically a pulmonologist, hematologist, or internist)
When to Admit
:
Patients with an acute PE should be admitted for stabilization, initiation of therapy, evaluation of cause of PE, and education
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thromboembolism
References Kearon C et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S–545S. [PMID: 18574272]
Quiroz R et al. Clinical validity of a negative computed tomography scan in patients with suspected pulmonary embolism: a systematic review. JAMA. 2005 Apr 27;293(16):2012–7.
[PMID: 15855435]
Roy PM et al. Systematic review and meta-analysis of strategies for the diagnosis of suspected pulmonary embolism. BMJ. 2005 Jul 30;331(7511):259. [PMID: 16052017]
Stein PD et al. Challenges in the diagnosis of acute pulmonary embolism. Am J Med. 2008 Jul;121(7):565–71. [PMID: 18589050]
Tapson VF. Acute pulmonary embolism. N Engl J Med. 2008 Mar 6;358(10):1037–52.
[PMID: 18322285]
van Belle A et al; Christopher Study Investigators. Effectiveness of managing suspected pulmonary embolism using an algorithm combining clinical probability, D-dimer testing, and computed tomography. JAMA. 2006 Jan 11;295(2):172–9. [PMID: 16403929]
Content adapted from CURRENT Medical Diagnosis & Treatment 2010.
Thrombophlebitis, Superficial Veins Key Features
| GO |
:
Essentials of Diagnosis
:
Induration, redness, and tenderness along a superficial vein, usually the
saphenous vein Induration at the site of a recent intravenous line or trauma Significant swelling of the extremity MAY NOT BE SEEN
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thromboembolism
General Considerations
:
May occur spontaneously, as in pregnant or postpartum women or in individuals with varicose veins or thromboangiitis obliterans
May be associated with
:
– Trauma – Occult deep vein thrombosis (DVT) (in about 20% of cases) – Short-term venous catheterization of superficial arm veins – Longer term peripherally inserted central catheter lines May also be a manifestation of systemic hypercoagulability secondary to abdominal cancer Pulmonary emboli are exceedingly rare and occur from an associated DVT
Observe intravenous catheter sites daily for signs of local inflammation
Clinical Findings
:
Symptoms and Signs :
Dull pain in the region of the involved vein Induration, redness, and tenderness along the course of a vein Process may be localized, or it tributaries longer
may involve most of the long saphenous vein and its
Inflammatory reaction generally subsides in 1–2 weeks; a firm cord may remain for much Edema of the extremity
is uncommon
Chills and high fever suggest septic phlebitis
Differential Diagnosis
:
Cellulitis Erythema nodosum Erythema induratum Panniculitis Fibrositis
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thromboembolism
Lymphangitis Deep thrombophlebitis See also DDx: Superficial thrombophlebitis
Diagnosis
:
Laboratory Tests
:
Blood culture: in septic thrombophlebitis, the causative organism is often Staphylococcus Imaging Studies
:
Ultrasonography to assess extent of thrombosis
Treatment
:
Medications :
Nonsteroidal anti-inflammatory drugs : For septic thrombophlebitis : – Broad-spectrum antibiotics ( vancomycin +/- gentamicin ) (Table 30-4); if cultures are positive, continue for 7–10 days or for 4–6 weeks if complicating endocarditis cannot be excluded
– Systemic anticoagulation with heparin Anticoagulation for rapidly progressing disease or extension into the deep system
Table 30-4. Drugs of choice for suspected or proved microbial pathogens, 2009.1 Suspected or
Drug(s) of First
Proved
Choice
Alternative Drug(s)
Etiologic Agent Gram-negative cocci Moraxella
TMP-SMZ,2 a
Cefuroxime, cefotaxime, ceftriaxone,
catarrhalis
fluoroquinolone 3
cefuroxime axetil, an erythromycin,4 a tetracycline,5 azithromycin, amoxicillin-clavulanic acid,
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thromboembolism clarithromycin Neisseria
Cefpodoxime
gonorrhoeae
proxetil,
(gonococcus)
ceftriaxone
Neisseria
Penicillin6
Ciprofloxacin, ofloxacin
Cefotaxime, ceftriaxone, ampicillin
meningitidis (meningococcus) Gram-positive cocci Streptococcus
Penicillin6
An erythromycin,4 a cephalosporin,7
pneumoniae8
vancomycin, TMP-SMZ,2 clindamycin,
(pneumococcus)
azithromycin, clarithromycin, a tetracycline,5 certain fluoroquinolones3
Streptococcus,
Penicillin6
An erythromycin,4 a cephalosporin,7
hemolytic,
vancomycin, clindamycin,
groups A, B, C,
azithromycin, clarithromycin
G Viridans
Penicillin6 ±
streptococci
gentamicin
Cephalosporin,7 vancomycin
Staphylococcus,
Vancomycin ±
TMP-SMZ,2 doxycycline, minocycline, a
methicillin-
gentamicin
fluoroquinolone,3 linezolid, daptomycin, quinupristin-dalfopristin
resistant Penicillin6
A cephalosporin,8 clindamycin
Staphylococcus,
Penicillinase-
Vancomycin, a cephalosporin,7
penicillinase-
resistant
clindamycin, amoxicillin-clavulanic
producing
penicillin9
acid, ticarcillin-clavulanic acid,
Staphylococcus, non-penicillinaseproducing
ampicillin-sulbactam, piperacillintazobactam, TMP-SMZ 2 Enterococcus
Ampicillin ±
faecalis
gentamicin10
Vancomycin ± gentamicin
Enterococcus
Vancomycin ±
Linezolid, quinupristin-dalfopristin,
faecium
gentamicin 10
daptomycin
Gram-negative rods Acinetobacter
Prevotella,
Imipenem,
Tigecycline, minocycline, doxycycline,
meropenem
aminoglycosides,11 colistin
Clindamycin
Metronidazole
Metronidazole
Clindamycin, ticarcillin-clavulanic acid,
oropharyngeal strains Bacteroides, gastrointestinal
ampicillin-sulbactam, piperacillin-
strains
tazobactam
Brucella
Tetracycline +
TMP-SMZ 2 ± gentamicin;
rifampin 5
chloramphenicol ± gentamicin; doxycycline ± gentamicin
Campylobacter
Erythromycin 4 or
jejuni
azithromycin
Tetracycline,5 a fluoroquinolone 3
Enterobacter
TMP-SMZ,2
Aminoglycoside, a fluoroquinolone,3
imipenem,
cefepime
meropenem Escherichia coli
Cefotaxime,
Imipenem or meropenem,
(sepsis)
ceftriaxone,
aminoglycosides,11 a fluoroquinolone 3
Escherichia coli
Fluoroquinolones,3 TMP-SMZ,2 oral cephalosporin
(uncomplicated
nitrofurantoin
urinary infection) Haemophilus
Cefotaxime,
(meningitis and
ceftriaxone
Aztreonam
other serious infections) Haemophilus (respiratory
TMP-SMZ 2
Ampicillin, amoxicillin, doxycycline, azithromycin, clarithromycin,
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thromboembolism infections, otitis)
cefotaxime, ceftriaxone, cefuroxime, cefuroxime axetil, ampicillinclavulanate
Helicobacter
Amoxicillin +
Bismuth subsalicylate + tetracycline +
pylori
clarithromycin +
metronidazole + PPI
proton pump inhibitor (PPI) Klebsiella
A cephalosporin
TMP-SMZ,2 aminoglycoside,11 imipenem or meropenem, a fluoroquinolone,3 aztreonam
Legionella
Erythromycin 4 or
species
clarithromycin or
(pneumonia)
azithromycin, or
Doxycycline ± rifampin
fluoroquinolones3 ± rifampin Proteus mirabilis
Ampicillin
An aminoglycoside,11 TMP-SMZ,2 a
Proteus vulgaris
Cefotaxime,
Aminoglycoside,11 imipenem, TMP-
and other
ceftriaxone
SMZ,2 a fluoroquinolone 3
Pseudomonas
Aminoglycoside11
Ceftazidime ± aminoglycoside;
aeruginosa
+
imipenem or meropenem ±
antipseudomonal
aminoglycoside; aztreonam ±
penicillin12
aminoglycoside; ciprofloxacin (or
fluoroquinolone,3 a cephalosporin7
species (Morganella, Providencia)
levofloxacin) ± piperacillin; ciprofloxacin (or levofloxacin) ± ceftazidime; ciprofloxacin (or levofloxacin) ± cefepime Burkholderia
Ceftazidime
Tetracycline,5 TMP-SMZ,2 amoxicillinclavulanic acid, imipenem or
pseudomallei
meropenem
(melioidosis) Burkholderia
Streptomycin +
mallei (glanders)
tetracycline 5
Chloramphenicol + streptomycin
Salmonella
Ceftriaxone
A fluoroquinolone 3
Cefotaxime,
TMP-SMZ,2 aminoglycosides,11
ceftriaxone
imipenem or meropenem, a
(bacteremia) Serratia
fluoroquinolone 3 Shigella
A fluoroquinolone
Ampicillin, TMP-SMZ,2 ceftriaxone
3 Vibrio (cholera,
A tetracycline 5
TMP-SMZ,2 a fluoroquinolone 3
Yersinia pestis
Streptomycin ± a
Chloramphenicol, TMP-SMZ 2
(plague)
tetracycline 5
sepsis)
Gram-positive rods Actinomyces
Penicillin6
Tetracycline,5 clindamycin
Bacillus
Penicillin6
Erythromycin,4 a fluoroquinolone 3
(including
(ciprofloxacin or
anthrax)
doxycycline for anthrax; see
Table 33-2 ) Clostridium (eg,
Penicillin6
Metronidazole, clindamycin, imipenem or meropenem
gas gangrene, tetanus) Corynebacterium
Erythromycin 4
Penicillin6
Vancomycin
A fluoroquinolone
Ampicillin ±
TMP-SMZ 2
diphtheriae Corynebacterium jeikeium Listeria
aminoglycoside11 Acid-fast rods
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thromboembolism Mycobacterium
Isoniazid (INH) +
Other antituberculous drugs (see
tuberculosis13
rifampin +
Tables 9-12 and 9-13 )
pyrazinamide ± ethambutol (or streptomycin) Mycobacterium
Dapsone +
leprae
rifampin ±
Minocycline, ofloxacin, clarithromycin
clofazimine Mycobacterium
INH + rifampin ±
kansasii
ethambutol
Mycobacterium
Clarithromycin or
avium complex
azithromycin +
Ethionamide, cycloserine
Amikacin
one or more of the following: ethambutol, rifampin or rifabutin, ciprofloxacin Mycobacterium
Amikacin +
Cefoxitin, sulfonamide, doxycycline,
fortuitum-
clarithromycin
linezolid
TMP-SMZ 2
Minocycline, imipenem or meropenem,
chelonei Nocardia
linezolid Spirochetes Borrelia
Doxycycline,
Ceftriaxone, cefotaxime, penicillin,
burgdorferi
amoxicillin,
azithromycin, clarithromycin
(Lyme disease)
cefuroxime axetil
Borrelia
Doxycycline 5
Penicillin6
Penicillin,6
Doxycycline 5
recurrentis (relapsing fever) Leptospira
ceftriaxone Penicillin6
Doxycycline, ceftriaxone
Penicillin6
Doxycycline
Erythromycin 4 or
Clarithromycin, azithromycin, a
doxycycline
fluoroquinolone 3
C psittaci
Doxycycline
Chloramphenicol
C trachomatis
Doxycycline or
Ofloxacin
(urethritis or
azithromycin
Treponema pallidum (syphilis) Treponema pertenue (yaws) Mycoplasmas
Chlamydiae
pelvic inflammatory disease) C pneumoniae
Doxycycline 5
Rickettsiae
Doxycycline 5
Erythromycin,4 clarithromycin, azithromycin, a fluoroquinolone 3,14 Chloramphenicol, a fluoroquinolone 3
1Adapted, with permission, from Med Lett Drugs Ther. 2004;2:13. 2 TMP-SMZ is a mixture of 1 part trimethoprim and 5 parts sulfamethoxazole. 3Fluoroquinolones include ciprofloxacin, ofloxacin, levofloxacin, moxifloxacin, and others (see text). Gemifloxacin, levofloxacin, and moxifloxacin have the best activity against grampositive organisms, including penicillin-resistant S pneumoniae and methicillin-sensitive S aureus. Activity against enterococci and S epidermidis is variable. 4 Erythromycin estolate is best absorbed orally but carries the highest risk of hepatitis;
erythromycin stearate and erythromycin ethylsuccinate are also available. 5All tetracyclines have similar activity against most microorganisms. Minocycline and doxycycline have increased activity against S aureus.
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thromboembolism 6 Penicillin G is preferred for parenteral injection; penicillin V for oral administration—to be used only in treating infections due to highly sensitive organisms. 7Most intravenous cephalosporins (with the exception of ceftazidime) have good activity against gram-positive cocci. 8Infections caused by isolates with intermediate resistance may respond to high doses of penicillin, cefotaxime, or ceftriaxone. Infections caused by highly resistant strains should be treated with vancomycin. Many strains of penicillin-resistant pneumococci are resistant to macrolides, cephalosporins, tetracyclines, and TMP-SMZ. 9Parenteral nafcillin or oxacillin; oral dicloxacillin, cloxacillin, or oxacillin. 10Addition of gentamicin indicated only for severe enterococcal infections (eg, endocarditis, meningitis). 11Aminoglycosides—gentamicin, tobramycin, amikacin, netilmicin—should be chosen on the basis of local patterns of susceptibility. 12Antipseudomonal penicillins: ticarcillin, piperacillin. 13Resistance is common and susceptibility testing should be done. 14 Ciprofloxacin has inferior antichlamydial activity compared with newer fluoroquinolones. Key: ±, alone or combined with.
Surgery
Ligation and division of vein at junction of deep and superficial veins indicated when process is extensive or progressing toward the saphenofemoral or cephalo-axillary junction
Therapeutic Procedures
:
Local heat Bed rest with leg elevation
Outcome
:
Complications
:
Serious thrombotic or septic complications can occur if intravenous catheters are not removed once local reaction develops in the vein
Prognosis
:
Course is generally benign and brief Prognosis depends on the underlying pathologic process In patients with phlebitis secondary to varicose veins, recurrent
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thromboembolism
episodes are likely unless correction of the underlying venous reflux and excision of varicosities is done
Mortality from septic thrombophlebitis – Low and prognosis is excellent with early treatment – 20% without aggressive treatment
References Katz SC et al. Superficial septic thrombophlebitis. J Trauma. 2005 Sep;59(3):750–3. [PMID:
16361925] van Weert H et al. Spontaneous superficial venous thrombophlebitis: does it increase risk for thromboembolism? A historic follow-up study in primary care. J Fam Pract. 2006 Jan;55(1):52–7.
[PMID: 16388768]
Content adapted from CURRENT Medical Diagnosis & Treatment 2010.
Osteoporosis
| GO |
Edema, Lower Extremity
| GO |
Pneumonia, Health Care–Associated
| GO |
Quick Answers > P
Pulmonary Hypertension |
GO
|
Trypanosomiasis, American (Chagas Disease)
|
GO |
Quick Answers > T
Angina Pectoris
|
GO |
Quick Answers > A
Contraception, Oral, Injections, & Implants Quick Answers > C
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Chronic Obstructive Pulmonary Disease (COPD)
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Quick Answers > C
Bronchogenic Carcinoma
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Quick Answers > B
1-12 of 12 Results
εικόνες, βίντεο, ήχου |
GO
|
DeGowin's Diagnostic Examination > Chapter 16. The Preoperative Evaluation |
GO
|
Venous Thromboembolism
Inquire whether studies for thrombophilia (e.g., factor V Leiden mutation, lupus anticoagulant, antithrombin III, protein C or S)
A history of deep venous thrombosis or PE perioperatively or without provocation is associated with an increased risk for perioperative deep vein thrombosis/PE.
were performed and obtain the results if possible.
fitzpatrick atlas of clinical dermatology
1-3 of 3 Results
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Trypanosomiasis
Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology > Section 29. Systemic Parasitic Infections
Raynaud Phenomenon
Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology > Section 14. The Skin in Immune, Autoimmune, and Rheumatic Disorders
Soft Tissue Infections (STIs)
Fitzpatrick's Color Atlas and Synopsis of Clinical Dermatology > Section 24. Bacterial Infections Involving the Skin
1-3 of 3 Results
------------------------------------
fitzpatrick dermatology in general medicine 1-12 of 12 Results
Homocystinuria Dermatology > Chapter 139. Heritable Disorders of Connective Tissue with Skin Changes
Other Venous Diseases Dermatology > Chapter 175. Cutaneous Changes in Venous and Lymphatic Insufficiency
References
Dermatology > Chapter 175. Cutaneous Changes in Venous and Lymphatic Insufficiency
Differential Diagnosis Dermatology > Chapter 171. Raynaud Phenomenon
Treatment Dermatology > Chapter 156. Lupus Erythematosus
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thromboembolism Differential Diagnosis Dermatology > Chapter 179. Myonecrosis
Soft-Tissue Infections: Erysipelas,
Cellulitis, Gangrenous Cellulitis, and
Clinical Reaction Patterns with Eosinophil Involvement
Dermatology > Chapter 35. Eosinophils in Cutaneous Diseases
Psychotropic Medications Used in Dermatology
Dermatology > Chapter 103. Psychocutaneous Diseases
References
Dermatology > Chapter 154. Cutaneous Cutaneous Paraneoplastic Syndromes
Manifestations of Internal Malignant Disease:
Chronic Venous Disease
Dermatology > Chapter 175. Cutaneous Changes in Venous and Lymphatic Insufficiency
Clinical Findings
Dermatology > Chapter 156. Lupus Erythematosus
References
Dermatology > Chapter 145. Hematologic Diseases
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goodman and gilman 1-3 of 3 Results
Chapter 54. Blood Coagulation and Anticoagulant, Thrombolytic, and Antiplatelet Drugs
Goodman & Gilman's Pharmacology* Antiplatelet Drugs
Goodman & Gilman's Pharmacology > Chapter 54. Blood Coagulation and Anticoagulant, Thrombolytic, and Antiplatelet Drugs > Antiplatelet Drugs* Oral Anticoagulants Goodman & Gilman's Pharmacology > Chapter 54. Blood Coagulation and Anticoagulant, Thrombolytic, and Antiplatelet Drugs > Oral Anticoagulants
1-3 of 3 Results
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hurst the heart 1-10 of 10 Results
Prevention of Venous Thromboembolism
Hurst's The Heart > Chapter 72. Pulmonary Embolism
Risk Factors and Pathogenesis of Venous Thromboembolism
Hurst's The Heart > Chapter 72. Pulmonary Embolism
Thromboembolism
Hurst's The Heart > Chapter 89. The Diagnosis and Management of Cardiovascular Disease
in Cancer Patients
Thromboembolism
Hurst's The Heart > Chapter 45. Indications and Techniques of Electrical Defibrillation and Cardioversion
Risk Factors for Thromboemboli
Antithrombotic Therapy for Valvular Heart Disease > Native Valve Disease Hurst's The Heart > Chapter 80.
Therapy at the Time of a Thromboembolic Event
Hurst's The Heart > Chapter 80. Antithrombotic Therapy for Valvular Heart Disease > Special Clinical Situations
Thromboembolic Complications
Hurst's The Heart > Chapter 96. Heart Disease Management of Cardiovascular Syndromes
Thromboembolic Disease
Hurst's The Heart > Chapter 71. Pulmonary Pulmonary Hypertension > Cardiac Disease
and Pregnancy
Hypertension
>
> Secondary
Thromboembolism
Hurst's The Heart > Chapter 37. Atrial Fibrillation, Atrial Flutter, and Atrial Tachycardia > Atrial Fibrillation > Hemodynamic Effects
Figure 80–1. Risk of thromboembolism. Clinical variables define valve disease patients as... Hurst's The Heart > Chapter 80. Antithrombotic Therapy for Valvular Heart Disease > Native Valve Disease 1-10 of 10 Results
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Prevention of Venous Thromboembolism > Other High-Risk Patients
Mechanism of cardiac biomarker release in patients with acute pulmonary embolism. Right ventricular pressure overload with increased myocardial shear stress are responsible for myocardial synthesis and secretion of natriuretic peptides. Troponin release is a result of myocardial ischemia and microinfarction (see also the discussion under Pathophysiology of Acute Pulmonary Embolism, Hemodynamic Alterations above).
Risk Factors and Pathogenesis of Venous Thromboembolism Table 72–1 Risk Factors for Venous Thromboembolism
Acquired factors Age older than 40 Prior history of venous thromboembolism Prior major surgical procedure Trauma Hip fracture Immobilization/paralysis Venous stasis Varicose veins Congestive heart failure Myocardial infarction Obesity Pregnancy/postpartum period Oral contraceptive therapy Cerebrovascular accident Malignancy Severe thrombocythemia Paroxysmal nocturnal hemoglobinuria
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Antiphospholipid antibody syndrome (including lupus anticoagulant ) Inherited factors Antithrombin III
deficiency
Factor V Leiden (activated
protein C
resistance)
Prothrombin gene (G20210A) defect Protein C
deficiency
Protein S deficiency Dysfibrinogenemia Disorders of plasminogen Hyperhomocysteinemia
The Diagnosis and Management of Cardiovascular Disease in Cancer Patients Thromboembolism
General Considerations The prevention,
:
challenges for physicians treating
A venous thromboembolism (VTE) occurs in 5 to 7 percent of patients with malignancy, an incidence that is much greater than
patients with cancer.
that for the general population, in
recognition, and treatment of thromboembolism are clinical
which the incidence is approximately 0.1 percent.
The incidence of thrombosis is higher in patients with cancer than in the general population; thrombosis in these patients portends a worse prognosis.
Patients with cancer constitute nearly 20 percent of all cases of thrombosis. they, too, occur at a much higher incidence than in the general Approximately 10 percent of all population.
noncancer patients with VTE will be
diagnosed with malignancy within 2 THE SOURCE OF ARTERIAL years. THROMBOEMBOLISM IS MOST LIKELY ATHEROSCLEROSIS, but the The incidence of arterial general inflammatory condition thromboembolism is less than that observed in patients with cancer and of VTE in cancer patients; treatment with the new antiangiogenic agents are also important determinants.
With the more widespread use of such agents, the incidence of arterial thrombosis likely will increase in cancer patients. The risk of death for cancer patients diagnosed with a DVT or pulmonary embolism is Thrombotic events, such substantially higher than that in cancer patients as deep venous thrombosis without such an event. The same is true for arterial (DVT), pulmonary embolism, thrombi. and arterial thrombosis have
The inhospital mortality may approach 20 to 30 percent, also been observed in approximately 11 percent of especially in those with pulmonary emboli. patients treated with IL-2.21
Nonbacterial endocarditis (marantic endocarditis) and disseminated intravascular coagulation are additional examples of life-threatening thrombotic conditions associated with cancer.
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Pathophysiology of Thrombosis
:
. This section focuses on venous and arterial thrombosis in the cancer patient However, there is an incomplete understanding of the initial triggers for thrombosis and no single explanation pertains to all conditions in which thrombosis occurs
The
pathophysiology
of
thrombosis is discussed in Chaps.
52 ,
53 ,
somewhat
and
72 ,
and
depending
varies
on
the
underlying etiology
VTE in cancer patients occurs as a result of the classic triad:
stasis, endothelial disruption, and hypercoagulability. In each situation, one component may predominate and, if identified, can be effectively treated.
If, for example, a patient has an abdominal tumor that is compressing the inferior vena cava causing stasis, and this tumor can be removed or reduced by chemotherapy or radiation, then the likelihood of VTE may be markedly reduced. Indwelling intravenous catheters may cause thrombus formation . Removal of an indwelling central catheter is also likely to be very effective in reducing the risk of subsequent recurrence or progression of a thrombus once the stimulus for hypercoagulability has been removed.
There are many ways platelets can be activated, including by generalized inflammatory conditions and by the malignancy itself.
Arterial thrombosis in cancer patients is most commonly associated with platelet activation either in the presence or absence of atherosclerosis.
The exact mechanism also may include microvessel constriction and platelet activation.
Pathophysiology of Thrombosis Table 89–5
Risks for Thrombolic Events in Cancer Patients
Immobilization Genetic Inherited coagulopathy Polymorphism(s) at risk for thrombosis Surgery Trauma Heart failure Estrogen therapy Prior thrombosis Indwelling catheters Chemotherapy or other agents Tamoxifen Thalidomide Bevacizumab Cyclooxygenase-2 inhibitors (Rofecoxib) Mechanical effects of cancer itself
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A and B. Two views from a transesophageal echocardiogram showing a large thrombus in the right atrium associated with an indwelling catheter. RA, right atrium.
Clinical Manifestations
:
The location of a thrombosis is of paramount importance with regard to how the thrombus will manifest itself. file:///C|/Documents and Settings/User/Επιφάνεια εργασίας/site finaL/thromboembolism.htm[18/8/2010 11:54:32 μμ]
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THE EXTENT AND POSITION OF COLLATERAL VESSELS IS ALSO CRUCIAL IN DETERMINING HOW THE THROMBUS WILL AFFECT THE PATIENT.
.
A deep venous thrombosis in a lower extremity, for example, is likely to cause pain, swelling, and erythema of that extremity.
A deep venous thrombosis of an arm may be revealed by unilateral arm swelling that develops fairly suddenly or a bluish discoloration because of poor venous return
Arterial thrombi usually result in pain, pallor, and pulselessness in an extremity.
An arterial thrombosis of an internal organ may be manifested by 1. 2. 3. 4.
an episode of unstable angina, an acute coronary syndrome, a cerebral vascular accident, or intestinal ischemia that may be difficult to detect.
The most common presentation of VTE is unilateral leg edema. This can be associated with erythema, but typically it is difficult to discern VTE from cellulitis. Unilateral extremity swelling is, therefore, a hallmark of VTE. Bilateral lower-extremity edema may be caused by a proximal venous thrombosis or even congestive heart failure, malnutrition, or other causes of edema.
Pulmonary emboli are most commonly manifested by the sudden onset of shortness of breath, chest discomfort, and tachypnea. In addition, patients may report hemoptysis and tachycardia.
Syncope, hypotension, and sudden cardiac death are manifestations of larger pulmonary emboli. Long-term effects of pulmonary embolus and DVT include pulmonary hypertension and the postphlebitic syndrome (see Chaps. 71 and 72 ). Computed tomographic (CT) angiography (see Chap. 22 ) is a reliable and sensitive tool for detecting pulmonary embolus and peripheral extremity ultrasound remains important in the evaluation of venous flow and/or thrombus
The diagnostic approaches used to detect thrombosis, either venous or arterial, in cancer patients are similar to those used in patients without malignancy;
The techniques used to detect arterial thrombus may vary and are determined mainly by the location of the arterial insufficiency.
these techniques are highlighted elsewhere.
A combination of ultrasound, sequential pressure measurements, angiography, computerized tomography, and magnetic resonance imaging (MRI), form the basis of diagnostic testing for patients with suspected arterial insufficiency.
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A contrast-enhanced CT scan showing a massive pulmonary embolus (white arrow).
Treatment of Thromboembolism
:
There may be associated thrombocytopenia or hepatic or renal dysfunction, or perhaps the malignancy is associated with the thrombus in a location that may predispose to bleeding complications.
The optimal treatment of VTE is a challenge in cancer patients. Typically, these patients are at increased risk for bleeding; they may be anemic so that the effects of bleeding are disproportionate [=δυσανάλογα ] .
ANTITHROMBOTIC THERAPY MAY CONSIST OF MEDICATIONS TO PREVENT OR LIMIT THE PROPAGATION OF A THROMBUS OR PERHAPS THROMBOLYTIC AGENTS TO ENHANCE THE REMOVAL OF A THROMBUS.
Furthermore, the risks associated with thrombus extension, embolization, or recurrence of the thrombus must be weighed against the risks of hemorrhage as part of the decision-making process. Unfractionated heparin has been superseded by LMWH as the initial treatment in most cancer patients with VTE in both inpatients and outpatients.
Standard treatment for VTE traditionally consists of low-molecularweight heparin (LMWH), unfractionated intravenous heparin, or adjusted-dose subcutaneous heparin, followed by long term therapy with an oral anticoagulant.
Guidelines for antithrombotic therapy for VTE have been published by the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. 22
Long-term treatment with warfarin may be complicated by several problems, including
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drug–drug interactions, malnutrition, nausea, and/or vomiting during chemotherapy, and thrombocytopenia.
Additionally, HEPATIC DYSFUNCTION IN CANCER PATIENTS MAY LEAD TO UNPREDICTABLE LEVELS OF ANTICOAGULATION, and result in increased bleeding complications. LMWH is more effective than oral anticoagulant therapy with warfarin for the prevention of recurrent VTE in patients with cancer who have had acute, symptomatic proximal DVT, pulmonary embolism, or both.23
Further advantages of LMWH are that the doses are more easily adjusted, the pharmacokinetic properties are more predictable, laboratory monitoring is minimized, and fewer drug interactions occur than is the case with oral anticoagulants.
Also in favor of heparin therapy in cancer patients are reports that the heparins have antiproliferative, antiangiogenetic, and anti metastatic effects, and that LMWH may increase the response to chemotherapy, thereby prolonging the survival of cancer patients. 24 For these several reasons, secondary prophylaxis with LMWH may be more effective and feasible than oral anticoagulant therapy in cancer patients with VTE, although the risk of bleeding is the same for both treatment approaches. More recently, low-dose aspirin was safely used to prevent thrombotic complications in patients with polycythemia vera, and has been advocated as an alternative option in patients with cancer presenting with paraneoplastic thrombocytosis. Such agents include new antithrombotic agents such as oral direct thrombin or long-acting synthetic factor Xa inhibitors.
Certain anticoagulants might also improve cancer survival rates independent of their effect on thromboembolism
Furthermore, mechanical treatments, such as compression stockings used to prevent postthrombotic syndrome, have value in the treatment of cancer patients with thromboembolism, as do selected surgical techniques to treat venous ulceration. Venacaval filters may be employed instead of anticoagulation in patients with recurrent pulmonary embolisms who also have a high risk of serious bleeding.
Indications and Techniques of Electrical Defibrillation and Cardioversion Thromboembolism
:
THERE IS A SIGNIFICANT RISK OF THROMBOEMBOLISM AFTER CARDIOVERSION. Three factors contribute to this risk: (l) If there is a preexisting thrombus in the fibrillating atrium (especially likely in the left atrial appendage),
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the electrical shock and/or the resumption of atrial contraction may dislodge the thrombus.
(2) The shock itself may have thrombogenic effects.
(3) With prolonged atrial fibrillation an atrial myopathy develops, which results in a slow return to normal atrial contraction following cardioversion. To prevent thromboembolism, therapeutic anticoagulation (international normalized ratio [INR] 2.0 to 3.0) for 3 weeks prior to cardioversion and 4 weeks afterward is traditionally recommended.20
THE RISK OF THROMBOEMBOLISM ASSOCIATED WITH ATRIAL FIBRILLATION AND CARDIOVERSION IS HIGHER IN PATIENTS WITH mitral stenosis, a large left atrium from any cause, chronic atrial fibrillation of long duration, previous thromboembolic events, diabetes, or hypertension.
Although transthoracic echocardiography is able to image the left atrial cavity well, it is usually unsatisfactory for visualization of the left atrial appendage, the site of most atrial thrombi.
However, the newer technique of transesophageal echocardiography (TEE) images the left atrial appendage well and is highly sensitive to the presence of thrombi.
Manning et al. 21 reported no embolic events during the cardioversion of atrial fibrillation when transesophageal echocardiography showed no thrombi were present in the atrial appendage and the patient received intravenous heparin for 2 days before cardioversion.
This approach is known as TEE-guided cardioversion.22 If a thrombus in the left atrial appendage is seen by TEE, cardioversion should be delayed, anticoagulation for 3 weeks should be undertaken. Some clinicians repeat the TEE to ensure that the thrombus has lysed.
Although thromboembolism after cardioversion of atrial flutter is less common, it has
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been reported, as have conditions associated with thromboembolism, such as left atrial "smoke" (spontaneous ultrasound contrast) on transesophageal echocardiography.23 , 24 Thus, anticoagulation before cardioversion of atrial flutter of more than short duration should be undertaken, similar to atrial fibrillation.25
At present TEE and cardioversion are generally carried out
as two separate procedures, both requiring conscious sedation or anesthesia. Recently the two procedures have been combined by adding an electrode to the external surface of the transesophageal echo probe. Another electrode is placed on the anterior chest wall using a self-adhesive electrode pad. This allows a cardioverting DC shock to be delivered, using the esophageal–chest pathway. Because the esophageal electrode is close to the heart and the pathway is shortened, less energy— typically 20 to 50 J—is required to terminate atrial fibrillation using this esophageal cardioversion technique. Initial clinical experience with this combined TEE–cardioversion approach has been reported. 26
Whether the traditional or TEE- guided anticoagulation scheme is used, it is considered mandatory to maintain anticoagulation for at least 4 weeks after cardioversion, because in the absence of anticoagulation thrombi may form postcardioversion and embolism may occur despite a negative TEE precardioversion.21–25 consistent with the long half-life of this drug).
Patients with paroxysmal atrial fibrillation, or those considered at high risk of recurrence of atrial fibrillation after cardioversion may require permanent anticoagulation.
Antiarrhythmic drugs such as amiodarone may facilitate cardioversion and maintenance of sinus rhythm after cardioversion. It is customary to withhold digitalis on the day of cardioversion (although this practice is not
Digitalis-toxic rhythms should not be cardioverted, as the enhanced automaticity of such arrhythmias, combined with the shock could result in ventricular fibrillation or ventricular
tachycardia. 27
Antithrombotic Therapy for Valvular Heart Disease Native Valve Disease
:
Figure 80–1.
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thromboembolism
Risk of thromboembolism. Clinical variables define valve disease patients as being at high or low risk of thromboembolic events. LV, left ventricle.
Risk Factors for Thromboemboli
Atrial Fibrillation Warfarin
In six large, prospective,
therapy reduced the stroke rate to 0.5 to 2 percent per year.3
randomized trials assessing the value of antithrombotic therapy for primary stroke prevention in
"Nonvalvular" is not well defined in these trials as individuals with "insignificant" valve disease were included; however, patients with mitral stenosis or prosthetic heart valves (PHVs) were excluded. When an individual with native value disease has associated intermittent or continuous atrial fibrillation, clinical trial data can be used to assess stroke risk and direct treatment guidelines. 3–7
patients with nonvalvular, constant or paroxysmal, atrial fibrillation, the embolic rate (essentially a stroke) was 3 to 8 percent per year in the placebo or untreated patients (see Chap. 37 , Atrial Fibrillation).
In summary, warfarin is recommended in any atrial fibrillation patient who has had a systemic embolus. It is also recommended in those with two or more of the following:
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thromboembolism
diabetes mellitus, a history of hypertension, coronary artery disease, congestive heart failure, and older than age 75 years. Those with none or only one of them can reasonably be given aspirin 325 mg/d as an alternative.
Left Ventricular Dysfunction Nevertheless, because the risk is sufficiently high, Systemic or pulmonary (international normalized ratio [INR] 2 to 3) may thromboemboli occur at a rate greater be used if the LV ejection fraction (EF) is 0.30, or than 5 percent per year in patients aspirin (325 mg daily) may be used if warfarin use w i t h L V s y s t o l i c d y s f u n c t i o n u n r e l a t e d valve disease, but antithrombotic is judged to be associated with an increased risk or is t o therapy is not of proven value in impractical. preventing or reducing the systemic Less is known about the stroke risk e m b o l i c r a t e . 8 , 9 with diastolic dysfunction . warfarin
Given its frequent occurrence with hypertension, it's possible that this is one of the explanations for the association of hypertension and strokes.
Previous Thromboemboli A thromboembolic event defines patients who are at high risk for having a recurrent event in clinical situations unrelated to native valve disease (e.g., in patients with atrial fibrillation or with a PHV).3, 10 , 11 It is unclear whether this is true in patients with native valve disease, but lifelong warfarin therapy should be considered if there are no contraindications to its use.
Hypercoagulable Conditions Hypercoagulable states clearly increase the risk of venous thrombosis (see
Chap. 108).
The most common are the factor V Leiden and prothrombin gene mutations; defects in protein C , protein S, or antithrombin; and many malignancies. Less is known about their effect on the incidence of thromboemboli related to valve disease, but their presence is a reason to more strongly consider anticoagulation.
Other Potential Thromboemboli Risk Factors Beyond an assessment of left ventricular systolic function, the use of transthoracic and transesophageal echocardiography to determine which patients are at risk of thromboemboli is not yet well defined.
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Left atrial enlargement or thrombi, a patent foramen ovale, an atrial septal aneurysm, or spontaneous echo contrast
are occasional findings of concern. The value of treatment based on these findings is unproven. Antithrombotic Treatment Regimens for Native Valve Disease
:
Antithrombotic therapy is recommended only in the presence of risk factors
The following treatment regimes are appropriate: Warfarin (INR 2–3) for previous thromboemboli, LV dysfunction (LVEF 0.30), hypercoagulable states that usually require treatment with this drug. Warfarin (INR 2–3) or aspirin (325 mg) for atrial fibrillation IF VALVE LESION IS OTHER THAN MITRAL STENOSIS.
Antithrombotic Therapy for Valvular Heart Disease Therapy at the Time of a Thromboembolic Event : Acute Management
:
Ideally, treatment would be started immediately to prevent recurrence of an embolus, but the early use
of heparin (within 72 hours) is associated with a 15 to 25 percent chance of converting a nonhemorrhagic stroke into a hemorrhagic stroke. 42
Data and opinions about optimal timing for initiating or continuing anticoagulants in patients in whom an embolus is the presumed cause of a stroke are conflicting.2,40–42
The risk of early recurrent emboli is less than 5 percent. 41
On balance, it seems preferable to withhold therapy for at least 72 hours. If a computed tomography (CT) scan at that time reveals little or no hemorrhage, heparin should be administered to maintain an aPTT at the lower end of the therapeutic level until warfarin ,
started at the same time, results in the desired INR.
If the CT scan demonstrates significant hemorrhage, antithrombotic therapy should be withheld until the bleed is treated or has stabilized (7 to 14 days). Anticoagulation can then be started as just described.
Long-Term Management
:
If the embolic event occurs when a patient is off antithrombotic therapy, long-term warfarin therapy is required.
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thromboembolism If the embolic event occurs while the patient is on adequate antithrombotic therapy with the following parameters, the therapy should be altered as follows2 : If on warfarin-INR 2 to 3: increase dose
to achieve an INR of 2.5 to 3.5
If on warfarin-INR 2.5 to 3.5: add aspirin 50 to 100 mg/d If on warfarin with INR 2.5 to 3.5, plus aspirin 80 to 100 mg/d: aspirin dose may also need to be increased to 325 mg/d If on aspirin 325 mg/d:
switch to warfarin-INR 2 to 3
Embolism occurring after this medical approach should lead to consideration of possible valve surgery if the valve is the likely source of
the thrombus.
Excessive Anticoagulation
:
In most patients with INR above the therapeutic range, excessive anticoagulation can be managed by
withholding
warfarin
and
following the level of anticoagulation with serial INR determinations.
Excessive anticoagulation (INR >5) greatly increases the risk of hemorrhage. However, rapid decreases in INR that lead to INR falling below the therapeutic level may increase the risk of thromboembolism.
Patients with PHVs with an INR of 5 to 10 who are not bleeding can be managed by the following: (1) hospitalization with administration of oral vitamin K; (2) withholding warfarin and administering (2.5 mg) daily until the INR returns to an acceptable range.
Warfarin therapy can then be restarted and dose adjusted appropriately to ensure that INR is in the therapeutic range.
In emergency situations, the use of fresh-frozen plasma is preferable to high-dose vitamin K1, especially parenteral vitamin K1, because use of the latter increases the risks of
overcorrection
to a hypercoagulable state and of anaphylaxis.
Human recombinant factor (rFVIIa ), dose 15 to 19 g/kg body weight, has been used to reverse critically prolonged INR and bleeding complications safely and rapidly. Indications include
an INR >10 in high-risk persons, clinical hemorrhage, and at time of life-sparing diagnostic and therapeutic procedures. 43
Therapy at the Time of a Bleed
:
If possible, the cause of bleeding should be corrected and antithrombotic therapy restarted as soon as possible.
With significant bleeding, antithrombotic therapy should be If this is not possible, treatment stopped and, if the patient is at risk, decisions are difficult. In patients with a d r u g e f f e c t s s h o u l d b e r e v e r s e d . 2
mechanical prosthesis or multiple risk factors for thromboemboli, acceptance of intermittent bleeding with acute management for the bleeds may be necessary. In valve patients who are at lower risk of emboli or in whom the role of antithrombotic treatment is less clear (e.g., LV dysfunction), it may be optimal to withhold chronic therapy or, if a patient is on warfarin, to switch to aspirin .
With mechanical PHVs, consideration should be
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given to replacing the mechanical valve with a biologic valve in some patients (e.g., in those who have had multiple, large, life- or organ-threatening bleeds) .
Thrombosis of Prosthetic Heart Valves
:
PHV obstruction is caused by thrombus in approximately 50 percent, pannus in 10 percent, and pannus plus thrombus in 40 percent of cases.
The cause may be difficult to determine and requires knowledge of the clinical presentation (result of valve obstruction) and findings on Doppler echocardiography, including transesophageal echocardiography.
Pannus is tissue ingrowth; therefore, thrombolytic therapy is ineffective and if obstruction is severe, valve replacement is indicated. If a patient has a thrombotic obstruction of a right-sided PHV, thrombolytics are the first choice of therapy as they are successful in 80 to 100 percent of treated patients. 44 , 45
Left-sided PHV thrombosis (aortic and mitral) is more serious. With use of thrombolytics, studies show a mortality of 2 to 16 percent depending on New York Heart Association (NYHA) functional status, thromboembolism in 12 to 15 percent, major bleeding in 5 percent, and nondisabling bleeding in 14 percent. Thrombolysis was ineffective in 16 to 29 percent, and thrombosis was recurrent in 11 to 20 percent.45–48 Best results were obtained in patients who are in NYHA functional classes I and II and who have a "small" thrombus.
Surgical replacement of the thrombosed PHV is associated with a mortality of 10 to 60 percent. Again, best results are obtained in patients who are NYHA functional classes I and II.
Antithrombotic Therapy in the Patient with Endocarditis In balance, we recommend the following: If a patient with valve disease develops endocarditis while on antithrombotic therapy, the medication should be continued (see Chap. 85 ).
:
Data on starting or stopping antithrombotic therapy in a patient with endocarditis are conflicting as noted in a recent review. 49
If the patient presents with or develops an embolic event involving the central nervous system, therapy should be stopped as described earlier for acute embolic events.41 , 42
Additionally, the issue of whether or not the embolus is caused by thrombus or infected vegetation should be addressed. If thrombus is likely, the chronic anticoagulation program will also
require alteration.
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Heart Disease and Pregnancy Thromboembolic Complications
:
Both can be the result of a woman's hypercoagulable status during pregnancy, and the likelihood of venous thrombosis is increased by venous stasis.
The risk of venous thromboemboli increases fivefold during and immediately after pregnancy, 62 and there is arguably an increase in arterial emboli as well.
Prevention is optimal.
Prophylactic full-dose heparin or low-molecular-weight heparin 63 is indicated in
those at high risk for a thromboembolic complication including women
with thromboemboli during a previous pregnancy
thrombus/embolus is 4 to 15 percent) ,
(percent risk of
antithrombin III deficiency (70 percent), protein C deficiency (33 percent), protein S deficiency (17 percent), and the anticardiolipin antibody syndrome.
Prothrombin gene mutations and factor V mutation resulting in the resistance to activated protein C (found in 3 to 5 percent of the population) may eventually be shown to be a reason for prophylaxis as well. 64 , 65 If a thrombus or embolus is identified, 5 to 10 days of intravenous heparin therapy followed by full-dose subcutaneous heparin is recommended. If a thromboembolus is lifethreatening (e.g., a massive pulmonary embolus or a thrombosed prosthetic valve), thrombolytic therapy can be used. 4
Pulmonary Hypertension Thromboembolic Disease
:
Elsewhere in the world, other intravascular particulates may cause pulmonary vascular occlusive disease. For example, in Egypt, where schistosomiasis is endemic , pulmonary vascular disease stemming from ova lodged in pulmonary vessels and hypersensitivity reactions to the organism (usually situated outside the lungs) is common.
Thromboembolic disease is a form of occlusive pulmonary vascular disease that may be acute or chronic. In the United States and Europe, clots originating in peripheral veins represent a common cause of chronic occlusive pulmonary vascular disease.
In some parts of Asia, filariasis is reputed to be an important cause of pulmonary hypertension. Tumor emboli to the lungs from extrapulmonary sites (e.g., the breast) can cause pulmonary hypertension by invading the adjacent minute vessels of the lungs.
Intravenous drug use may be associated with talc or cotton fiber embolism
to the lungs,
which can result in a granulomatous pulmonary arteritis.
The syndromes of thromboembolic pulmonary hypertension can be categorized according to the segments of the pulmonary arterial tree
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that are primarily affected: (1) small (muscular pulmonary arteries and arterioles), (2) intermediate arteries, and (3) large central arteries. Some overlap is inevitable because clots lodged in large vessels are fragmented by the churning motion of the heart, and both the parent clot and its derivatives tend to move peripherally for final lodging.
Atrial Fibrillation, Atrial Flutter, and Atrial Tachycardia Thromboembolism
:
Most thrombi associated with AF arise within the left atrial appendage.71 Flow velocity within the
left atrial appendage is reduced during AF because of the loss of organized mechanical contraction. 72
Compared with transthoracic echocardiogram, the transesophageal echocardiogram offers a much more sensitive and specific means of assessing left atrial thrombi and spontaneous echo contrast, an indicator of reduced flow.73
Stroke is the most feared consequence of AF, and its prevention is a major focus of the management of patients with this condition.
Several factors contribute to the enhanced thrombogenicity of AF.
Nitric oxide (NO) production in the left atrial endocardium is reduced in experimental
increase in levels of the prothrombotic protein plasminogen activator
AF, with an
inhibitor 1 (PAI-1).74
The lowest levels of NO and the highest levels of PAI-1 were recorded in the left atrial appendage during AF. Patients with AF have elevated levels of -thromboglobulin and platelet factor 475 , 76 ; elevated plasma levels of
von Willebrand factor (vWF), soluble thrombomodulin, and fibrinogen have been reported in patients with permanent AF with no evidence of diurnal variation in thrombogenicity.77 , 78
In the Stroke Prevention in Atrial Fibrillation (SPAF) III study, 79 increased plasma levels of vWF were strongly correlated with the clinical predictors of stroke in AF (age, prior cerebral ischemia, CHF, diabetes, and body mass index). There was a stepwise increase in vWF with increasing clinical risk of stroke in this population.
current diagnosis and treatment
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Thromboembolic disease
CURRENT Medical Dx & Tx > Chapter 18. Gynecologic Disorders > Contraception > Oral Contraceptives > Combined Oral Contraceptives > Contraindications and Adverse Effects
1-1 of 1 Results
-----------------------------------------
Gynecologic Disorders Thromboembolic disease
:
While the overall risk is very An increased low (15 per 100,000 woman-years), thromboembolism is several studies have reported a twofold contraceptive users, increased risk in women using oral dose of estrogen is contraceptives containing the progestins gestodene
(not available in the United States) or
compared with women using oral contraceptives with
rate of venous found in oral especially if the 50 mcg or more.
desogestrel
levonorgestrel
and
norethindrone .
Women in whom thrombophlebitis develops should stop using this method, as should those at risk for thrombophlebitis because of surgery, fracture, serious injury, or immobilization. Women with a known thrombophilia should not use oral contraceptives. Cerebrovascular disease
:
Overall, a small increased risk of hemorrhagic stroke and subarachnoid hemorrhage and a somewhat greater increased risk of thrombotic stroke have been found;
smoking, hypertension, and age over 35 years are associated with increased risk. Women should stop using contraceptives if such warning symptoms as severe headache, blurred or lost vision, or other transient neurologic disorders develop.
Combined Oral Contraceptives > Contraindications and Adverse Effects
Table 18–4. Contraindications to use of oral contraceptives.
Absolute contraindications Pregnancy Thrombophlebitis or thromboembolic disorders (past or present) Stroke or coronary artery disease (past or present) Cancer of the breast (known or suspected) Undiagnosed abnormal vaginal bleeding Estrogen-dependent cancer (known or suspected)
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thromboembolism Benign or malignant tumor of the liver (past or present) Uncontrolled hypertension Diabetes mellitus with vascular disease Age over 35 and smoking >15 cigarettes daily Known thrombophilia Migraine with aura Active hepatitis Surgery or orthopedic injury requiring prolonged immobilization
Relative contraindications Migraine without aura Hypertension Heart or kidney disease Diabetes mellitus Gallbladder disease Cholestasis during pregnancy Sickle cell disease (S/S or S/C type) Lactation
william obstetrics
1-2 of 2 Results
Chapter 47. Thromboembolic Disorders
Williams Obstetrics, 23e
Thromboembolic Disease
Williams Obstetrics, 23e > Chapter 30. The Puerperium > Care of the Mother during the
Puerperium
1-2 of 2 Results
-------------------------------------------
Thromboembolic Disorders : Introduction : In a recent study from Norway of more than 600,000 pregnancies, Jacobsen and colleagues (2008) reported that deep-veno
The risk of
Indeed, the risk of pulmonary embolism has been estimated to be as much as four - to sixfold higher during pregnancy (Christiansen and Collins,
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venous thrombosis and 2006; Marik and Plante, 2008). The pulmonary embolism in incidence of all thromboembolic events otherwise healthy women aa vn ed r aagbeosu ta baonu te q1u aple rn u1m0b0e0r parreeg n a n c i e s , identified antepartum and in the is considered highest puerperium. during pregnancy and the puerperium. us thrombosis alone was more common antepartum whereas pulmonary embolism was more common in the first 6 weeks postpartum.
The frequency of venous thromboembolic disease during the puerperium has decreased remarkably as early ambulation has become more widely practiced. 2009).
Even so, there is evidence that it has increased 50 percent from 1999 to 2005 (Kuklina and associates, Importantly, pulmonary embolism still remains a leading cause of maternal death in the United States
By way of example, pulmonary embolism caused approximately 9 percent of the 623 pregnancy-related deaths in the United States in 2005 (Kung and co-workers, 2008).
Pathophysiology
:
In 1856, Rudolf Virchow postulated the conditions that predispose to the development of venous thrombosis: (1) stasis, (2) local trauma to the vessel wall, and (3) hypercoagulability. The risk for each increases during normal pregnancy. For example, compression of the pelvic veins and inferior vena cava by the enlarging uterus renders the venous system of the lower extremities particularly vulnerable to stasis (see Chap. 5, Hemodynamic Function in Late Pregnancy). From their review, Marik and Plante (2008) cite a 50-percent reduction in venous flow velocity in the legs that lasts from the early third trimester until 6 weeks postpartum. This stasis is the most constant predisposing risk factor for venous thrombosis.
Venous stasis and delivery may also contribute to endothelial cell injury . Lastly, marked increases in the synthesis of most clotting factors
during pregnancy
favor coagulation.
As shown in Table 47-1, Using data from the Agency for Healthcare Research and there are a number of factors Quality that included 90 percent of all hospital discharges associated with an increased risk during 2000 and 2001, James and co-workers (2006) of developing thromboembolism during pregnancy. identified the diagnosis of venous thromboembolism in 7177 women during pregnancy and 7158 during the postpartum period. They calculated that risks for thromboembolism were approximately doubled in women with
multifetal gestation, anemia, hyperemesis, hemorrhage, and cesarean delivery. The risk was even greater in pregnancies complicated by postpartum infection. These data are consistent with those reported by Ros and associates (2002), who studied a population-based cohort of more than 1 million deliveries in Sweden. Compared with uncomplicated delivery, they calculated the relative risk of pulmonary embolism to be 4.8 3.8 2.7 2.3
with with with with
severe preeclampsia, cesarean delivery, diabetes, and multifetal gestation.
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thromboembolism By contrast, analyzing data from the United Kingdom Obstetrical Surveillance System, Knight (2008) found significantly increased risk with a body mass index
multiparity.
(BMI) 30 kg/m2 or with
Table 47-1. Some Risk Factors Associated with an Increased Risk for Thromboembolism.
Risk Factor
Chapter Referral
Obstetrical
Cesarean delivery
25
Diabetes
52
Hemorrhage and anemia
35
Hyperemesis
49
Immobility—prolonged bed rest
47
Multifetal gestation
39
Multiparity
Preeclampsia
34
Puerperal infection
31
General
Age 35 years or older
12
Cancer
57
Connective-tissue disease
54
Dehydration
Immobility—long-distance travel
8
Infection and inflammatory disease
58
Myeloproliferative disease
51
Nephrotic syndrome
48
Obesity
43
Oral contraceptive use
32
Orthopedic surgery
42
Paraplegia
Prior thromboembolism
47
Sickle cell disease
51
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Smoking
8
Thrombophilia
47
Indeed, the American College of Chest Physicians now estimates that approximately half of pregnant women with thrombosis have an identifiable underlying genetic disorder (Bates and co-workers, 2008).
The likelihood of developing a thrombosis during pregnancy is especially increased in women with certain genetic risk factors.
Importantly, 50 to 60 percent of patients with a hereditary basis for thrombosis probably do not experience a thrombotic event until one of the other risk factors is present (American College of Obstetricians and Gynecologists,
2007).
Thrombophilias
:
Several important regulatory proteins act as inhibitors in the coagulation cascade. Normal values for many of these proteins during pregnancy are
found in the Appendix.
Inherited or acquired deficiencies of these inhibitory proteins are collectively referred to as
thrombophilias .
These can lead to hypercoagulability and recurrent venous thromboembolism. Some aspects of the more common inherited thrombophilias are summarized in Table 47-2 and Figure 47-1.
Although these disorders are collectively present in about 15 percent of white European populations, they are Recommendations for antepartum and postpartum thromboprophylaxis for women diagnosed r e s p o n s i b l e f o r m o r e t h a n 5 0 p e r c e n t o f with a thrombophilia are discussed later in this chapter a l l t h r o m b o e m b o l i c e v e n t s d u r i n g (Thrombophilia Prophylaxis to Prevent Adverse pregnancy (Lockwood, 2002). Pregnancy Outcomes).
Thrombophilia
Percentage Relative Probability Risk (95% CI) of VTE During of VTE During Pregnancy of VTE During Pregnancy and Pregnancy Postpartum in Patients Without Personal or Family History (Percent)
Factor V Leiden (homozygous)
<1a
25.4 (8.8–66)
1.5
Factor V Leiden (heterozygous)
44
6.9 (3.3–15.2)
0.26
Prothrombin G20201A (homozygous)
<1a
Prothrombin G20201A (heterozygous)
17
Factor V Leiden and prothrombin G20201A (compound heterozygous)
<1a
inemia
NA
9.5 (2.1–66.7)
369)
2.8
0.37
84 (19–
4.7
119
3–7.2
Hyperhomocyste-
Antithrombin
1–8
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thromboembolism deficiencyb (heterozygous)
(N/A)
Protein S deficiencyc (heterozygous)
12.4
Protein C deficiencyd (heterozygous)
<14
123)
NA
<1–6.6
13 (1.4–
0.8–1.7
a = Calculated based on Hardy-Weinbery equation. b = Less than 60-percent activity. c = Less than 55-percent activity. d = Less than 50-percent activity. CI = confidence interval; NA = not available; VTE = venous thromboembolism. Adapted from Lockwood (2007).
Overview of the inherited thrombophilias and their effect(s) on the coagulation cascade. (Adapted from Seligsohn and Lubetsky, 2001.)
There is a considerable variety of opinion concerning which patients should be advised
Lockwood (2007) concluded that it would be prudent to test pregnant women with a history of venous thromboembolism associated with temporary and reversible risk factors because the presence of a thrombophilic state would be an indication for
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to undergo thrombophilia testing (Scifres and Malone, 2008).
antepartum thromboprophylaxis.
The current recommendation of the American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2007) is that women with a personal or family history of venous thromboembolic disease be evaluated for hereditary and acquired thrombophilic disorders.
They concluded that women with unexplained fetal loss at 20 weeks' gestation or later; severe preeclampsia or hemolysis, elevated liver enzymes, low platelet count (HELLP) syndrome before weeks; or
In addition to these indications, a consensus panel organized by Aventis Pharmaceuticals—the manufacturer of enoxaparin (Pharmacokinetics in Pregnancy)—listed additional indications. 34
severe fetal-growth restriction may also benefit from thrombophilia screening (Duhl and associates, 2007).
The American College of Chest Physicians takes a more conservative stance (Bates and colleagues, 2008). Because of uncertainty associated with the magnitude of risk as well as uncertainty associated with any benefits of prophylaxis given to prevent pregnancy complications in women with heritable thrombophilias, it remains unproven that screening is in the best interests of these women. We agree with this position.
Antithrombin Deficiency This protein, formation.
:
previously known as antithrombin III , is one of the most important inhibitors of thrombin in clot
Antithrombin functions as a natural anticoagulant by binding to, and inactivating, 1.
2.
thrombin and the activated coagulation factors IXa, Xa, XIa, and XIIa (Franchini and co-workers, 2006).
Antithrombin deficiency may result from numerous mutations that are almost always autosomal dominant . Homozygous antithrombin deficiency is lethal
Antithrombin deficiency is rare—it affects about 1 in and it is the most thrombogenic of the heritable coagulopathies. Indeed,
(Katz, 2002).
5000 individuals
,
the risk of thrombosis during pregnancy among antithrombin-deficient women without a
personal or family history
is
3 to 7 percent, and it is 11 to 40 percent with such a history (Lockwood, 2007).
Given this risk, many recommend that these women be treated during pregnancy with heparin regardless of whether a prior thrombosis has occurred. Seguin and colleagues (1994) reviewed the outcomes of 23 newborns with antithrombin deficiency. There were 11 cases of thrombosis and 10 deaths.
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Protein C Deficiency : It also activates protein C, a natural anticoagulant that
presence of protein S
in the
controls thrombin generation, in part,
When thrombin is bound to thrombomodulin on endothelial cells of small vessels, its procoagulant activities are neutralized.
by inactivating factors Va and VIIIa (see Fig. 47-1).
Activated protein C also inhibits the synthesis of
plasminogen-activator inhibitor 1.
The prevalence of protein C deficiency is 2 to 3 per 1000, and inheritance is autosomal dominant.
More than 160 different protein C gene mutations have been described.
These prevalence estimates correspond with functional activity cutoff values of 50 to 60 percent, which are used by most laboratories and which are associated with a six- to 12-fold increased risk for venous thromboembolism (Lockwood, 2007).
Protein S Deficiency
:
This circulating anticoagulant is activated by protein C to decrease thrombin generation. Protein S deficiency may be caused by more than 130 different mutations
with an aggregate prevalence of about 2 per 1000 (Lockwood, 2007).
Protein S deficiency is measured by antigenically determined
free, functional, and total S levels.
All three of these levels decline substantively during normal gestation, thus the diagnosis in pregnant women—as well as in those taking certain oral contraceptives—is difficult (Archer and associates, 1999). Detection of free protein S antigen levels of
less than 55 percent in nonpregnant patients and less than 30 percent in pregnant women appears to most closely correlate with a mutated gene. Using such criteria, the prevalence of free protein S deficiency is low—0.03 to 0.13 percent — and as shown in Table 47-2, its degree of thrombogenicity is modest (Lockwood, 2007).
One woman had a cerebral vein thrombosis. Similarly, Burneo and associates (2002) reported cerebral venous thrombosis at 14 weeks.
Conard and colleagues (1990) described thrombosis in 5 of 29 pregnant women with protein S deficiency.
Neonatal homozygous protein C or S deficiency is usually associated with a severe clinical phenotype known as purpura fulminans, which is characterized by extensive thromboses in the microcirculation soon after birth leading to
skin necrosis
(Salonvaara and colleagues, 2004).
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Activated Protein C Resistance (Factor V Leiden Mutation) : A number of mutations have been described, but the most common is the factor V Leiden mutation, which was named after the city where it was described.
The most prevalent of the known thrombophilic syndromes, this condition is characterized by resistance of plasma This missense mutation in the factor V gene results in a substitution of glutamine for arginine at position t o t h e a n t i c o a g u l a n t e f f e c t s o f activated protein C.
506 in the factor V polypeptide , which confers resistance to degradation by activated protein C (Kalafatis and colleagues, 1994). 47-1).
The unimpeded abnormal factor V protein retains its procoagulant activity and predisposes to thrombosis (see Fig.
Heterozygous inheritance for factor V Leiden is the most common heritable thrombophilia.
It is found in 3 to 15 percent of select European populations, 3 percent of African Americans, and it is virtually absent in African blacks and
Asians (Lockwood, 2007).
Moreover, factor V Leiden mutation is found in up to half of nonpregnant individuals with thromboembolic disease.
Homozygous inheritance of two aberrant copies is rare and increases the risk of thrombosis during pregnancy by more than tenfold (Lockwood,
2007).
Diagnosis is made in one of two ways. In the bioassay,
resistance to activated protein C is measured (Bloomenthal
One caveat is that
antibody syndrome
and colleagues, 2002).
activated protein C resistance can also be caused by the antiphospholipid
(Eldor, 2001).
More importantly, and as discussed in Chapter 5, Regulatory Proteins,
resistance is normally increased after early pregnancy because of alterations in other coagulation proteins (Walker and associates, 1997). Thus, during pregnancy, DNA analysis for the mutant factor V gene is used to confirm the diagnosis .
Despite the large number of publications, however, they cautioned that data remain limited. One of the more meticulously executed studies was a prospective observational study of approximately 5000 women conducted by the Maternal-Fetal Medicine Units Network (Dizon-Townson and associates, 2005). These investigators found that the h e t e r o z y g o u s m u t a n t gene incidence was 2.7 percent. Of the three pulmonary emboli and one deep-venous thrombosis—a rate of none were among these carriers.
In a comprehensive review of 63 studies, Biron-Andreani and associates (2006) reported that the Leiden mutation was associated with a four- to eightfold increased risk of a firstepisode venous thromboembolism during pregnancy.
0.8 per 1000 pregnancies —
There was no increased risk of
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preeclampsia, placental abruption, fetal-growth restriction, or pregnancy loss in heterozygous women.
The investigators concluded that universal prenatal screening for the Leiden mutation and prophylaxis for carriers without a prior venous thromboembolism is not indicated. Clark and colleagues (2002) concluded that such routine prenatal screening was not cost effective.
Prothrombin G20210a Mutation
:
Found in approximately 2 percent of This missense mutation in the the white population, it is extremely p r o t h r o mbin gene leads to excessive uncommon in nonwhites (Federman and
accumulation of prothrombin, which then may be converted to thrombin.
Kirsner, 2001).
Case-control studies suggest that t h e relative risk of thromboembolism is increased 3- to 15- fold during pregnancy (Gerhardt and associates, 2000; Martinelli and colleagues, 2002).
Homozygous patients and those who co-inherit a G20210A mutation with a factor V Leiden mutation have an even greater risk of thromboembolism. Stefano and associates (1999) performed a retrospective cohort study of 624 nonpregnant patients with one prior episode of deep-venous thrombosis.
a 2.6-fold increased risk of recurrence relative to those with the homozygous Leiden mutation alone . They found that those doubly heterozygous individuals had
They concluded that carriers of both mutations are candidates for lifelong anticoagulation after a first thrombotic episode.
Hyperhomocysteinemia
:
Inheritance is autosomal recessive , and Kupferminc and co-workers (1999) found a homozygote prevalence of 8 percent in normally pregnant women .
The most common cause of elevated homocysteine is the C667T thermolabile mutation of the enzyme 5,10-methylene-tetrahydrofolate reductase (MTHFR).
Elevated levels of homocysteine may also result from deficiency of one of several enzymes
involved in methionine metabolism
correctible nutritional deficiencies of
folic acid, vitamin B6, or vitamin B12
(Hague, 2003; McDonald and Walker, 2001).
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and from
thromboembolism
During normal pregnancy, mean homocysteine plasma concentrations are decreased (López-Quesada and colleagues, 2003; McDonald and Walker, 2001).
Thus, to make a diagnosis in pregnancy, Lockwood (2002) recommends
a fasting cutoff level of >12 mol/L to define hyperhomocysteinemia .
The precise pathological mechanism(s) by which high levels of homocysteine increase the risk of thromboembolism remains undefined. Possible pathways include decreased activation of protein C as well as interference with the ability of activated protein C to inactivate factor Va (Gatt and Makris, 2007).
It may be that
reduced risk is related to
physiologically lower homocysteine levels during pregnancy and/or that most pregnant women take folic acid supplements
Although hyperhomocysteinemia is associated with an increased risk of venous thromboembolism in nonpregnant patients, it is unclear whether MTHFR C667T homozygotes have an in -creased risk during pregnancy.
(Bates and co-workers, 2008).
Recall that folic acid serves as a cofactor in the remethylation reaction of homocysteine to methionine. Also of note, hyperhomocysteinemia increases the lifetime risk of having a fetus with a neural-tube defect as well as premature atherosclerosis (see Chap. 12, Neural-Tube Defects).
Other Thrombophilia Mutations
:
A number of potentially thrombophilic polymorphisms are being discovered at an everincreasing rate. Unfortunately, information regarding the prognostic significance of such newly discovered rare mutations is limited.
Protein Z Deficiency
:
This vitamin K-dependent protein serves as a
cofactor in the inactivation of factor Xa
(see Chap. 5, Regulatory Proteins).
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Studies in nonpregnant patients have found that low levels of protein Z are associated with an increased risk of thromboembolism (Santacroce and associates, 2006).
Preliminary studies in pregnant women have suggested that low protein Z levels may be associated with
early pregnancy losses, preterm labor, fetal-growth restriction, and late-pregnancy fetal demise (Bretelle and co-workers, 2005; Kusanovic and associates, 2007; Vasse, 2008).
Antiphospholipid Antibodies These autoantibodies are
thrombosis.
:
detected in about 2 percent of patients who have nontraumatic venous
The antibodies are directed against cardiolipin(s) or against phospholipid-binding proteins such as
They are commonly found
2-glycoprotein I.
in patients with systemic lupus erythematosus
and are described in Chapter 54, Systemic Lupus Erythematosus (SLE).
Women with moderate- to high levels of these antibodies may have antiphospholipid syndrome
, which is defined by a number of clinical features such as
thromboembolism or certain obstetrical complications that
include. unexplained fetal death at or beyond 10 weeks;
1.
at least one otherwise
2.
at least
o n e p r e t e r m b i r t h b e f o r e 3 4 w e e k s ; or
3.
at least
three consecutive spontaneous abortions before 10 weeks.
In these patients, thromboembolism—either venous or arterial—most commonly involves the lower extremities. Importantly, the syndrome also should be considered in women with thromboses in unusual sites, such as
the portal, mesenteric, splenic, subclavian, and cerebral veins (American College of Obstetricians and Gynecologists, 2005).
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Antiphospholipid antibodies are also a predisposing factor for arterial thromboses. In fact, they account for up to 5 percent of arterial strokes in otherwise healthy young women (see Chap. 55, Ischemic Stroke). Thromboses may occur in relatively unusual locations, such as the
retinal, subclavian, brachial, or digital arteries.
Branch and Khamashta (2003) and Levine and colleagues (2002) have reviewed a number of hypotheses proposed to explain mechanism(s) by which antiphospholipid antibodies promote thrombosis. For example, they may interfere with the normal function of phospholipids or
phospholipid-binding proteins
involved in
coagulation regulation, including
prothrombin, protein C, annexin V, and tissue factor.
directed against 2-glycoprotein I , which may itself
Many of these antibodies are function as a natural anticoagulant
(see Chap. 54, Antiphospholipid Antibodies).
Another proposed mechanism is that these antibodies promote thrombosis through
platelet and/or complement activation.
Thrombophilias and Pregnancy Complications
augmented
:
Considerable attention has been directed recently toward a possible relationship between thrombophilias and certain pregnancy complications other than venous thrombosis (De Santis and associates, 2006).
Table 47-3 summarizes the findings of 79 studies systematically reviewed by Robertson and associates (2005).
The heterogeneity of these findings is apparent. FOR EXAMPLE, ONLY HETEROZYGOUS FACTOR V LEIDEN AND PROTHROMBIN GENE MUTATIONS ARE CONSISTENTLY ASSOCIATED WITH MOST OF THESE ADVERSE OUTCOMES.
Recent investigations continue to underscore the heterogeneity of results. with
For example, Kahn and co-workers (2009) found no increased risk for early-onset or severe preeclampsia in women factor V Leiden mutation, prothrombin G20210A mutation, MTHFR C677T polymorphism, or hyperhomocysteinemia.
Falcao and associates (2009) found no association between the latter thrombophilia and the development of preeclampsia in an animal model.
Conversely, Facchinetti and colleagues (2009) found that
recurrent preeclampsia was significantly
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more common in Italian women diagnosed with a thrombophilia.
The associations between thrombophilias and certain pregnancy complications are discussed in greater detail in other chapters: preeclampsia and HELLP syndrome (see Chap. 34, Long-Term Sequelae), fetal-growth restriction (see Chap. 38, Drugs with Teratogenic and Fetal Effects), placental abruption (see Chap. 35, Traumatic Abruption), recurrent miscarriage (see Chap. 9, Recurrent Miscarriage), stillbirth (see Chap. 29, Placental Causes), and placental findings of intervillous or spiral artery thrombosis (see Chap. 27, Maternal Blood Flow Disruption). Table 47-3. Obstetrical Complications Associated with Some Inherited and Acquired Thrombophilias
Thrombophilia
Early Pregnancy Loss
FVL—homozygous
2.7 (1.3–5.6)
9.7)
FVL—heterozygous
1.7 (1.1–2.6)
3.9)
2.5 (1.2–5.0)
5.5)
MTHFR—homozygous
1.4 (0.8–2.6)
1.1)
Hyperhomocysteinemia
6.3 (1.4–28.4)
5.6)
0.9 (0.2–4.5)
196.4)
Protein C deficiency
2.3 (0.2–26.4)
38.5)
Protein S deficiency
3.6 (0.4–35.7)
20.1 (3.7–109.2)
Acquired activated protein C resistance
4.0 (1.7–9.8)
3.9)
Anticardiolipin antibody
3.4 (1.3–8.7)
3.3 (1.6–6.7)
3.0 (1.0–8.6)
7.0)
Prothrombin— heterozygous
Antithrombin deficiency
Lupus anticoagulant
Stillbirth
Preeclampsia
2.0 (0.4–
1.9 (0.4–7.9)
2.1 (1.1–
2.2 (1.5–3.3)
2.7 (1.3–
2.5 (1.5–4.2)
1.3 (0.9–
1.0 (0.2–
1.8)
10.1)
7.6 (0.3–
3.1 (0.2–
1.4 (1.1–
3.5 (1.2–
3.9 (0.2–97.2)
102.2)
0.9 (0.2–
2.4 (0.8–
5.2 (0.3–
2.8 (0.8–10.6)
1.8 (0.7–4.6)
2.7 (1.7–4.5)
Placental FetalAbruption Growth Restriction
171.2)
19.6)
19.8)
5.4)
15.9)
18.1)
151.6)
9.3)
4.4)
4.8)
1.5 (0.8–2.8)
8.4 (0.4–
4.6 (0.2–115.7)
4.7 (1.1–
2.7 (0.6–12.1)
7.7 (3.0–
2.9 (0.6–13.7)
1.5 (0.4–
1.2 (0.8–1.8)
2.4 (0.4–
N/A
1.1 (0.1–
N/A
5.9 (0.2–
N/A
2.1 (0.5–
N/A
1.3 (0.4–
N/A
1.4 (0.4–
6.9 (2.7–17.7)
N/A
N/A
Data presented as odds ratios (95-percent confidence intervals). Bolded numbers are statistically significant. FVL = factor V Leiden, MTHFR = methylenetetrahydrofolate reductase, N/A = data not available. Data from Robertson and associates (2005).
Thrombophilia Prophylaxis to Prevent Adverse Pregnancy Outcomes . Even so, some recommend consideration for empirical
:
There are no randomized trials to guide prophylaxis to
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thromboembolism aspirin and/or low-molecular-weight heparin (Lockwood, 2002).
prevent recurrent adverse pregnancy outcomes in women with any of the inherited thrombophilias
There are a few observational studies designed to assess the efficacy of treatment during pregnancy. De Carolis and co-workers (2006) t r e a t e d 3 8 w o m e n w i t h a n i n h e r i t e d t h r o m b o p h i l i a and a prior thromboembolic event and/or poor obstetrical outcome during 39 consecutive pregnancies. Among the previous pregnancies,
only 18 resulted in a live birth, and only 12 neonates survived.
In general, treatment during subsequent pregnancies consisted of
enoxaparin, 40 mg daily in those with previous pregnancy complications, and 60 mg daily in those with a prior thromboembolic event.
Among the 39 subsequent pregnancies,
32 resulted in a term delivery, six delivered preterm, and there was one spontaneous abortion. There were no thromboembolic events.
In another observational study, Folkeringa and associates (2007) observed that thromboprophylaxis resulted in a significant reduction in the rate of historical fetal loss in women with hereditary deficiencies of
antithrombin, protein C, or protein S.
Similarly, Leduc and colleagues (2007) in a retrospective chart review found that
the combination of dalteparin (see Pharmacokinetics in Pregnancy) and low-dose aspirin given to women with an inherited thrombophilia and a prior pregnancy complicated by fetal death, placental abruption, early-onset severe preeclampsia, or fetal-growth restriction decreased the risks of the latter two in a subsequent pregnancy.
Other observational studies have not found improved perinatal outcomes with heparin (Warren and co-workers, 2009).
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Deep-Venous Thrombosis Clinical Presentation
:
:
Most cases of venous thrombosis during pregnancy are probably confined to the deep veins of the lower extremity. The frequency and extent to which they involve the pelvic veins is not known precisely, but preliminary observations indicate that iliac vein thrombosis may be frequent in those after cesarean delivery (Rodger and colleagues, 2006).
Interestingly, most cases The signs and symptoms vary during pregnancy occur in the left g r e a t l y a n d d e p e n d i n l a r g e m e a s u r e o n on and the leg. Ginsberg and colleagues (1992) reported that 58 ti nhtee ndsei gt yr e eo f otfh eo c icnl uf lsaim matory response.
of 60 antepartum women—97 percent—had left leg thromboses.
Blanco-Molina and co-workers (2007) reported that 78 percent were diagnosed in the left leg. Our experiences at Parkland Hospital are similar—90 percent of lower extremity thromboses involved the left leg. Greer (2003) hypothesizes that this may result from compression of the left iliac vein by the
right iliac artery and ovarian artery, both of which cross the vein only on the left side. Yet, as described in Chapter 5, Ureters, the ureter is compressed more on the right side!
Classical thrombosis involving the lower extremity is abrupt in onset, and there is pain and edema of the leg and thigh. pale, cool extremity with diminished pulsations.
The lower-extremity thrombus typically involves much of the deep venous system to the iliofemoral region. Occasionally, reflex arterial spasm causes a
Conversely, there may be appreciable clot, yet little pain, heat, or swelling. Importantly, calf pain, either spontaneous or in response to squeezing or to stretching the Achilles tendon—Homans sign—may be caused by a strained muscle or a contusion.
A fourth of untreated cases have an associated pulmonary embolism. Anticoagulation reduces this risk to less than 5 percent as discussed subsequently.
Diagnosis
:
Because clinical diagnosis of deep-venous thrombosis is difficult, other methods are imperative for confirmation. For example, in one study of pregnant women, clinical diagnosis was confirmed in only 10 percent of patients (Hull and co-workers, 1990).
Shown in Figure 47-2 is one algorithm promulgated by the American College of Obstetricians and Gynecologists that can be used for evaluation of pregnant women.
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thromboembolism With a few modifications, we follow a similar evaluation at Parkland Hospital. Importantly, many of the tests used commonly in various diagnostic algorithms that have been extensively investigated in nonpregnant patients have not been validated in pregnant women. These include
compression ultrasonography (CUS), ventilation-perfusion scintigraphy, and helical computed tomography-angiography (Nijkeuter and co-workers, 2006). Figure 47-2
Algorithm for evaluation of suspected deep-venous thrombosis in pregnancy. *Pretest risk score calculated by assigning 1 point for each of the nine following characteristics: active cancer, immobilization, bed rest more than 3 days or surgery within 12 weeks, local tenderness, entire leg swollen, asymmetric calf swelling greater than 3 cm when measured 10 cm below tibial tuberosity, pitting edema only in symptomatic leg, collateral nonvaricose superficial veins, or prior deep-venous thrombosis. Two points are subtracted if an alternative diagnosis is at least as likely as deep-venous thrombosis. aHigh risk = 3 or more points, moderate risk = 1 or 2 points, low risk = 0 or less points. (From Lockwood, 2007, with permission.) Venography Invasive contrast venography remains the standard to exclude lower extremity deep-venous thrombosis (Chunilal and Ginsberg, 2001). It has a negative-predictive value of 98 percent, and as discussed in Chapter 41, Contrast Agents, fetal radiation exposure without shielding is only about 300 mrad (Nijkeuter and co-workers, 2006). But venography is associated with significant complications, including thrombosis, and it is time consuming and cumbersome. Thus, noninvasive methods are usually used to confirm the clinical diagnosis.
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Impedance Plethysmography This is an extremely accurate test to assess thromboses in the lower iliac, femoral, and popliteal veins. It is based on the observation that alterations in venous return in the calf, produced by inflation and deflation of a pneumatic thigh cuff, result in changes in electrical resistance detected at the skin surface. These changes occur when the popliteal or more proximal veins are obstructed (Chunilal and Ginsberg, 2001). Impedance plethysmography, however, is only 50-percent sensitive for detection of clots in the small calf veins (Davis, 2001). Moreover, because of decreased venous return of the lower extremities, it is associated with increased false-positive results during pregnancy (Andres and Miles, 2001). Given these limitations as well as the wide availability of ultrasonography, it is seldom used today. Compression Ultrasonography This noninvasive technique is currently the most-used first-line test to detect deep-venous thrombosis (Greer, 2003). The diagnosis is based on the noncompressibility and typical echoarchitecture of a thrombosed vein (Davis, 2001). In symptomatic nonpregnant patients, examination of the femoral, popliteal, and calf trifurcation veins is more than 90-percent sensitive and more than 99-percent specific for proximal thrombosis. Moreover, it has a negative-predictive value of 98 percent (American College of Obstetricians and Gynecologists, 2000a, b). For nonpregnant patients with suspected thrombosis, the safety of withholding anticoagulation has been established for those who have normal serial compression examinations over a week (Birdwell and co-workers, 1998; Heijboer and associates, 1993). Specifically, in these nonpregnant patients, isolated calf thromboses extend into the proximal veins in up to a fourth of cases. They do so within 1 to 2 weeks of presentation and are usually detected by serial ultrasonographic compression. In pregnant women, the important caveat is that normal findings with venous ultrasonography results do not always exclude a pulmonary embolism. This is because the thrombosis may have already embolized or because it arose from deep pelvic veins inaccessible to ultrasound evaluation (Goldhaber and colleagues, 2004). In pregnant women, thrombosis associated with pulmonary embolism frequently originates in the iliac veins. Moreover, the natural history of calf deep-venous thrombosis during pregnancy is unknown. Thus, the safety of withholding anticoagulation with negative compression ultrasonography has not been evaluated in pregnant women who may have an isolated iliac vein thrombosis that is less accessible for imaging (Bates and Ginsberg, 2002). Computed Tomography Spiral computed tomography (CT) scanning is widely available and very useful for detecting lower extremity deep-venous thrombosis as well as those within the vena cava and iliac and pelvic venous systems. Although radiation and contrast agents are required, the benefits of CT outweigh any theoretical risks if lead shielding is used. Fetal radiation exposure is negligible unless the pelvic veins are imaged (see Chap. 41, Computed Tomography). Magnetic Resonance (MR) Imaging This imaging technique allows excellent delineation of anatomical detail above the inguinal ligament. Thus, in many cases, MR imaging is immensely useful for diagnosis of iliofemoral and pelvic vein thrombosis. The venous system can also be reconstructed using MR venography as discussed in Chapter 41 (Fig. 41-5). Erdman and co-workers (1990) reported that MR imaging was 100-percent sensitive and 90-percent specific for detection of venographically proven deep-venous thrombosis in nonpregnant patients. Importantly, almost half of those without deep-venous thrombosis had detectable nonthrombotic conditions to explain the clinical findings. These included cellulitis, myositis, edema, hematomas, and superficial phlebitis. More recent studies have confirmed the high levels of sensitivity and specificity as well as the additional advantage of low interobserver variability (Palareti and associates, 2006). D-Dimer Screening Tests These specific fibrin degradation products are generated when fibrinolysin degrades fibrin, as occurs in thromboembolism. Their measurement is frequently incorporated into diagnostic algorithms for venous thromboembolism in nonpregnant patients (Kelly and Hunt, 2002; Wells and co-workers, 2003). Screening with the D-dimer test in pregnancy, however, is problematic for a number of reasons. Depending on assay sensitivity, D-dimer serum levels increase with gestational age along with substantively elevated plasma fibrinogen concentrations (Kenny and associates, 2009). In a serial study of 50 healthy women, Kline and colleagues (2005) found not only that Ddimer levels increased progressively during pregnancy, but that 22 percent of women in midpregnancy and no women in the third trimester had a D-dimer concentration below 0.50 mg/L—a conventional cut-off used to exclude thromboembolism. D-Dimer concentrations can also be elevated in certain pregnancy complications such as placental abruption, preeclampsia, and sepsis syndrome. For these reasons, their use during pregnancy remains uncertain, but a negative D-dimer test should be considered reassuring (Lockwood, 2007; Marik and Plante, 2008).
Management
with
:
There is, however, consensus for treatment anticoagulation and limited activity .
If thrombophilia testing is performed, it is done before anticoagulation because
Optimal management of venous thromboembolism during pregnancy has not undergone major clinical studies to provide evidence-based practices (Copplestone and colleagues, 2004).
heparin induces a decline in antithrombin levels, and warfarin decreases protein C and S concentrations (Lockwood, 2002).
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Anticoagulation is initiated with either unfractionated or low-molecular-weight heparin. DURING PREGNANCY, HEPARIN THERAPY IS CONTINUED, AND FOR POSTPARTUM WOMEN, ANTICOAGULATION IS BEGUN SIMULTANEOUSLY WITH WARFARIN.
Recall that pulmonary embolism develops in about 25 percent of patients with untreated venous thrombosis, and anticoagulation decreases this risk to less than 5 percent .
In nonpregnant patients, the mortality rate is less than 1 percent (Douketis and co-workers, 1998; Weiss and Bernstein, 2000).
Over several days, leg pain dissipates. After symptoms have abated, graded ambulation should be started. Elastic stockings are fitted and anticoagulation is continued. Recovery to this stage usually takes 7 to 10 days.
Heparinization
:
Treatment of thromboembolism during pregnancy is with either unfractionated or lowmolecular-weight heparin. Although either type is acceptable, most recommend one of the low-molecular-weight heparins. In its recently revised guidelines, the American College of Chest Physicians suggests preferential use of this heparin class during pregnancy but scores this recommendation a Grade 2C level of evidence—the lowest quality (Bates and colleagues, 2008; Guyatt and co-workers, 2008).
Unfractionated Heparin (UFH) : The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2007) recommend heparin
an initial bolus of intravenous unfractionated at a
Treatment is with an intravenous heparin bolus followed by continuous infusion titrated to achieve full anticoagulation.
dose of 80 units/kg.
This is followed by
continuous infusion of at least 30,000 IU for 24 hours ,
titrated to achieve an activated partial thromboplastin time (aPTT) of
1.5 to 2.5
times control values.
There are a number of protocols to accomplish this, and the one used at Parkland Hospital is shown in Table 47-4.
Intravenous anticoagulation should be maintained for at least 5 to 7 days, after which, treatment is converted to subcutaneous heparin.
Injections are then given every 8 hours to maintain the aPTT to at least 1.5 to 2.5 times control throughout the dosing interval.
For women with antiphospholipid syndrome, aPTT does not accurately assess heparin anticoagulation, and thus anti-factor Xa levels are
preferred.
Table 47-4. Parkland Hospital Protocol for Continuous Heparin Infusion for Patients with Venous Thromboembolism
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Initial Heparin Dose:
__ units IV push (recommended 80 units/kg rounded to nearest 100, maximum 7500 units), then
__ units/hr by infusion (recommended 18 units/kg/hr rounded to nearest 50).
Infusion Rate Adjustments—based on partial thromboplastin time (PTT):
(sec)a
PTT
<45
54
84
100
45–
Interventionb
bolus
bolus
Baseline Infusion Rate Changec
80 units/kg
by 4 units/kg/hr
40 units/kg
by 2 units/kg/hr
55–
None
85–
None
by 2 units/kg/hr
Stop infusion 60 minutes
by 3 units/kg/hr
>100
None
aPTT goal 55–84; bRounded to nearest 100; cRounded to nearest 50.
The American College of Chest Physicians (Bates and colleagues, 2008) recommends anticoagulation throughout pregnancy and for 6 weeks postpartum but for a minimum total duration of 6 months.
The duration of full anticoagulation varies, and there are several acceptable schemes. The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2007) recommend therapeutic anticoagulation for at least 3 months after the acute event.
Lockwood (2007) recommends full anticoagulation be pregnant.
continued for at least 20 weeks followed by prophylactic doses if the woman is still
Prophylactic doses of subcutaneous unfractionated heparin can range from 5000 to 10,000 units every 12 hours titrated to maintain an antifactor Xa level of 0.1 to 0.2 units, measured 6 hours after the last injection.
If the venous thromboembolism occurs during the postpartum period, Lockwood (2007) recommends a minimum of 6 months of anticoagulation treatment.
:
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thromboembolism Low-Molecular-Weight Heparin
None of these heparins cross the placenta, and all exert their anticoagulant activity by activating antithrombin.
This is a family of derivatives of unfractionated heparin, and their molecular weights average 4000 to 5000 daltons compared with 12,000 to 16,000 daltons for conventional heparin.
The primary difference is in their relative inhibitory activity against factor Xa and thrombin (Garcia and Spyropoulos, 2008).
Specifically, unfractionated heparin has equivalent activity against factor Xa and thrombin , but low-molecular-weight heparins have
greater activity against factor Xa than thrombin.
They also have a more predictable anticoagulant response and fewer bleeding complications than unfractionated heparin because of their better bioavailability, longer half-life, dose-independent clearance, and decreased interference with platelets (Tapson, 2008). Their major drawback is expense.
A number of studies have shown that venous thromboembolism is treated effectively with lowmolecular-weight heparin (Quinlan and colleagues, 2004; Tapson, 2008).
Using serial venograms, Breddin and co-workers (2001) observed that low-molecular-weight heparins were more effective than the unfractionated form in reducing thrombus size without increasing mortality rates or major bleeding complications.
Pharmacokinetics in Pregnancy : Several low-molecular-weight heparins are available for use in pregnancy and include enoxaparin, dalteparin, and tinzaparin.
They were given 40 mg Enoxaparin (Lovenox) subcutaneously daily, and serial measurements of anti-factor Xa activity p h a r m a c o k i n e t i c s w e r e s t u d i e d b y Casele and colleagues (1999) in 13 were determined during early pregnancy, the third trimester, and then p r e g n a n t w o m e n . postpartum. They concluded that, likely because of increased renal clearance, twice-daily dosing may be necessary to maintain anti-factor Xa activity above 0.1 U/mL.
They also suggested that optimal dosing was best achieved with periodic monitoring of peak activity—about 3.5 hours after a dose—and predose anti-factor Xa activity.
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The dose was approximately 1 mg/kg given twice daily based on early pregnancy weight. Treatment was monitored by peak anti-factor Xa activity 3 hours postinjection, U/mL.
Rodie and co -workers (2002) studied 36 women with venous thromboembolism during pregnancy or immediately postpartum who were treated with enoxaparin.
with a target therapeutic range of 0.4–1.0
In 33 women, enoxaparin provided satisfactory anticoagulation. In the other three women, dose reduction was necessary. None developed recurrent thromboembolism or bleeding complications.
Those given once-daily dalteparin subcutaneously had
mean anti-factor Xa levels that were significantly lower across pregnancy
Dalteparin (Fragmin) pharmacokinetics were studied by Sephton and associates (2003) in a longitudinal investigation of 24 pregnant women.
compared with levels measured 6 weeks' postpartum.
Smith and co-workers (2004) reported similar results with tinzaparin (Innohep) given as a once-daily 50 U/kg dose. They found that
a dosage of 75 to 175 U/kg/day was necessary
to achieve peak anti-factor Xa levels of 0.1 to 1.0 U/mL.
that
The American Academy of Pediatrics and the American College of Obstetricians and Gynecologists (2007) recommend
anti-factor Xa levels be periodically reevaluated during pregnancy in a woman fully anticoagulated with these agents. Monitoring anti-Xa levels during pregnancy is especially important in women who also have
impaired renal or hepatic function, weigh less than 50 kg or greater than 100 kg, or have risk factors for bleeding (Duhl and associates, 2007).
Dosing should be enough to achieve a peak antifactor Xa level of 0.5 to 1.2 U/mL. Importantly, each low-molecular-weight heparin compound has a somewhat different pharmacodynamic pattern.
Thus, a peak concentration of 1.0 U/mL may be appropriate in an enoxaparin-treated patient but
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may be an overdose in a dalteparin-treated patient (Gris and associates, 2006).
Fox and colleagues (2008) reviewed anti-factor Xa levels in 77 women given "pregnancy-adjusted" doses of either dalteparin or enoxaparin for thromboprophylaxis. They reported that a fourth of 321 determinations showed "subtherapeutic" levels defined as less
For women given thromboprophylaxis, most authorities do not recommend monitoring anti -factor Xa levels.
than 0.2 to 0.4 units/mL .
They called for consideration of such monitoring.
At this time, however, this is considered unnecessary for prophylactic dosing because the "therapeutic range" is uncertain (Bates and associates, 2008).
Safety in Pregnancy : Early reviews by Sanson and associates (1999) and Lepercq and co-workers (2001) concluded that LOW-MOLECULAR-WEIGHT HEPARINS WERE SAFE AND EFFECTIVE.
Despite this, in 2002, been associated with
the manufacturer of Lovenox warned that
its use in pregnancy had
congenital anomalies and an increased risk of hemorrhage.
After its own extensive review, the American College of Obstetricians and Gynecologists (2002) concluded that these risks were rare, that their incidence was not higher than expected, and that no cause-and-effect relationship had been established.
The committee further concluded that enoxaparin and dalteparin could be given safely during pregnancy. A subsequent review by Deruelle and Coulon (2007) also confirmed their safety.
Caveats are that low-molecular-weight heparins should not be used in women with prosthetic heart valves because of
reports of valvular thrombosis (see Chap. 44, Anticoagulation with Heparin).
They also should be avoided in women with renal failure (Krivak and Zorn, 2007).
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When given within 2 hours of cesarean delivery, these agents increase the risk of wound hematoma (van Wijk and co-workers, 2002).
Lee and Goodwin (2006) described development of a massive subchorionic hematoma associated with enoxaparin use.
Frosnes and associates (2009) reported a woman who developed a spontaneous thoracolumbar epidural hematoma that required surgical drainage.
As discussed in Chapter 19, Anticoagulation, use of low-molecular-weight heparins may also increase the risk of spinal hematoma
associated with regional analgesia.
As a result, the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2007) advise that
women receiving once-daily prophylactic low-dose low-molecular-weight heparin not be offered regional analgesia until at least 10 to 12 hours after the last injection. In addition, low-molecular-weight heparin should be withheld for at least 2 hours after the removal of an epidural catheter.
The safety of regional analgesia in women receiving twice-daily therapeutic low-molecular-weight heparin has not been studied sufficiently, and it is not known whether delaying regional techniques for 24 hours after the last injection is adequate. protaminesulfate (Anticoagulation and Delivery) may help partially reverse the effects of low-
Of note, molecular-weight heparin.
Anticoagulation with Warfarins
:
Warfarin derivatives are generally contraindicated because they readily cross the placenta and cause fetal death and malformations from hemorrhages [see Chap. 14, Warfarin (Coumadin Derivatives)].
Like unfractionated and low-molecular-weight heparin, however,
breast feeding
they are safe during
(American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 2007; Bates and associates, 2004).
Postpartum venous thrombosis is usually treated with
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intravenous heparin and oral warfarin initiated simultaneously.
To avoid paradoxical thrombosis and skin necrosis from the early anti-protein C effect of warfarin, these women are maintained on therapeutic doses of unfractionated or low-molecular-weight heparin for 5 days and until the international normalized ratio (INR) is in a therapeutic range (American Academy of Pediatrics and American College of Obstetricians and Gynecologists, 2007).
The initial dose of warfarin is usually 5 to 10 mg for the first 2 days.
Subsequent doses are titrated to achieve an INR of 2 to 3.
Brooks and colleagues (2002) compared anticoagulation in postpartum women with that of age-matched nonpregnant controls. Recently delivered women required a significantly larger median total dose of warfarin—45 versus 24 mg—and a longer time—7 versus 4 days—to achieve the target INR. Moreover, the mean maintenance dose was higher in postpartum women compared with that in the control group— 4.9 versus 4.3 mg.
Duration of Therapy
:
The optimal duration of continued anticoagulation after delivery is uncertain, but anticoagulation with warfarin is continued for at least 4 to 6 weeks. Most recommendations have been extrapolated from studies in nonpregnant patients (Kearon and colleagues, 1999; Ridker and co-workers, 2003).
This is problematic because most studies in nonpregnant patients included bedridden older patients with medical complications. The current consensus of the American College of Chest Physicians is that
but
warfarin anticoagulation be given for at least 6 weeks postpartum, to complete a minimum 6-month course following the initial episode (Bates and colleagues, 2008).
Lockwood (2007) recommends a minimum of 6 weeks. As previously mentioned (Pharmacokinetics in Pregnancy), most agree that deep-venous thrombosis that develops postpartum requires a minimum of 6 months of anticoagulation (Lockwood, 2007).
Complications of Anticoagulation :
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thromboembolism Three significant complications associated with anticoagulation are
hemorrhage, thrombocytopenia, and osteoporosis.
The latter two are unique to heparin, and their risk may be reduced with low-molecular-weight heparins (American College of Obstetricians and Gynecologists, 2000).
The most serious complication is hemorrhage, which is more likely if there has been recent surgery or lacerations. Troublesome bleeding also is more likely if the heparin dosage is excessive. Unfortunately, management schemes using laboratory testing to identify when a heparin dosage is sufficient to inhibit further thrombosis, yet not cause serious hemorrhage, have been discouraging.
Heparin-Induced Thrombocytopenia : There are two types of heparin-induced thrombocytopenia—commonly referred to as HIT.
therapy
The most common is a nonimmune ,
benign, reversible form that
occurs within the first few days of
and
resolves in about 5 days without cessation of therapy (American College of Obstetricians and Gynecologists, 2000).
The second is the more severe form of HIT, which results from an immune reaction involving IgG antibodies directed against complexes of platelet factor 4 and heparin.
When most severe, HIT paradoxically causes thrombosis, which is the
most common presentation.
The American College of Chest Physicians advises that
the diagnosis of HIT be considered
when the
platelet count decreases by 50 percent between 5 and 14 days after the initiation of heparin therapy
(Greinacher and Warkentin, 2006).
Interestingly, however, Fausett and colleagues (2001) reported no cases of HIT among 244 heparin-treated pregnant women compared with 10 among 244 nonpregnant controls. The American College of Obstetricians and Gynecologists (2000) recommends that platelet counts be measured
The incidence of HIT is approximately 3 to 5 percent in nonpregnant individuals.
on day 5 and then periodically for the first 2 weeks
of heparin therapy.
If unchanged, further platelet counts are not indicated because most cases manifest within 15 days of standard heparin initiation.
If thrombocytopenia is severe, heparin therapy must be stopped and alternative anticoagulation initiated. Low-molecular-weight heparin may not be an entirely safe alternative because it has some cross reactivity with unfractionated heparin. In these cases, many recommend
danaparoid—a sulfated glycosaminoglycan
heparinoid. In a review of approximately 50 pregnant women with either HIT or skin rashes, Lindhoff-Last and associates (2005)
danaparoid was a reasonable alternative, however, two fatal maternal hemorrhages and three fetal deaths were recorded.
also concluded that
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Direct thrombin inhibitors—examples include hirudin, argatroban, and lepirudin— also have been used as a heparin alternative (Chapman and associates, 2008; Tapson, 2008). There are reports, however, that hirudin crosses the placenta and is fetotoxic (Gris and associates, 2006; Mazzolai and co-workers, 2006).
Lockwood (2007) recommends the use of fondaparinux—a pentasaccharide factor Xa inhibitor—in pregnant women for whom there are no alternatives. Successful use in pregnancy has been reported, including a case report describing a woman with an intolerance to both heparin and danaparoid (Mazzolai and colleagues, 2006).
At least one recent report suggests that fondaparinux can rarely cause a disorder that resembles HIT (Warkentin and co-workers, 2007).
Interestingly, heparin-dependent antibodies do not invariably reappear with subsequent heparin use (Warkentin and Kelton, 2001).
Heparin-Induced Osteoporosis
:
Low-molecular-weight heparins can cause osteopenia (Deruelle and Coulon, 2007),
Bone loss may develop with long term heparin administration—usually 6 months or longer—and is more prevalent in cigarette smokers (see Chap. 53, Pregnancy-Associated Osteoporosis).
although such a result is less likely than with unfractionated heparin.
Women treated with any heparin should be encouraged to take a daily supplement of 1500 mg of calcium (Cunningham, 2005; Lockwood, 2007).
Low-molecular-weight heparins may cause less adverse effects.
Rodger and colleagues (2007) found that longer-term use with a mean of 212 days
with dalteparin ,
5000 units subcutaneously given daily until 20 weeks and 5000 units twice daily thereafter,
bone mineral density.
Anticoagulation and Abortion
was not associated with a significant decrease in
:
The treatment of deep-venous thrombosis with heparin does not preclude termination of pregnancy by careful curettage. After the products are removed without trauma to the reproductive tract, full-dose heparin can be restarted in several hours.
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Anticoagulation and Delivery
:
The effects of heparin on blood loss at delivery depend on a number of variables:
Dose, route, and time of administration Number and severity of incisions and lacerations Intensity of postpartum myometrial contractions Presence of other coagulation defects. Blood loss should not be greatly increased with vaginal delivery if the midline episiotomy is modest in depth, there are no lacerations, and the uterus promptly contracts. Unfortunately, such ideal circumstances do not always prevail. For example, Mueller and Lebherz (1969) described 10 women with antepartum thrombophlebitis treated with heparin. Three women who continued to receive heparin during labor and delivery bled remarkably and developed large hematomas. Thus, heparin therapy generally is stopped during labor and delivery. If the uterus is well contracted and there has been negligible trauma to the lower genital tract, it can be restarted after about 12 hours. Otherwise,
a delay of 1 or 2 days may be prudent .
Protamine sulfate administered slowly intravenously generally reverses the effect of heparin promptly and effectively. It should not be given in excess of the amount needed to neutralize the heparin, because
anticoagulant effect .
it also has an
Serious bleeding is likely when heparin in usual therapeutic doses is administered to a woman who has undergone cesarean delivery within the previous 24 to 48 hours.
Superficial Venous Thrombophlebitis
:
THROMBOSIS LIMITED STRICTLY TO THE SUPERFICIAL VEINS OF THE SAPHENOUS SYSTEM is treated with analgesia, elastic support, and rest.
If it does not soon subside, or if deep-venous involvement is suspected, appropriate diagnostic measures are performed. Heparin is given if deep-
venous involvement is confirmed.
Superficial thrombophlebitis is typically seen in association with varicosities or as a sequela to an
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indwelling intravenous catheter.
Pulmonary Embolism The incidence averages about
:
1 in 7000 pregnancies.
There is an almost equal prevalence for antepartum and postpartum embolism, but those developing postpartum have a higher mortality rate.
Although it causes about 10 percent of maternal deaths, pulmonary embolism is relatively uncommon during pregnancy and the puerperium.
According to Marik and Plante (2008), 70 percent of women presenting with a pulmonary embolism have associated clinical evidence of deep-venous thrombosis. In women presenting with a deep-venous thrombosis, almost half will have a silent pulmonary embolism.
Clinical Presentation : Findings from the international cooperative pulmonary embolism registry were reported by Goldhaber and colleagues (1999). Over a 2-year period, almost 2500 nonpregnant patients with a proven pulmonary embolism were enrolled.
Common symptoms included
dyspnea in 82 percent, chest pain in 49 percent, cough in 20 percent, syncope in 14 percent, and hemoptysis in 7 percent. Other predominant clinical findings typically include tachypnea, apprehension, and tachycardia.
In some cases, there is an accentuated pulmonic closure sound, rales, and/or friction rub.
Right axis deviation and T-wave inversion in the anterior chest leads may be evident on the electrocardiogram. On chest radiography, there may be loss of vascular markings in the region of the lungs supplied by the obstructed artery. In contrast, the alveolar-arterial oxygen tension difference is a more useful indicator of disease, as more than 86 percent of patients with acute pulmonary embolism will have an alveolar-arterial difference
of more than 20 mm Hg
(Lockwood, 2007).
Although most women are hypoxemic, it is emphasized that a normal arterial blood gas analysis does not exclude pulmonary embolism. Approximately a third of patients younger than 40 years will have pO2 values >80 mm Hg.
Even with massive pulmonary embolism, signs, symptoms, and laboratory data to support the diagnosis may be deceptively nonspecific.
Massive Pulmonary Embolism This is defined as embolism
:
causing hemodynamic instability
(Tapson, 2008). Acute mechanical obstruction of the pulmonary vasculature causes increased vascular resistance and pulmonary hypertension.
Acute right ventricular dilatation follows.
In otherwise healthy patients,
significant pulmonary hypertension
percent of the pulmonary vascular tree is occluded
does not develop
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until 60 to 75
thromboembolism (Guyton and colleagues, 1954).
Moreover, circulatory collapse requires 75- to 80-percent obstruction. This is depicted schematically in Figure 47-3 and emphasizes that most acutely symptomatic emboli are large and likely a saddle embolism.
These are suspected when pulmonary artery pressure is substantively increased as estimated by echocardiography.
Schematic of pulmonary arterial circulation. Note that the cross-sectional area of the pulmonary trunk and the combined pulmonary arteries is 9 cm2. A large saddle embolism could occlude 50 to 90 percent of the pulmonary tree causing hemodynamic instability. As the arteries give off distal branches, the total surface area rapidly increases, that is, 13 cm2 for the combined five lobar arteries, 36 cm2 for combined 19 segmental arteries, and more than 800 cm2 for the total 65 subsegmental arterial branches. Thus, hemodynamic instability is less likely with emboli past the lobar arteries. (Data from Singhal and colleagues, 1973.)
If there is evidence of right ventricular dysfunction, the mortality rate approaches 25 percent, compared with 1 percent without such dysfunction (Kinane and co-workers, 2008). It is important in these cases to infuse crystalloids carefully and to support blood pressure with vasopressors. Oxygen treatment, tracheal intubation, and mechanical ventilation are carried out preparatory to thrombolysis, filter placement, or embolectomy (Tapson, 2008).
Diagnosis
:
As with deep-venous thrombosis, the diagnosis of pulmonary embolism requires an initial high index of suspicion followed by objective testing (Chunilal and colleagues, 2003). As shown in Figure 47-4, the initial imaging evaluation for suspected pulmonary embolism during pregnancy generally includes ventilation-perfusion scintigraphy, computed tomography, or bilateral compression ultrasonography. Of note, a chest radiograph should be performed if there is underlying suspicion for other diagnoses. The current opinion of the American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2007) is that, in contemporary practice, pulmonary embolism is commonly diagnosed with multidetector-row spiral computed tomography pulmonary angiography (MDCT).
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Evaluation of suspected pulmonary embolism during pregnancy. The decision to begin with helical computed tomography (CT), ventilation/perfusion (V/Q) scan, or bilateral CUS depends on local availability and expertise. CTA = CT angiography; CUS = compression ultrasonography; MRA = magnetic resonance angiography; PE = pulmonary embolism. aSee text (see Computed Tomography) for discussion. bNondiagnostic results are those that indicate an intermediate or low probability of pulmonary embolism, or that do not indicate a high probability. (Adapted from Nijkeuter and colleagues, 2006, and Tapson, 2008.)
Computed Tomographic Pulmonary Angiography It is likely that multidetector spiral CT will replace pulmonary angiography as the gold standard for diagnosis of pulmonary embolism (Goldhaber, 2004; Srivastava and colleagues, 2004). The technique is described further in Chapter 41, Computed Tomography, and an imaging example is shown in Figure 47-5. Except in late pregnancy, fetal x-ray exposure is less than with V/Q scanning (Table 475). In a prospective study of 102 consecutive nonpregnant patients with suspected pulmonary embolism who underwent multidetector spiral CT, Kavanagh and co-workers (2004) found that during a mean follow-up period of 9 months, only one patient had a false-negative scan. Stein and colleagues (2006) reported that combined MDCT angiography and venography was even more sensitive.
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Axial image of the chest from a four-channel multidetector spiral computed tomographic scan performed after administration of intravenous contrast. There is enhancement of the pulmonary artery with a large thrombus on the right (arrow) consistent with pulmonary embolism. (Courtesy of Dr. Michael Landay.)
Table 47-5. Estimated Mean Fetal Radiation Dosimetry from Ventilation-Perfusion (V/Q) Lung Scanning Compared with 4-Channel Multidetector Spiral Computed Tomography (CT) Scanning V/Q Scintigraphy
Spiral CT Scanning
Pregnancy Duration
mGy
mrem
mGy
mrem
Early
0.46
46
0.04
4
First trimester
0.46
46
0.04
4
Second trimester
0.57
57
0.11
11
Third trimestera
0.45
45
0.31
31
We now use multidetector spiral CT as first-line evaluation of pregnant women both at Parkland Hospital and at the University of Alabama at Birmingham Hospital. Although the technique has many advantages, we have found that the better resolution allows detection of previously inaccessible smaller distal emboli that have uncertain clinical significance. Similar observations have been reported by Anderson and associates (2007). Others have found that the hyperdynamic circulation and increased plasma volume associated with pregnancy lead to a higher number of nondiagnostic studies compared with nonpregnant patients (Scarsbrook and associates, 2006). Ventilation–Perfusion Scintigraphy—Lung Scan Although used less commonly in the past 5 years, ventilation–perfusion (V/Q) lung scanning is still used by some centers. As seen in Figure 47-4, V/Q scintigraphy may be used if compression ultrasonography results are negative. The technique involves a small dose of radiotracer such as intravenously administered 99mtechnetium-macroaggregated albumin. As shown in Table 47-5, there is negligible fetal radiation exposure. The scan may not provide a definite diagnosis because many other conditions—for example, pneumonia or local bronchospasm—can cause perfusion defects. Ventilation scans with inhaled xenon-133 or technetium-99m were added to perfusion scans to detect abnormal areas of ventilation in areas with normal perfusion such as with pneumonia or hypoventilation. The method is not precise, and although ventilation scanning increased the probability of an accurate diagnosis with large perfusion defects and ventilation
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thromboembolism mismatches, normal V/Q scan findings do not exclude pulmonary embolism. Because of these uncertainties, the National Heart, Lung and Blood Institute commissioned the Prospective Investigation of Pulmonary Embolism Diagnosis to determine sensitivities and specificities of V/Q lung scans (PIOPED, 1990). The investigators concluded that a high-probability scan usually indicates pulmonary embolism, but that only a small number of patients with emboli have a highprobability scan. A low-probability scan, combined with a strong clinical impression that embolism is unlikely, makes the possibility of pulmonary embolism remote. Similarly, near-normal or normal scans make the diagnosis very unlikely. Finally, an intermediate-probability scan is of no help in establishing the diagnosis. Thus, the V/Q lung scan combined with clinical assessment permits a noninvasive diagnosis or exclusion of pulmonary embolism for only a minority of patients. Indeed, two thirds of nonpregnant patients with a suspected pulmonary embolism have a nondiagnostic scan and require additional testing (Raj, 2003). In our experience, this proportion is smaller in pregnant women, probably because they are younger and usually healthy and less likely to have coexisting pulmonary disease. Similarly, Chan and associates (2002) reported that only 25 percent of 120 pregnant women had a nondiagnostic scan. Magnetic Resonance Angiography (MRA) Although conventional magnetic resonance angiography has a high sensitivity for detection of central pulmonary emboli, the sensitivity for detection of subsegmental emboli is less precise (Scarsbrook and associates, 2006). In a study of 141 nonpregnant patients with suspected pulmonary embolism, Oudkerk and co-workers (2002) performed MRA before conventional angiography. About a third of patients were found to have an embolus, and the sensitivity of MRA for isolated subsegmental, segmental, and central or lobar pulmonary embolism was 40, 84, and 100 percent, respectively. There are no currently published reports specifically involving magnetic resonance angiography during pregnancy. Pulmonary Angiography This requires catheterization of the right side of the heart and is the most definitive study for pulmonary embolism. In addition to being invasive, it is also time consuming, uncomfortable, and associated with dye-induced allergy and renal failure. The procedure-related mortality rate is about 1 in 200 (Stein and colleagues, 1992). If absolutely necessary for confirmation when less invasive tests are equivocal, angiography should be considered.
Management
:
Immediate treatment for pulmonary embolism is full anticoagulation similar to that for deep-venous thrombosis as discussed in Pharmacokinetics in Pregnancy. A number of complementary procedures may be indicated. Vena Caval Filters The woman who has very recently suffered a pulmonary embolism and who must undergo cesarean delivery presents a particularly serious problem. Reversal of anticoagulation may be followed by another embolus, and surgery while fully anticoagulated frequently results in life-threatening hemorrhage or troublesome hematomas. In these, placement of a vena caval filter should be considered before surgery (Marik and Plante, 2008). Routine filter placement has no added advantage to heparin given alone (Decousus and associates, 1998). In the very infrequent circumstances in which heparin therapy fails to prevent recurrent pulmonary embolism from the pelvis or legs, or when embolism develops from these sites despite heparin treatment, a vena caval filter may be indicated. Such filters can also be used with massive emboli in patients who are not candidates for thrombolysis (Deshpande and colleagues, 2002). The device may be inserted through either the jugular or femoral vein. Retrievable filters may be used as short-term protection against embolism. These may be removed before they become endothelialized, or they can be left in place permanently (Tapson, 2008). Neill and colleagues (1997) placed a Gunther Tulip filter at 37 weeks, and it was removed 5 days postcesarean delivery at 38 weeks. Jamjute and co-workers (2006) described successful placement in a woman during labor. Thrombolysis Compared with heparin, thrombolytic agents provide more rapid lysis of pulmonary clots and improvement of pulmonary hypertension (Tapson, 2008). Konstantinides and colleagues (2002) studied 256 nonpregnant patients heparinized for an acute submassive pulmonary embolism. They also were assigned randomly to a placebo or the recombinant tissue plasminogen activator, alteplase. Those given the placebo had a threefold increased risk of death or treatment escalation compared with those given alteplase. Agnelli and associates (2002) performed a meta-analysis of nine randomized trials involving 461 nonpregnant patients. They reported that the risk of recurrence or death was significantly lower in patients given thrombolytic agents compared with those given heparin alone—10 versus 17 percent. Importantly, there were five—2 percent—fatal bleeding episodes in the thrombolysis group and none in the heparin-only group. There are very few studies of thrombolysis during pregnancy. In their review of the literature, Leonhardt and associates (2006) identified 28 reports of thrombolytic therapy using tissue plasminogen activator during pregnancy. Ten of these cases were for thromboembolism. Complication rates were similar compared with reports from nonpregnant patients, and the authors concluded that such therapy should not be withheld during pregnancy if indicated. Tissue plasminogen activator does not cross the placenta. Our anecdotal experiences with these drugs has been favorable. Embolectomy Surgical embolectomy is uncommonly indicated with use of thrombolysis and filters. Published experience with emergency embolectomy during pregnancy is limited to case reports such as those by Funakoshi (2004) and Taniguchi (2008) and their co-workers. Based on their review, Ahearn and associates (2002) found that although the operative risk to the mother is reasonable, the stillbirth rate is 20 to 40 percent.
Thromboprophylaxis
:
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Thromboembolism Antedating Pregnancy Optimal management of women with firm evidence of a prior thromboembolism is unclear. Most recommendations represent consensus guidelines, and some are diametrically opposed to others. The confusion that has ensued has provided fertile ground for the plaintiff bar to plow. Cleary-Goldman and colleagues (2007) surveyed 151 fellows of the American College of Obstetricians and Gynecologists and reported that intervention without firm indications is common. In Table 47-6 are listed a number of consensus recommendations for thromboprophylaxis from recognized experts. In some cases, a number of different options are listed, thus illustrating the confusion that currently reigns. Table 47-6. Various Recommendations for Thromboprophylaxis during Pregnancy
Clinical Scenario
Pregnancya
Postpartumb
Prior single-episode VTEc
Associated with a risk factor that is no longer present
Surveillance only(1,2,4) or prophylactic UFH or LMWH(4)
Warfarin or prophylactic LMWH 4(1) to 6(1,2,4) weeks
VTE in a prior pregnancy, estrogenrelated, or with additional risk factors (such as obesity)
Surveillance only(1) or prophylactic or intermediate-dose UFH(1,2,4) or LMWH(1,2,3,4)
Prophylactic UFH or LMWH(1,3,4)
Idiopathic—no known associations
Surveillance Postpartum only(1); prophylactic anticoagulants(1,3) UFH(1,2,4) or or postpartum UFH or LMWH(1,2,3,4) LMWH prophylaxis(2,4)
Associated with a heterozygous thrombophilia trait or strong family history of thrombosis
Surveillance only(1); prophylactic(1,2,3) or intermediatedose(1) LMWH or UFH(1)
Postpartum anticoagulants(1,3) or postpartum UFH or LMWH prophylaxis(2)
Women with AT deficiency not receiving long-term anticoagulation; compound heterozygotes for prothrombin G20210A and FVL; FVL homozygous; or prothrombin G20210A homozygous
Prophylactic or intermediatedose(1) or adjusteddose(2,4) LMWH; or prophylactic or intermediatedose(1) or adjusteddose(2,4) UFH
Postpartum anticoagulants(1) or warfarin for 12 months(2)(AT deficiency may require lifetime anticoagulation
Two or more prior episodes of VTE and/or women receiving long-term anticoagulationc
Adjusteddose UFH or adjusted-dose LMWH(1,4)
Warfarin 6 weeks(4) or resumption of longterm anticoagulation(1)
and:
No prior VTE
Require prolonged Graduated bed rest and are at an elastic compression increased risk for VTE due stockings(2) to obesity, thrombophilia, or strong family history
Graduated elastic compression stockings(2)
Delivery by elective cesarean
Risk assessment—see Table 47–7
Known thrombophilia and no prior VTE and:
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AT deficiency not receiving long-term anticoagulation
Prophylactic UFH or LMWH(1); or adjusted-dose UFH or LMWH throughout pregnancy(2)
Prophylactic UFH or LMWH(1); or warfarin 6 weeks or longer(4); or adjusted-dose UFH or LMWH(2)
Compound heterozygotes for prothrombin G20210A and FVL; FVL homozygous; or prothrombin G20210A homozygous
Surveillance only(1); prophylactic UFH or LMWH(1); or adjusted-dose UFH or LMWH throughout pregnancy(2)
Prophylactic UFH or LMWH(1); warfarin 6 weeks or longer(4); or adjusted-dose UFH or LMWH(2)
Less Surveillance thrombogenic only(1,2) or thrombophilias— prophylactic UFH or heterozygous FVL or LMWH(1) heterozygous prothrombin gene mutations; protein C, S, or Z deficiencies
Prophylactic UFH or LMWH(1); or postpartum anticoagulation with cesarean delivery or with an affected firstdegree relative(2)
Homozygous for thermolabile variant (C677T) of MTHFR
Folic acid supplementation prior to and throughout pregnancy
Consider warfarin for 6 weeks if homocysteine serum levels abnormally high(?)(2)
Prophylactic or intermediatedose UFH or prophylactic LMWH combined with lowdose aspirin(1)
Prophylactic UFH or LMWH(1) for 6–8 weeks(5)
Prophylactic or intermediatedose LMWH or UFH(1); adjusteddose LMWH or adjusted-dose UFH(5) plus lowdose aspirin after 1st trimester(1)
Full anticoagulation for 6– 8 weeks and referral to specialist(5) or long-term anticoagulation(1,2)
Surveillance only(1) or prophylactic LMWH(1,5) or UFH(1,5) and (5) low-dose aspirin
Prophylactic heparin and low-dose aspirin for 6–8 weeks(5)
Antiphospholipid antibodies and:
History of 3 or more early pregnancy losses; one or more late pregnancy loss
History of VTE
No prior VTE or pregnancy loss
AT = antithrombin; FVL = factor V Leiden; LMWH = low-molecular-weight heparin; UFH = unfractionated heparin; VTE = venous thromboembolism. Various UFH and LMWH regimens: Prophylactic UFH—5000 units SC q 12h(1); 5000 to 10,000 units SC q 12h to maintain anti-Xa level of 0.1-0.2 units, 6h after the last injection(2); or 5000 to 7500 units q 12h during the 1st trimester, 7500 to 10,000 units q 12 hours during the 2nd trimester, and 10,000 units q 12h during the 3rd trimester unless the aPTT is elevated(4); or 5000 to 10,000 units q 12h throughout pregnancy(4).
U/mL(1).
Intermediate-dose UFH-SC q 12h in doses adjusted to target anti-Xa level of 0.1-0.3
Adjusted-dose UFH-SC q 12h in doses adjusted to target a mid-interval aPTT in the therapeutic range(1) or UFH SC q 8–12h to maintain the aPTT value at 1.5-2.0 times control, 6h after the injection(2). Prophylactic LMWH-dalteparin 5000 U SC q 12(4) or q 24h(1,4) or enoxaparin 40 mg SC q 12(4) or q 24h(1) or enoxaparin 40 mg SC q 12h adjusted to maintain anti-Xa levels at 0.12-0.2 unit/mL, 4h after an injection.(2) (At extremes of body weight, dose modification may be required.)
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Intermediate-dose—dalteparin 5000 units SC q 12h or enoxaparin 40 mg SC q 12h(1). Adjusted-dose LMWH—weight-adjusted, therapeutic doses of LMWH administered once or twice daily—dalteparin 200 units/kg q 12h or enoxaparin 1 mg/kg q 12h(1). The anti-Xa level is maintained at 0.6–1 unit/mL, 4–6h after an injection(2). aSuggest LMWH over UFH for all pregnant patients(1). bPostpartum anticoagulation—initial UFH or LMWH until the INR is 2.0 to overlap with warfarin for 4(1) to 6(1,3,4) weeks with a target INR of 2.0 to 3.0(1); or prophylactic LMWH for 4 to 6 weeks(1). cGraduated elastic compression stockings both ante- and postpartum(1). Recommendations from the: (1) American College of Chest Physicians (Bates and co-workers, 2008). (2) Lockwood (2007). (3) American Academy of Pediatrics and American College of Obstetricians and Gynecologists (2007). (4) American College of Obstetricians and Gynecologists (2000b). (5) American College of Obstetricians and Gynecologists (2005). In general, and as shown in Table 47-6, either antepartum surveillance or heparin prophylaxis is recommended for women without a recurrent risk factor, including no known thrombophilia. The study by Tengborn and colleagues (1989) suggested that such prophylaxis is not effective. They reported outcomes in 87 pregnant Swedish women who had prior thromboembolic disease. Despite heparin prophylaxis which was usually 5000 U twice daily, three of 20—15 percent—of women developed antepartum recurrence, compared with eight of 67—12 percent—of women not given heparin. These women were not tested for thrombophilia. Brill-Edwards and associates (2000) prospectively studied 125 pregnant women with a single previous episode of venous thromboembolism. Antepartum heparin was not given, but anticoagulant therapy was given for 4 to 6 weeks postpartum. A total of six women had a recurrent venous thrombosis—three antepartum and three postpartum. There were no recurrences in the 44 women without a known thrombophilia or whose prior thrombosis was associated with a temporary risk factor. These findings imply that prophylactic heparin may not be required for these two groups of women. In contrast, women with a prior thrombosis in association with a thrombophilia or in the absence of a temporary risk factor generally should be given both antepartum and postpartum prophylaxis (see Table 47-6). More recently, De Stefano and co-workers (2006) studied 1104 women who had a first-episode venous thromboembolism before the age of 40 years. After excluding those with antiphospholipid antibodies, 88 women were identified who subsequently had a total of 155 pregnancies and who were not given antithrombotic prophylaxis. There were 19 women—22 percent—who had a subsequent pregnancy- or puerperium-related venous thromboembolism. Of 20 women whose original thrombosis was associated with a transient risk factor—not including pregnancy or oral contraceptive use—there were no recurrences during pregnancy, but two during the puerperium. Like the findings by Brill-Edwards and associates (2000), these data suggest that for women with a prior venous thromboembolism, antithrombotic prophylaxis during pregnancy could be tailored according to the circumstances of the original event. It is emphasized that more data are needed. Our practice at Parkland Hospital for many years for women with a history of prior thromboembolism has been to administer subcutaneous unfractionated heparin, 5000 to 7500 units two to three times daily. With this regimen, the recurrence of documented deep-venous thrombosis embolization has been rare. More recently, we have successfully used 40-mg enoxaparin given subcutaneously daily. Cesarean Delivery and Antepartum Bed Rest Currently in the United States, use of thromboprophylaxis for women undergoing cesarean delivery or antepartum bed rest is not widely employed. In a survey of 157 members of the Society for Maternal-Fetal Medicine, for example, Casele and Grobman (2007) found that only 8 percent of respondents routinely used thromboprophylaxis—defined as compression boots, stockings, or heparin—for women undergoing cesarean delivery. And only 25 percent routinely used such measures for pregnant women placed on bed rest for more than 72 hours. The risk for deep-venous thrombosis and especially for fatal thromboembolism is increased manyfold in women following cesarean compared with vaginal delivery. When considering that a third of women giving birth in the United States yearly undergo cesarean delivery, it is easily understandable that pulmonary embolism is a major cause of maternal mortality (see Chap. 1, Maternal Mortality. Because of this, the Royal College of Obstetricans and Gynaecologists (2004) now recommends risk assessment for women undergoing uncomplicated cesarean delivery. The American College of Chest Physicians (Bates and colleagues, 2008) suggests risk assessment with thromboprophylaxis—mechanical, pharmacological, or both—for factors such as those shown in Table 47-7. They note this to be Grade 2C level of recommendation because of "low- or very-low quality evidence." According to Clark and associates (2008), some prophylaxis scheme for all women undergoing cesarean delivery in the Hospital Corporation of America system likely would result in a substantively lower maternal mortality rate from pulmonary embolism. Table 47-7. Risk Assessment to Determine Thromboprophylaxis Following Uncomplicated Cesarean Delivery
Risk
Intervention
Low
Early ambulation
In hospital, consider compression stockings
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Medium or
high
Early ambulation
Age older than 35 yrs
In hospital, consider compression or pneumatic stockings
BMI > 30
Multiparity (?
3)
or
6)
In hospital, consider prophylactic LMWH or UFH (see Table 47-
Varicosities
Preeclampsia
Postpartum hemorrhage
delivery
Emergency
Hysterectomy
Very high
factors
Consider stockings as above and prophylactic heparin. For persistent risks, consider prophylactic heparin for 4-6 wks
Multiple risk
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J Thromb Haemost 5:1600, 2007 [PMID: 17663731] Rodie VA, Thomson AJ, Stewart FM, et al: Low molecular weight heparin for the treatment of venous thromboembolism in pregnancy: A
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thromboembolism case series. Br J Obstet Gynaecol 109:1020, 2002 [PMID: 12269676] Ros SH, Lichtenstein P, Bellocco R, et al: Pulmonary embolism and stroke in relation to pregnancy: How can high-risk women be identified? Am J Obstet Gynecol 186:198, 2002 [PMID: 11854635] Salonvaara M, Kuismanen K, Mononen T, et al: Diagnosis and treatment of a newborn with homozygous protein C deficiency. Acta Paediatr 93:137, 2004 [PMID: 14989454] Sanson BJ, Lensing AW, Prins MH, et al: Safety of low-molecular-weight heparin in pregnancy: A systematic review. Thromb Haemost 81:668, 1999 [PMID: 10365733] Santacroce R, Sarno M, Cappucci F, et al: Low protein Z levels and risk of occurrence of deep vein thrombosis. J Thromb Haemost 4:2417, 2006 [PMID: 16938126] Scarsbrook AF, Evans AL, Owen AR, et al: Diagnosis of suspected venous thromboembolic disease in pregnancy. Clin Radiol 61:1, 2006 [PMID: 16356811] Scifres CM, Macones GA: The ultility of thrombophilia testing in pregnant women with thrombosis: Fact or fiction? Am J Obstet Gynecol 199:344.e1, 2008 Seguin J, Weatherstone K, Nankervis C: Inherited antithrombin III deficiency in the neonate. Arch Pediatr Adolesc Med 148:389, 1994 [PMID: 8148939] Seligsohn U, Lubetsky A: Genetic susceptibility to venous thrombosis. N Engl J Med 344:1222, 2001 [PMID: 11309638] Sephton V, Farquharson RG, Topping J, et al: A longitudinal study of maternal dose response to low molecular weight heparin in pregnancy. Obstet Gynecol 101:1307, 2003 [PMID: 12798541] Singhal S, Henderson R, Horsfield K, et al: Morphometry of the human pulmonary arterial tree. Cir Res 33:190, 1973 [PMID: 4727370] Smith MP, Norris LA, Steer PJ, et al: Tinzaparin sodium for thrombosis treatment and prevention during pregnancy. Am J Obstet Gynecol 190:495, 2004 [PMID: 15530888] Srivastava SD, Eagleton MJ, Greenfield LJ: Diagnosis of pulmonary embolism with various imaging modalities. Semin Vasc Surg 17:173, 2004 [PMID: 15185184] Stefano VD, Martinelli I, Mannucci PM, et al: The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 341:801, 1999 [PMID: 10477778] Stein PD, Athanasoulis C, Alavi A, et al: Complications and validity of pulmonary angiography in acute pulmonary embolism. Circulation 85:462, 1992 [PMID: 1735144] Stein PD, Fowler SE, Goodman LR, et al: Multidetector computed tomography for acute pulmonary embolism. N Engl J Med 354:2317, 2006 [PMID: 16738268] Taniguchi S, Fukuda I, Minakawa M, et al: Emergency pulmonary embolectomy during the second trimester of pregnancy: Report of a case. Surg Today 38:59, 2008 [PMID: 18085366] Tapson VF: Acute pulmonary embolism. N Engl J Med 358:1037, 2008 [PMID: 18322285] Tengborn L, Bergqvist D, Matzsch T, et al: Recurrent thromboembolism in pregnancy and puerperium: Is there a need for thromboprophylaxis? Am J Obstet Gynecol 160:90, 1989 [PMID: 2912109] van Wijk FH, Wolf H, Piek JM, et al: Administration of low molecular weight heparin within two hours before caesarean section increases the risk of wound haematoma. Br J Obstet Gynaecol 109:955, 2002 Vasse M: Protein Z, a protein seeking a pathology. Thromb Haemost 100(4):548, 2008 Virchow R: Gesammelte Abhandlungen zur wissenschaftlichen Medizin. Frankfurt: Medinger Sohn & Co., 1856, p 219 Walker MC, Garner PR, Keely EJ, et al: Changes in activated protein C resistance during normal pregnancy. Am J Obstet Gynecol 177:162, 1997 [PMID: 9240601] Warkentin TE, Kelton JG: Temporal aspects of heparin-induced thrombocytopenia. N Engl J Med 344:1286, 2001 [PMID: 11320387] Warkentin TE, Maurer BT, Aster RH: Heparin-induced thrombocytopenia associated with fondaparinux, N Engl J Med 356:2653, 2007 [PMID: 17582083] Warren JE, Simonsen SE, Branch W, et al: Thromboprophylaxis and pregnancy outcomes in asymptomatic women with inherited thrombophilias. Am J Obstet Gynecol 200:281.e1, 2009 Weiss N, Bernstein PS: Risk factor scoring for predicting venous thromboembolism in obstetric patients. Am J Obstet Gynecol 182:1073, 2000 [PMID: 10819831] Wells PS, Anderson DR, Rodger M, et al: Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med 349:1227, 2003 [PMID: 14507948]
william gynecology
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thromboembolism
1-1 of 1 Results
Thromboembolism Williams Gynecology > Chapter 39.
Perioperative Considerations >
Special Considerations
1-1 of 1 Results
-----------------------------
Perioperative Considerations
Special Considerations Surgical Site Infection Prophylaxis Antibiotic prophylaxis can reduce hospital-acquired infections significantly following gynecologic surgery. Decisions regarding the choice, timing, and duration of antibiotic prophylaxis are guided by the intended procedure and the anticipated organisms to be encountered. Prophylaxis is summarized in Table 39-7 and discussed in Chapter 3, Clean Wounds .
Perioperative Considerations > Special Considerations > Surgical Site Infection Prophylaxis >
Table 39-7 Antimicrobial Prophylactic Regimens by Procedure
Procedure
Antibiotic
Dose
Vaginal/abdominal hysterectomya
Cefazolin
1- or 2-g single dose IV
Cefoxitin
2-g single dose IV
Metronidazoleb
1-g single dose IV
Tinidazole b
2-g single oral dose (4–12 hours before surgery)
Laparoscopy
None
Laparotomy
None
Hysteroscopy
None
Hysterosalpingogram
Doxycyclinec
IUD insertion
None
Endometrial biopsy
None
Induced abortion/D&C
Doxycycline
Metronidazole
100 mg orally twice daily for 5 days
100 mg orally 1 hour before procedure and 200 mg orally after procedure
500 mg orally twice daily for 5 days
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thromboembolism Urodynamic testing
None
IV = intravenously; IUD = intrauterine device; D&C = dilatation and curettage. aA convenient time to administer antibiotic prophylaxis is just before induction of anesthesia. bAntimicrobial agents of choice in women with a history of immediate hypersensitivity to penicillin. cIf hysterosalpingogram demonstrated dilated fallopian tubes. No prophylaxis is indicated for a study without dilated tubes. From American College of Obstetricians and Gynecologists, 2006 , with permission.
Subacute Bacterial Endocarditis Prophylaxis Sufficient evidence exists regarding the association between bacteremia and postprocedural endocarditis (Durack, 1995; van der Meer, 1992 ). Despite a lack of randomized trials, prevention of this highly morbid complication with preoperative antibiotics is justified in patients at risk of developing disease (Table 39-8 ) (Dajani, 1997; Seto, 2007 ). The mechanism behind the prevention of subacute bacterial endocarditis (SBE) is unclear, but evidence suggests that antibiotics alter bacterial adhesion to heart valves (Moreillon, 1986 ).
Perioperative Considerations > Special Considerations > Subacute Bacterial Endocarditis Prophylaxis >
Table 39-8 Subacute Bacterial Endocarditis Prophylaxis by Surgical Procedure < Cardiac Conditions Associated with Endocarditis
Endocarditis Prophylaxis by Surgical Procedure
Endocarditis prophylaxis recommended
Endocarditis prophylaxis recommended
High-risk category
Prosthetic cardiac valves, including bioprosthetic and homograft valves
Previous bacterial endocarditis
Complex cyanotic congenital heart disease (e.g., single-ventricle states, transposition of the great arteries, tetralogy of Fallot)
Surgically constructed systemic pulmonary shunts or conduits
Moderate-risk category
below)
Most other congenital cardiac malformations (other than those listed above and
Acquired valvar dysfunction (e.g., rheumatic heart disease)
Hypertrophic cardiomyopathy
Mitral valve prolapse with valvar regurgitation, thickened leaflets, or both
Gastrointestinal tracta
Surgical operations that involve intestinal mucosa
Genitourinary tract
Cystoscopy
Urethral dilation
Other genitourinary procedures only in presence of infection
Endocarditis prophylaxis not recommended
Genitourinary tract
Vaginal hysterectomyb
Urethral catheterization
Endocarditis prophylaxis not recommended
Uterine dilation and curettage
Negligible-risk category (risk no greater than that of the general population)
Therapeutic abortion
Isolated secundum atrial septal defect
Sterilization procedures
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thromboembolism Surgical repair of atrial septal defect, ventricular septal defect, or patent ductus arteriosus (without residua beyond 6 months)
device
Insertion or removal of intrauterine
aProphylaxis is recommended for high-risk patients; option for medium-risk patients. bProphylaxis is option for high-risk patients. From American College of Obstetricians and Gynecologists, 2006, and Dajani, 1997, with permissions.
Candidates for SBE prophylaxis are classified by their underlying cardiac disease and the degree of bacteremia anticipated from the planned surgical procedure. The American Heart Association identifies cardiac lesions as negligible, moderate, or high-risk for developing postprocedural infection (Dajani, 1997 ). For those at risk, antibiotics should be administered prior to the procedure. Recommended antibiotic prophylaxis guidelines endorsed by the American Heart Association and the American College of Obstetricians and Gynecologists are summarized in Table 39-9 .
Perioperative Considerations > Special Considerations > Subacute Bacterial Endocarditis Prophylaxis >
Table 39-9 Endocarditis Prophylaxis Regimens for Genitourinary and Gastroinestinal Procedures
Situation
High-risk patients
Agents
Ampicillin
Adults: ampicillin 2.0 g IM or IV plus gentamicin 1.5 mg/kg (not to exceed 120 mg) within 30 min of starting procedure; 6 h later, ampicillin 1 g IM/IV or amoxicillin 1 g orally
Vancomycin
Adults: vancomycin 1.0 g IV over 1–2 h plus gentamicin 1.5 mg/kg IV/IM (not to exceed 120 mg); complete injection/infusion within 30 min of starting procedure
Amoxicillin
Adults: amoxicillin 2.0 g orally 1 h before procedure, or ampicillin 2.0 g IM/IV within 30 min of starting procedure
Vancomycin
Adults: vancomycin 1.0 g IV over 1–2 h; complete infusion within 30 min of starting procedure
plus gentamicin
High-risk patients allergic to ampicillin/amoxicillin
Moderate-risk patients
Moderate-risk patients allergic to ampicillin/amoxicillin
Regimen
plus gentamicin
or ampicillin
IM = intramuscular; IV = intravenous. From Dajani, 1997 , with permission.
Gastrointestinal Bowel Preparation Surgical dogma drives the use of mechanical bowel preparation as a means to prevent postoperative complications (Bucher, 2004 ). Studies conducted prior to the routine administration of antibiotic prophylaxis argued that bowel cleansing prior to colorectal
surgery improved bowel handling, prevented anastomosis disruption with the passage of hard feces, and decreased fecal and bacterial loads. Thus, bowel cleansing was thought to reduce wound infection rates (Barker, 1971; Nichols, 1971 ).
Multiple recent studies, however, question the routine use of mechanical bowel preparations (Guenaga, 2003; Platell, 1998 ). Ram and co-workers (2005) prospectively randomized 329 patients undergoing elective large bowel resection to see whether routine
mechanical bowel preparation reduced postoperative morbidity and mortality, including anastomotic breakdown and wound infections. They found no differences. Similar results have been found following gynecologic and urologic procedures (Muzii, 2006; Shafii, 2002 ). Moreover, a recent report contradicts the belief that mechanical bowel preparation decreases microbial contamination of the peritoneal cavity and subcutis after elective open-colon surgery (Fa-Si-Oen, 2005 ). It is not surprising to find that patients who do not have a mechanical bowel preparation are more satisfied and experience shorter times to their first postoperative bowel movement (Jung, 2007 ). Although its routine use should be limited, mechanical bowel preparation is often preferred for many female pelvic reconstructive procedures involving the posterior vaginal wall and anal sphincter. In these cases, evacuation of rectal stool provides additional operating space and undistorted anatomy. Moreover, preoperative evacuation typically delays stooling and allows initial healing following sphincteroplasty. Other instances in which mechanical bowel preparation may be recommended include those in which the entire colon may be palpated during surgery for evaluation of tumor involvement. Table 39-10 provides a summary of various commercially available preparations used commonly for bowel preparation (Valantas, 2004 ).
Perioperative Considerations > Special Considerations > Gastrointestinal Bowel Preparation >
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thromboembolism Table 39-10 Colon Cleansing Preparation Methods
Diet and Cathartics
Diet
Clear liquids for 3 days or a diet designed to leave a minimal colonic fecal residue for 1–3 days
Cathartics
Extract of senna fruit (X-Prep) 240 mL or magnesium citrate 240 mL
Additional cathartic
Bisacodyl 20 mg orally and suppositories
Enemas
Sodium phosphate or tap water
Kits
Liqui Prep, Nutra Prep, LoSo Prep System
Gut Lavage Methods
Polyethylene glycol–electrolyte lavage solution (PEG-ELS)
Sodium sulfate and polyethylene glycol (PEG) GoLYTELY, CoLyte
Sulfate-free–electrolyte lavage solution (SF-ELS)
PEG without sulfate NuLYTELY
Reduced volume with bisacodyl or magnesium citrate Half Lytely
Phosphate Preps
Oral sodium phosphate
Fleet's Phosphosoda
Phosphate Tablets
Visicol
From Valantas, 2004 , with permission.
Thromboembolism Prevention Venous thromboembolism (VTE) is a general category used to describe venous clot formation and includes the more specific entities of deep vein thrombosis (DVT) and pulmonary thromboembolism (PTE). Prophylaxis against VTE ranks in the top 10 patient safety practices recommended by the Agency for Healthcare Research and Quality (AHRQ) and the National Quality Forum (Michota, 2006 ). In the United States alone, it is estimated that the incidence of DVT approaches 450,000, with an additional 350,000 nonfatal PTE and 250,000 fatal PTE (Bick, 2002 ). National recommendations for prophylaxis against VTE follow a risk-based approach. The American College of Obstetricians and Gynecologists (2007) provides a summary of VTE risk factors pertinent during gynecologic surgery and successful prevention strategies of DVT/PTE (Table 39-11 ).
Chapter 39. Perioperative Considerations > Special Considerations > Thromboembolism > Prevention >
Table 39-11 Levels of Thromboembolism Risk in Surgical Patients Without Prophylaxis
DVT, %
PE, %
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Successful Prevention Strategies
thromboembolism
Level of Risk
Calf
Proximal
Clinical
Fatal
Low risk
2
0.4
0.2
<0.01
No specific prophylaxis; early and "aggressive" mobilization
10–
2–4
1–2
0.1–
LDUH (q12h), LMWH ( 3400 units daily), GCS, or IPC
20–
4–8
2–4
0.4–
LDUH (q8h), LMWH ( 3400 units daily), or IPC
40–
10–20
4–10
Minor surgery in patients <40 yr with no additional risk factors
Moderate risk
20
0.4
Minor surgery in patients with additional risk factors Surgery in patients aged 40–60 yr with no additional risk factors
High risk
40
1.0
Surgery in patients >40–60 yr with additional risk factors (prior VTE, cancer, molecular hypercoagulability)
Highest risk
60
0.2–5
Surgery in patients with multiple risk factors (age >40 yr, cancer, prior VTE, or molecular hypercoagulability)
Hip or knee arthroplasty,
HFS Major trauma, SCI
LMWH
(>3400 units daily),
fondaparinux , oral VKAs (INR 2–3), or IPC/GCS + LDUH/LMWH Consider continuing prophylaxis for 2–4 weeks after discharge
DVT = deep vein thrombosis; GCS = graduated compression stockings; HFS = hip fracture surgery; INR = international normalized ratio; IPC = intermittent pneumatic compression; LDUH = low-dose unfractionated heparin ; LMWH = low-molecular-weight heparin; PE = pulmonary embolism; SCI = spinal cord injury; VKAs = vitamin K antagonists; VTE = venous thromboembolism. From Geerts, 2004, and American College of Obstetricians and Gynecologists, 2007 , with permission.
Hormone Discontinuation Of risks, hormone use is one factor that can be modified prior elective surgery. Combined oral contraceptive pills (COCs) induce hypercoagulable changes that are reversed if COCs are stopped at least 6 weeks prior to surgery (Robinson, 1991; Vessey, 1986 ). To balance the risk of unintended pregnancy in women halting COCs, a suitable alternative is recommended with clear instructions on use. Postmenopausal hormone replacement therapy (HRT) appears also to increase the incidence of postoperative VTE. Grady and colleagues (2000) estimate a fivefold increase in the risk of developing a venous thrombotic event during the first 90 days after inpatient
surgery. Thus, women should be counseled appropriately on this additional postoperative risk, but the value and duration of HRT cessation to negate this increased risk are unclear. Prophylaxis Options Various modalities for prophylaxis exist. Early ambulation, though encouraged after surgery, is not regarded as a primary strategy for DVT prophylaxis (Michota, 2006 ). Graded compression stockings (TED hose), when used in conjunction with other methods of prophylaxis, offer additional benefit (Amaragiri, 2000 ). Intermittent pneumatic compression (IPC) works primarily by improving venous flow. It appears to be effective in moderate- and high-risk patients if initiated prior to the induction of anesthesia and continued until patients are fully ambulatory (Clarke-Pearson, 1993; Geerts, 2004 ). Pharmacologic methods of VTE prophylaxis include low-dose unfractionated heparin , low-molecular-weight heparin, and new classes of medications such as factor Xa inhibitors. Diagnosis and Treatment of Thromboembolism
If VTE is suspected, evaluation begins with clinical examination and estimation of the woman's likelihood for disease. Wells and colleagues (1995) published one of the most widely used clinical prediction algorithms (Fig. 39-4 and Table 39-12 ). When indicated, duplex sonography is highly sensitive for detecting proximal DVT, with a false-negative rate of 0 to 6 percent (Gottlieb, 1999 ). For PTE, clinicians continue to use ventilation-perfusion (VQ) scanning and helical computed-tomographic (CT) scanning as alternatives to the invasive "gold standards"—pulmonary angiography or contrast venography.
Special Considerations > Thromboembolism > Diagnosis and Treatment of Thromboembolism >
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thromboembolism
Table 39-12 Pretest Probability for Deep Vein Thrombosis
Clinical Probability
High 3 major points and no alterative diagnosis 2 major points and 2 minor points + no alternative diagnosis
Low 1 1 0 0
major major major major
point + 2 minor points + has an alterative diagnosis point + 1 minor point + no alterative diagnosis points + 3 minor points + has an alterative diagnosis points + 2 minor points + no alterative diagnosis
Moderate All other combinations
From Wells, 1995 , with permission.
Acute management of VTE involves anticoagulation with intravenous unfractionated heparin or subcutaneous low-molecular-weight heparin. After achieving adequate anticoagulation, oral vitamin K antagonists such as warfarin are initiated. Therapy duration is dictated by clinical circumstance and typically is administered for: (1) 3 to 6 months following a first idiopathic DVT, (2) 6 months for PTEs, and (3) indefinitely for those with a thrombophilic condition or a second VTE. Postoperative Nausea and Vomiting This is one of the most common complaints following surgery, and its incidence ranges from 30 to 70 percent in high-risk patients (Moller, 2002 ). Those at risk for postoperative nausea and vomiting (PONV) include females, nonsmokers, those with a history of motion sickness or PONV, those with extended surgeries, and those undergoing laparoscopic or other gynecologic surgery (Apfelbaum, 2003 ). A multimodal approach to prevention is recommended (Apfel, 2004 ). Currently, combinations of 4 to 8 mg dexamethasone prior to anesthesia induction are followed by less than 1 mg droperidol and 4 mg ondansetron toward the end of surgery. This pretreatment significantly reduces symptoms by 25 percent. However, if symptoms develop within 6 hours of surgery, antiemetics from a different pharmacologic class than previously administered should be considered (Habib, 2004 ). Persistent nausea may benefit from combining agents from different classes (Table 39-13 ).
Perioperative Considerations > Special Considerations > Postoperative Nausea and Vomiting >
Table 39-13 Commonly Used Medications for Nausea and Vomiting
Class/Medication
Usual Dosage
Route(s)
Adverse Effects
1 patch every 3 d
Transdermal
Dry mouth, drowsiness, impaired eye accommodation
Anticholinergic
Scopolamine (Transderm Scop)
Antihistamines
Diphenhydramine
(Benadryl)
Hydroxyzine
(Atarax, Vistaril)
Meclizine (Antivert)
q4–6h
q6h
q6h
25–50 mg
IM, IV, PO
25–100 mg
IM, PO
25–50 mg
PO
Sedation, dry mouth, constipation, blurred vision, urinary retention
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thromboembolism Promethazine
(Phenergan)
12.5–25 mg q4–6h
PR
IM, IV, PO,
Benzamides
Metoclopramide
(Reglan)
(Tigan)
Trimethobenzamide
q6h
q6–8h
5–15 mg
IM, IV, PO
250 mg
IM, PO, PR
0.5–2.5 mg
IM, IV, PO
4 mg q6h
IM, IV, PO
Sedation or agitation, diarrhea, extrapyramidal effects, hypotension
Benzodiazepines
Lorazepam
(Ativan)a
q8–12h
Sedation, amnesia, respiratory depression, blurred vision, hallucinations
Corticosteroids
Dexamethasone
GI upset, anxiety, insomnia, hyperglycemia
(Decadron)a
Phenothiazines
Prochlorperazine
(Compazine )
5–10 (25 PR) mg q6h
IM, IV, PO,
Sedation, extrapyramidal effects, cholestatic jaundice, hyperprolactinemia
8 mg q8h
IV, PO
Headache, fever, arrhythmias, ataxia, somnolence or nervousness, elevated hepatic transaminases
2 mg per
IV, PO
PR
5-HT3 Serotonin Antagonists
Ondansetron
(Zofran)
Granisetron (Kytril)
Dolasetron
(Anzemet)
24 h
100 mg per 24 h
IV, PO
GI = gastrointesintal; HT = hydroxytryptamine; IM = intramuscular; IV = intravenous; PO = orally; PR = per rectum. aNot FDA approved for this indication. From Miser, 2006 , with permission.
william hematology
1-7 of 7 Results
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thromboembolism
Definition and History
Williams Hematology, 8e > Chapter 131. Hereditary Thrombophilia
Epidemiology
Williams Hematology, 8e > Chapter 131. Hereditary Thrombophilia
Interactions between Different Thrombophilias and between Thrombophilia and Environmental Factors
Williams Hematology, 8e > Chapter 131. Hereditary Thrombophilia
Pathogenesis
Williams Hematology, 8e > Chapter 131. Hereditary Thrombophilia
Prophylaxis
Williams Hematology, 8e > Chapter 131. Hereditary Thrombophilia
Thrombosis and Thromboembolism
Williams Hematology, 8e > Chapter 130. Disseminated Intravascular Coagulation > Clinical Features
Thromboembolic Events
Williams Hematology, 8e > Chapter 7. Hematology during Pregnancy > Bleeding Disorders and Causes of Thrombocytopenia > Thrombophilia
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tintinalli
1-3 of 3 Results
Thromboembolism
Tintinalli's Emergency Medicine > Chapter 105. Comorbid Diseases in Pregnancy
Thromboembolism Tintinalli's Emergency Medicine > Chapter 225. Hematologic Derangement
Emergency Complications of Malignancy >
Deep Venous Thrombosis or Pulmonary Embolism
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Related to
thromboembolism Tintinalli's Emergency Medicine > Chapter 224. Anticoagulants, Fibrinolytics > Indications for Fibrinolytic Therapy
Antiplatelet Agents, and Fibrinolytics
>
1-3 of 3 Results
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Emergency Complications of Malignancy
Related to Hematologic Derangement Granulocytopenia and Infection A febrile, neutropenic patient is an absolute medical emergency. Neutropenia, or an absolute neutrophil count of fewer than 500/ L, is the most frequent factor predisposing patients with cancer to infection, especially bacteremia. If untreated, the mortality rate of a neutropenic patient with a bacteremic infection is about 50 percent. 6 The most common presenting symptom is fever, defined as a temperature of 38.3°C on one occasion or 38.0°C for longer than 1 h. Due to an impaired inflammatory response and granulocytopenia, the usual findings of infection may be muted or masked. Signs of infection, such as purulence, may not develop, and erythema or pain may be the only findings. During the physical examination, all portals of entry, including mucosal surfaces, must be inspected. Funduscopic examination may show evidence of disseminated infection or papilledema. Manifestations of pneumonia may be auscultatory only, because granulocytopenia may preclude development of a visible infiltrate on chest radiograph. A detailed skin examination, in particular the perirectal area of acute leukemia patients, is important. Digital rectal examination is relatively contraindicated in neutropenic patients and should be withheld until after initial antibiotic administration. Clotted catheters represent a high risk of infection due to bacterial colonization, and central venous catheters may be associated with the development of endocarditis. 9 To evaluate for occult infection, ancillary tests include blood and urine cultures and chest radiograph. Sputum, stool, and wound drainage Gram's stain and culture should be obtained if productive cough, diarrhea, or wound drainage is present. Lumbar puncture is not routine, because the incidence of meningitis is not increased with neutropenia. The choice of initial empiric antimicrobial therapy should be broad spectrum to cover the range of potential bacterial pathogens. There are several combination regimens in use. Bacteremia is most frequently due to aerobic gram-positive cocci (coagulase-negative staphylococci, viridans streptococci, or Staphylococcus aureus) or aerobic gram-negative bacilli (Escherichia coli, Klebsiella pneumoniae, or Pseudomonas aeruginosa). An aminoglycoside combined with an antipseudomonal -lactam has become standard for empiric treatment. Vancomycin should be added if the following are present: severe mucositis, catheter infection, quinolone prophylaxis, hypotension, institutions with methicillin-resistant S. aureus, or known colonization with resistant gram-positive organisms. 6–9 Fungi are common secondary infections in those who have received courses of broad-spectrum antibiotics. 9 Hyperviscosity Syndrome Hyperviscosity syndrome describes a group of pathologic conditions in which blood flow is impaired due to abnormal blood characteristics. The flow properties of blood are dependent on its fluid and cellular contents. Abnormal plasma contents are most commonly Waldenström macroglobulinemia, followed by immunoglobulin A myeloma. Hyperproduction of any cell line can lead to hyperviscosity. 10 Polycythemia (with a hematocrit >60 percent) and leukemias (with a white blood cell count >100,000/ L or a leukocrit >10 percent) often are associated with clinically significant hyperviscosity. Dehydration will exacerbate the effects of all hyperviscosity syndromes. Initial symptoms are vague and may include fatigue, abdominal pain, headache, or, most commonly, altered mental status. Thrombosis may occur, with the creation of focal or unusual findings. Specific physical findings other than retinal hemorrhages, exudates, and "sausage-linked" vessels are rare. The diagnosis depends on a high index of suspicion coupled with laboratory findings. The peripheral blood smear may reveal rouleaux formation (red cells stacked like coins). The laboratory may be unable to perform serological testing due to serum stasis in the analyzers. Serum viscosity and protein electrophoresis can be diagnostic. Initial therapy consists of intravascular volume repletion, early involvement of a hematologist, and emergency plasmapheresis. When coma is present and the diagnosis established, a temporizing measure can be a two-unit (1000 mL) phlebotomy with concomitant volume replacement with 2 to 3 L of NS. Thromboembolism Thromboembolism occurs with all tumor types and is the second leading cause of death in cancer patients. Symptomatic deep venous thrombosis (DVT) occurs in approximately 15 percent of all patients with cancer and up to 50 percent of those with advanced malignancies. 11 A hypercoagulable state, decreased proteins C, S, and antithrombin III, the effect of metastases on activation of the coagulation pathway, chemotherapy, invasive procedures, and long-term venous catheterization increase thromboembolism risk. 12 Coagulation activation may contribute to the tumor progression; as such, anticoagulants may have anticancer activity. Treatment with low molecular weight heparin (LMWH) or unfractionated heparin as a bridge to chronic warfarin therapy is appropriate for most newly diagnosed cases of DVT, although some recommend the use of LMWH in view of data suggesting a survival advantage for cancer patients receiving LMWH. Cancer patients do not appear at increased risk for anticoagulant -related bleeding complications, including those with brain metastases. More frequent monitoring of the International Normalized Ratio is required, because warfarin is
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thromboembolism more difficult to control than in other patients. 11 Thrombolytic therapy for treatment of DVT is not indicated, because anticoagulant therapy alone is generally successful. A pulmonary embolus with hemodynamic stability is treated with unfractionated heparin or LMWH. Because of the high mortality rate for pulmonary embolus and hemodynamic instability, right ventricular failure, or thrombus in the right atrium or ventricle, thrombolytic therapy is recommended. Of the available agents, no agent or dosing range has currently been shown to be superior to another. Less ill patients should not receive thrombolytic therapy, because major bleeding can occur in 20 percent of patients, and there is no improvement in mortality. However, a blocked indwelling catheter due to catheter tip thrombosis can be treated with a local infusion of low-dose thrombolytic therapy. 12 This is best done with the approval of the local specialist.
Anticoagulants, Antiplatelet Agents, and Fibrinolytics: Introduction Antithrombotic therapy is standard for numerous arterial and venous thromboembolic conditions, including acute myocardial infarction (AMI)—both ST-segment elevation MI (STEMI) and non-ST-segment elevation MI (NSTEMI)—unstable angina pectoris, deep venous thrombosis (DVT), pulmonary embolism (PE), and transient ischemic attack (TIA) or cardiovascular accident (CVA). Moreover, antithrombotic agents help prevent occlusive vascular disease in patients at risk for thrombosis. These agents, however, also have the potential to cause life-threatening complications, primarily uncontrolled hemorrhage. This chapter provides an overview of antithrombotic agents, including mechanisms of action, indications, and contraindications, as well as evaluation and management of acute bleeding complications. Detailed management of thromboembolic disorders is discussed in their respective chapters. Hemostasis is initiated by platelet interaction with the vascular subendothelium and continues with a series of plasma coagulation proteins reactions that generate the final product of cross-linked fibrin, an insoluble protein, meshed with the initial platelet plug (see Chap. 218). Arterial thrombi, composed primarily of platelets bound by thin fibrin strands, develop under high-flow conditions, especially at sites of ruptured atherosclerotic plaques. Both anticoagulants and platelet-inhibiting drugs may effectively prevent and treat arterial thrombosis. In contrast, venous thrombi form in areas of sluggish blood flow, and are composed mainly of red blood cells and large fibrin strands. Anticoagulant drugs are effective in preventing and treating venous thromboembolism, while platelet-suppressing agents are less useful. Both arterial and venous thrombi may result in local vascular obstruction or distant embolization. Antithrombotic agents interfere with these processes either by preventing formation of the platelet-fibrin net (blocking thrombin activation or platelet function) or by accelerating clot breakdown (fibrinolysis). Antithrombotic agents are classified by mechanism of action. Anticoagulants block the synthesis and activation of clotting factors, interfering with the coagulation cascade at one or more steps. Antiplatelet agents interfere with platelet activation or aggregation. Fibrinolytics (often but inaccurately referred to as thrombolytic agents) enzymatically dissolve the fibrin component of thrombi. Anticoagulants Warfarin Pharmacology of Warfarin Oral anticoagulants are used to 1) stop further thrombosis when the condition already exists (e.g., DVT), 2) reduce the risk of embolism in patients with thrombotic disease (e.g., DVT or left ventricular mural thrombus), and 3) prevent thrombi from forming in patients with risk factors for their development (e.g., prolonged immobilization or venous disease) (Table 224-1). Sodium warfarin, a hydroxycoumarin compound, is the most widely used oral anticoagulant in North America. Readily absorbed from the gut, it reaches peak blood concentrations in 90 min and has a circulating half-life of 36 to 42 h. Warfarin is bound to albumin, metabolized by the liver, and excreted in the urine. Warfarin blocks activation of vitamin K and thereby interferes with hepatic carboxylation of coagulation factors II, VII, IX, and X. Without these vitamin K-dependent cofactors, the extrinsic coagulation pathway is blocked. Warfarin also blocks the synthesis of the antithrombotic proteins C and S; proteins that inhibit the function of factors V and VII in the coagulation cascade. Table 224-1 Antithrombotic Therapy Guidelines
Clinical Indication
Comments
Treatment of DVT and PE Unfractionated heparin: 80 U/kg IV bolus, then 18 U/kg per h continuous In most cases, heparin and warfarin can be started infusion, with the aPTT checked after 6 h and the infusion adjusted to simultaneously, with an overlap of 3–5 days. maintain the aPTT 1.5–2.5 times control with concurrent institution of Warfarin should be continued for at least 3 months. warfarin. Enoxaparin: 1 mg/kg SC bid or 1.5 g/kg SC per d SK: 250,000 units IV bolus, then 100,000 U/h continuous infusion for 1– 3d Alteplase: 15 mg bolus, then 0.75 mg/kg over 30 min (maximum 50 mg), then 0.50 mg/kg over 60 min (maximum 35 mg) Urokinase: 4400 U/kg IV bolus then 4400 U/kg per h continuous infusion for 1–3 d Prophylaxis of DVT and PE Unfractionated heparin: 5000 units SC bid or tid Ardeparin: 50 U/kg SC bid Dalteparin: 2500 to 5000 units SC per d Enoxaparin 30 mg SC bid or 40 mg SC per d STEMI
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thromboembolism Aspirin (nonenteric coated): 160–325 mg PO per d
All postmyocardial infarction patients should receive aspirin 160–325 mg/d for an indefinite period (unless contraindicated or if on warfarin).
Unfractionated heparin: 60 U/kg IV bolus, then 12 U/kg per h continuous Optimal strategies are unclear. Research is evolving rapidly. infusion adjusted to keep aPTT 1.5–2.5 times control or 17,500 units SC bid Enoxaparin: 1 mg/kg SC bid Patients at high risk for mural thrombosis or systemic embolism: heparin, then warfarin for 1–3 months (INR 2.0–3.0) Streptokinase: 1–1.5 million units IV over 60 min Alteplase: 15 mg bolus, then 0.75 mg/kg over 30 min (maximum 50 mg), then 0.50 mg/kg over 60 min (maximum 35 mg) Reteplase: 10 units IV bolus, then a second dose at 30 min Tenecteplase: weight-tiered single bolus (approximately 0.5 mg/kg with maximum of 50 mg) over 5 s Unstable angina or NSTEMI Aspirin: 162 mg PO per d Clopidogrel: 75 mg PO per d Heparin: 60 U/kg IV bolus, then 12 U/kg per h continuous infusion to keep aPTT 1.5–2.5 times control Enoxaparin 1 mg/kg SC bid Glycoprotein IIb-IIIa inhibitor depending upon risk and whether PCI is planned Peripheral vascular disease Aspirin: 160–325 mg/d for all patients with peripheral vascular disease Acute stroke Alteplase: 90 mg over 1 h, with 0.9 mg/kg as initial bolus, if within 3 h of Use of fibrinolytics in acute CVA requires strict adherence to symptom onset and no intracranial hemorrhage on brain CT national guidelines and should be done with informed consent. Adjunctive use of anticoagulants must be avoided for 48 h. Heparin: for acute cardioembolic stroke, small to moderate size, no hemorrhage on CT or MRI
Some evidence suggests that clopidogrel may be the preferred agent in patients with completed stroke.
Delay anticoagulation: for large-size stroke or poorly controlled hypertension Aspirin: 81 mg PO per d for completed stroke Clopidogrel: 75 mg PO per d Ticlopidine: 250 mg PO per bid TIA Aspirin: 81 mg PO per d
Use clopidogrel or ticlopidine if "aspirin-failure" or aspirin allergic.
Clopidogrel: 75 mg PO per d Ticlopidine: 250 mg PO bid
Abbreviations: aPTT = activated partial thromboplastin time; AMI = acute myocardial infarction; CT = computed tomography; CVA = cerebrovascular accident; DVT = deep venous thrombosis; INR = International Normalized Ratio; MRI = magnetic resonance imaging; NSTEMI = non-ST-segment elevation myocardial infarction; PCI = percutaneous coronary intervention; PE = pulmonary embolism; SK = streptokinase; STEMI = ST-segment elevation myocardial infarction; TIA = transient ischemic attack. Warfarin dosing is guided by measurement of the International Normalized Ratio (INR), a standardized measurement of prothrombin time (PT), with a desired therapeutic range of 2 to 3 in most cases.1 Drugs and food that interfere with warfarin absorption, binding to albumin, or hepatic metabolism can have a profound effect on warfarin activity (Table 224-2). Warfarin is contraindicated in pregnancy because it is teratogenic (especially during the sixth to twelfth week of gestation) and causes fetal hemorrhage. Table 224-2 Warfarin Interactions
Consideration
Prothrombin Time (PT) or INR*
Major Vitamin K malabsorption or dietary deficiency Excess vitamin K Reduced gut bacteria (antibiotics) Decreased warfarin absorption Altered warfarin metabolism (cytochrome P450)
or
Drug effects
or
Other Decreased clotting factor production (liver disease) Increased metabolism of clotting factors (fever) Confounding technical or laboratory factors (e.g., phlebotomy, handling in transport, thromboplastin
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or
thromboembolism reagents)
* = Prothrombin time (PT) or International Normalized Ratio (INR) prolonged;
= PT or INR decreased.
Protein C has a short half-life (8 h), and its plasma level falls quickly after starting warfarin. The coagulation factors have variable half-lives; from about 7 h for factor VII to about 60 h for prothrombin (factor II). The phase delay between the fall in protein C (an antithrombotic protein) and the fall in the affected four coagulation factors (prothrombotic proteins) results in a transient state of increased thrombogenesis at the start of warfarin therapy that lasts for about 24 to 36 h. This potential hypercoagulable state is reduced but not eliminated by initiating warfarin therapy with 5 mg/d doses.2 For patients in whom sudden intravascular thrombosis can be fatal (e.g., those with a prosthetic heart valve), anticoagulation should be ensured with a heparin product (unfractionated or low molecular weight) before starting oral warfarin. Thus, a noncompliant patient with a prosthetic heart valve who has stopped oral anticoagulants should not simply be discharged with instructions to restart warfarin. There is also a prothrombotic rebound during warfarin withdrawal. During the first 4 days after cessation of therapy, factors VII and IX increase more rapidly than proteins C and S, resulting in an imbalance between provokers and inhibitors of coagulation.3 This potential hypercoagulable condition appears to exist biochemically, although prospective studies have shown no increased incidence of clinical episodes of thrombosis with sudden termination of warfarin therapy compared to gradual tapering during this interval. Thromboembolic events that occur in patients after warfarin discontinuation are related more to the underlying condition than to the method of termination. Complications and Management The two major complications of warfarin therapy are major bleeding episodes and skin necrosis. The most important factor influencing the risk of bleeding is the intensity of anticoagulant therapy. For most purposes, the target INR is 2.0 to 3.0, except for patients with mechanical heart valves and antiphospholipid antibody syndrome, who require more intense anticoagulation with an INR of 2.5 to 3.5. The risk of clinically significant bleeding is increased when the INR is in the 3.0 to 4.5 range, and an exponential increase in bleeding events occurs when the INR is >5.0. Reversal with vitamin K1 or factor replacement may be necessary for major hemorrhage. Skin necrosis occurs primarily in patients with protein C deficiency. This complication usually develops 3 to 8 days after starting treatment and is caused by thrombosis of small cutaneous vessels. Treatment includes discontinuation of warfarin, administration of UFH or LMWH, vitamin K1 administration, and screening for protein C and S deficiencies. Bleeding is the most common complication of warfarin treatment. Risk factors for bleeding include hypertension, anemia, prior cerebrovascular disease, gastrointestinal lesions, and renal disease. Medications that increase warfarin activity and antiplatelet medications can also increase bleeding risks (see Table 224-2). The relationship between advanced age and warfarin-associated bleeding is controversial. Elderly individuals who are otherwise good candidates for anticoagulant therapy should not have it withheld because of their age. However, elderly patients require more frequent and careful monitoring. Two general principles are important when warfarin-treated patients bleed with a prolonged INR: 1) attempt to identify and attenuate the cause of bleeding, and 2) lower the intensity of the anticoagulant effect. In patients with a high INR without clinically evident bleeding, cessation of warfarin, careful observation, and periodic monitoring is the safest course.4 With clinically significant bleeding, however, reversal may be required, but the speed and extent of reversal must be balanced against the risk of recurrent thromboembolism in patients who require therapeutic anticoagulation. For example, an over-anticoagulated patient with a prosthetic mitral valve may develop fatal thrombosis if rapidly and fully reversed. Three approaches can be taken to reverse warfarin-induced coagulopathy. The first is to stop warfarin therapy; the second is to administer vitamin K1 (PO, SC, or IV); the third is to administer fresh-frozen plasma (FFP) or prothrombin concentrate (see Table 224-3). One mg of oral vitamin K1 decreases the INR faster than 1 mg of subcutaneous vitamin K1 in asymptomatic patients with elevated INR values while receiving warfarin. To reduce the risk of hemorrhage, 1 mg of oral vitamin K1 should be considered for asymptomatic patients who are receiving warfarin and who present with an INR of 4.5 to 9.5 Reversal is significant by 16 h, and the INR is within the therapeutic range by the second day. While subcutaneous vitamin K1 (1 to 2 mg) reverses warfarin, with a measurable effect on the INR usually by 8 to 12 h, the response may be less predictable and delayed when compared to oral administration. At least some normal liver function is required for vitamin K1 to be effective and to reverse the coagulopathy associated with warfarin. Low-dose oral and subcutaneous vitamin K1 carry a small risk for patients who require therapeutic anticoagulation, and it is recommended that the emergency physician consult an appropriate specialist before using either approach. Table 224-3 Emergency Treatment of Bleeding Complications of Antithrombotic Therapy
Agent
Management
Warfarin INR <5.0 without clinically evident bleeding INR 5–9 and no significant bleeding
Cessation of warfarin administration and observation with serial PT/INR Hold warfarin, may resume at lower dose once INR therapeutic Oral vitamin K1 1–2 mg if patient at increased bleeding risk
INR >9 and no significant bleeding
Hold warfarin and monitor INR frequently Oral vitamin K1 2–4 mg
INR >20 or clinically significant bleeding (major or life-threatening)
FFP: 10–15 mL/kg to acutely restore coagulation factors to
30% of normal
Vitamin K1: 5–10 mg slow IV infusion Vitamin K1 therapy requires 12–24 h for full effect and may require >1 treatment Vitamin K1 may induce unwanted thrombosis and/or overcorrection
Heparin Clinically significant/bleeding
Immediate cessation of heparin administration Supratherapeutic aPTT not always present Anticoagulation effect lasts up to 3 h from last dose
Minor bleeding
Observation with serial aPTT may be sufficient
Major bleeding
Protamine: 1 mg per 100 units of heparin, given slowly IV over 1–3 min to a maximum of 50 mg over any 10-min period
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thromboembolism Protamine may need to be repeated Protamine has anaphylaxis risk Protamine does not reverse LMWH (e.g., enoxaparin) Aspirin and NSAID Clinically significant bleeding: correlates poorly with BT Other Antiplatelet Agents
Cessation of aspirin or NSAID administration
Platelet transfusion to increase count by 50,000 (typically requires at least 6 units of random donor platelets) Aspirin inhibition lasts for life of affected platelets so repeat platelet transfusions sometimes required NSAID platelet inhibition typically lasts less than 1 day
Fibrinolytics Minor external bleeding
Manual pressure
Significant internal bleeding
Immediate cessation of fibrinolytic agent, antiplatelet agent, and/or heparin Reversal of heparin with protamine as above Typed and cross-matched blood ordered with verification of aPTT, CBC, TCT, and fibrinogen level Volume replacement with crystalloid and PRBC as needed
Massive bleeding with hemodynamic compromise
All measures listed for significant internal bleeding, above Cryoprecipitate: 10 units and recheck fibrinogen level If fibrinogen level <100 mg/dL, repeat cryoprecipitate If bleeding remains after cryoprecipitate or despite fibrinogen level >100 mg/dL: administer 2 units of FFP If bleeding continues after FFP: check BT If BT <9 min: give -aminocaproic acid 5 g IV over 60 min, then 1 g/h infusion for 8 h or until bleeding stops or tranexamic acid 10 mg/kg q6–8h If BT >9 min: give -aminocaproic acid or tranexamic acid as above with 10 units of random donor platelets
Intracranial hemorrhage
All measures listed for significant internal and massive bleeding Immediate neurosurgery consultation.
Abbreviations: aPPT = activated partial thromboplastin time; BT = bleeding time; CBC = complete blood count; INR = international normalized ratio; LMWH = low-molecular-weight heparin; FFP = fresh-frozen plasma; NSAID = nonsteroidal antiinflammatory drug; PRBC = packed red cells; PT = prothrombin time; TCT = thrombin clotting time. Intravenous vitamin K1 carries a rare but serious, non-dose-dependent risk of anaphylaxis, and should not be used for routine reversal of therapeutic over-anticoagulation. For patients who require continued anticoagulation, intravenous administration carries the risk of overcorrection not associated with oral or subcutaneous use. Intravenous vitamin K1 should be restricted to those patients with life-threatening bleeding or with an INR >20, and for symptomatic patients poisoned by an ingestion of warfarin (suicidal overdose) or a rodenticide (brodifacoum). Generally, such patients do not require therapeutic anticoagulation, and reversal does not carry the risk of recurrent thrombosis. Because of the long half-life of these superwarfarin rodenticides, significantly poisoned patients may require treatment with high doses of vitamin K1, up to 125 mg/d, for several weeks. From the standpoint of the risk of recurrent thrombosis, the safest method of reversing therapeutic over-anticoagulation is with coagulation factor infusion using either FFP or factor concentrates. A dose of FFP 10 to 15 mL/kg (typically 3 to 4 units) will acutely restore coagulation factor levels to at least 30 percent of normal in most adults, and will control most bleeding without undue risk. Reversal of anticoagulation with FFP is usually safe for short periods, regardless of indication for anticoagulant therapy.6 For patients with life-threatening hemorrhage and who require rapid, complete reversal, coagulation factor concentrates are more reliable and preferred.7 Heparin Pharmacology of Unfractionated Heparin Unfractionated heparin (UFH) is a heterogeneous mixture of polysaccharides ranging in molecular weight from 2000 to 40,000 Da. The anticoagulant effect of UFH requires binding to antithrombin III (ATIII). The heparin-ATIII complex is capable of inhibiting multiple steps in the extrinsic and common coagulation pathways, including factors Xa, IXa, XIa, and XIIa, and thrombin (factor IIa). UFH inhibition of thrombin is dependent upon saccharide chain length, with shorter chain lengths (<18 saccharide units) possessing greater anti-Xa activity and longer chain lengths having greater antithrombin activity. These wide variations in chain lengths in UFH likely contribute to the unpredictable nature of its dose-response relationship. UFH must be given parenterally (IV or SC). Its half-life (30 to 150 min) depends on the dose and route. Weight-based intravenous heparin-dosing protocols are the most reliable approach for achieving a therapeutic effect and preventing further thrombosis during acute thromboembolic events. The subcutaneous method is not recommended for the treatment of acute thromboembolic disease because the bioavailability of subcutaneous UFH ranges from 10 to 90 percent, depending on the dose. However, subcutaneous UFH can be used to prevent thromboembolism with a 60 to 70 percent risk reduction for DVT and fatal PE (see Table 224-1). Because UFH interferes with most laboratory investigations for hypercoagulable states, these tests should ideally be ordered before the patient is anticoagulated. Neither UFH nor low-molecular-weight heparin (LMWH) crosses the placenta; consequently, both are safe to use in pregnancy. Despite extensive use in clinical practice over several decades, UFH continues to possess several important limitations. UFH has an unpredictable anticoagulation effect, requires frequent monitoring, and is inactivated by plasma proteins and platelet factor-4 (PF4). The unpredictable inhibition of thrombin by UFH is attributable to a low bioavailability from extensive nonspecific binding to serum proteins,
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thromboembolism macrophages, and endothelial cells. The anticoagulant effect of heparin can be monitored with the activated partial thromboplastin time (aPTT), which is widely available from clinical laboratories (see Table 224-1).8 There is not a linear relationship between heparin concentration, the anticoagulant activity of heparin (as measured by its antifactor Xa activity), and the aPTT. For most purposes, a therapeutic range for heparin can be either an aPTT of 1.5 to 2.5 the "normal" value, a heparin level of 0.2 to 0.4 U/mL when assayed by protamine titration, or 0.3 to 0.7 U/mL when assayed for anti-Xa activity.8 UFH can increase the PT and INR by a variable amount, depending on the heparin concentration and the thromboplastin reagent used in the assay. Typically, therapeutic concentrations of heparin increase the PT by approximately 1 to 5 s. Pharmacology of Low-Molecular-Weight Heparin Fraction The LMWH has made a significant contribution to the advancement of anticoagulation therapy. Both UFH and LMWH exert their anticoagulant effect by activating ATIII.9 Their interaction with ATIII is mediated by a unique pentasaccharide sequence that is randomly distributed along the heparin chains. When ATIII interacts with the pentasaccharide sequence on the heparin molecule, it undergoes a conformational change that allows it to bind thrombin 1000 times faster. This coupling with thrombin requires an additional 13-saccharide group that brings the key binding regions of ATIII and thrombin into contact. However, only the specific pentasaccharide sequence is necessary to bind to ATIII for effective inhibition of factor Xa. UFH binds factor Xa and thrombin in roughly equal proportions (anti-Xa: anti-IIa ratio = 1.0) because chains of at least 18 residues predominate. In contrast, LMWH are manufactured from UFH through depolymerization using either a chemical or an enzymatic process. This results in a smaller molecule (4000 to 5000 Da) with less than half containing the required 13-saccharide residues to bind ATIII and thrombin. The shorter chains results in a reduced ability to inactivate thrombin and enhanced affinity for inactivating factor Xa. There are many clinical advantages associated with the use of LMWH (Table 224-4). The plasma half-life of LMWH is two to four times as long as UFH, allowing for once- or twice-daily dosing. LMWH has a decreased binding to plasma proteins, endothelial cells, and macrophages, thus yielding a more predictable anticoagulant and dose-response relationship. This allows for subcutaneous administration of fixed dosages. Laboratory monitoring of these agents is generally unnecessary except in patients with renal insufficiency and obesity. LMWH is cleared by the kidneys, and toxicity can occur in patients with significant renal impairment. LMWH therapy may be monitored by anti-Xa activity.10 Anti-Xa activity and half-life is prolonged with decreasing renal function, resulting in a higher tendency for hemorrhagic complications. Because of the lack of clear dosing guidelines, these agents should be dosed with caution in patients with renal impairment. LMWH dosing in obese patients has not been specifically addressed in large clinical trials. Safety data in the obese population are thus derived from studies in the ACS population.11 In these trials, LMWH dosing was based on total body weight up to a maximum of 160 kg. In patients over 160 kg, the use of anti-Xa activity should be considered. Table 224-4 Advantages of LMWH Over Unfractionated Heparin
Pharmacologic Effects
Clinical Benefit
Quick and predictable SC absorption
More reliable level of anticoagulation
More stable dose response
Eliminates need for monitoring
Resistance to inhibition by PF4
Decreased incidence of thrombocytopenia
Decreased antiheparin antibody production by 70% Greater antithrombotic effects Greater anti-Xa activity
Potential to reduce bleeding
Less antithrombin activity
Absence of "rebound"
Ease of administration
Outpatient therapy
Abbreviations: LMWH = low-molecular-weight heparin; PF4= platelet factor-4. Enoxaparin, dalteparin, and ardeparin are the most widely available of the LMWH products. Current indications for LMWH use are treatment of DVT, PE, unstable angina, and AMI. Only enoxaparin is approved for outpatient management of DVT. Although acquisition costs of LMWH are higher than for UFH, formal studies of cost-effectiveness suggest that LMWH use pays for itself, and may ultimately be cost-saving. This cost benefit can be magnified if patients with DVT are treated primarily in the outpatient setting. Complications and Management Unfractionated Heparin The two major complications of UFH are major bleeding episodes and HIT. Up to one-third of patients receiving heparin develop some form of bleeding complication, with a 2 to 6 percent risk for major bleeding. An increased risk (up to 20 percent) for major bleeding is associated with a number of comorbid conditions, including recent surgery or trauma, renal failure, alcoholism, malignancy, liver failure, and gastrointestinal bleeding, as well as the concurrent use of warfarin, fibrinolytics, steroids, or antiplatelet drugs. Bleeding in patients being treated with UFH is treated according to the clinical severity and aPTT level.12 Unfortunately, heparinassociated bleeding is not always reflected by a supratherapeutic aPTT. If bleeding develops during UFH therapy, UFH administration should be stopped immediately. While UFH half-life is dose dependent (30 to 150 min), its anticoagulation effect can last up to 3 h. Thus, observation may be appropriate in less-severe cases, with serial aPTT used to determine when therapy may be resumed. While protamine can reverse the anticoagulant effect of UFH (a ratio of 1 mg intravenous protamine neutralizes 100 units of UFH administered in the prior 4 h), the adverse effects of protamine are significant. Protamine should be given slowly intravenously over 1 to 3 min and should not exceed 50 mg in any 10-min period. However, because the half-life of protamine is short, a heparin rebound may occur, requiring a second treatment. Allergic reactions are possible, and approximately 0.2 percent of patients receiving protamine develop anaphylaxis, which has a 30 percent mortality rate. Thus, protamine should be reserved for major bleeding complications. There are two types of HIT: type I and type II. HIT type I is the more common type, and is caused by UFH-induced direct platelet aggregation. It occurs early (1 to 5 days) and is usually transient and benign. HIT type II is caused by IgG or IgM autoantibody formation directed against both heparin and PF4. Thus platelet activation occurs, producing both thrombocytopenia and a tendency for thrombosis. Thrombosis may involve the skin (similar to warfarin-induced cutaneous necrosis), major arteries (e.g., ischemic limbs), or the veins (e.g., recurrent DVT or PE). The onset of HIT type II is usually 5 to 12 days after UFH treatment is started, but may be sooner for patients who developed the antibody from a previous exposure. Overall, the incidence of HIT type II is between 1 and 3 percent in patients treated with UFH, but is significantly less in patients treated with LMWH products. The platelet count nadir is often modest, typically 20,000 to 150,000/ L. However, a drop of 50 percent from baseline is concerning, even if the platelet count is normal. It is important to assess for recent use of UFH or LMWH before instituting therapy for a new DVT that may in fact be a thrombotic complication of HIT.
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thromboembolism In HIT type II, UFH therapy must be stopped as soon as the condition is recognized. Protamine is not effective against the immune-mediated response. The platelet count generally returns to normal in 4 to 6 days. During the recovery phase, however, the risk of arterial or venous thrombosis is substantially elevated, and the potential complications include gangrene, stroke, and death. It is unclear whether such patients should ever be exposed to UFH again. Thrombocytopenia appears to be less common with porcine UFH than with bovine UFH. LMWH are not recommended for use in treating HIT because of cross-reactivity between LMWH and the antiplatelet antibody. Additionally, warfarin should not be started until the patient is sufficiently anticoagulated by an alternative measure to avoid precipitating arterial or venous thrombosis or producing skin necrosis. Prophylactic transfusion of platelets is not indicated because bleeding is not usually a manifestation of HIT type II, and platelet transfusion may precipitate thrombosis. Anticoagulation with a DTI should be considered in patients with clinically suspected HIT type II, even in the absence of symptomatic thrombosis. Low-Molecular-Weight Heparins In general, LMWH preparations cause less bleeding than does UFH. Reported side effects of LMWH include bleeding, HIT, local skin reaction, pruritus, and rare skin necrosis. Protamine will neutralize the antithrombin effect of LMWH, but incompletely reverses factor Xa inhibition. In the event of bleeding, 1 mg of protamine can neutralize 1 mg of enoxaparin and 100 units of dalteparin. The use of FFP and packed red blood cells should be considered in patients with ongoing or life-threatening bleeding. Hirudin and Analogues Pharmacology of Hirudin and Hirudin Analogues Direct thrombin inhibitors (DTIs), hirudin and hirudin analogues, have several potential advantages over heparin. Unlike heparin, DTIs are capable of inhibiting both circulating and clot bound thrombin, do not inhibit other coagulation pathway or fibrinolytic enzymes, do not require ATIII as a cofactor, and are not inactivated by PF4 or plasma proteins. Therefore, DTIs have a more predictable anticoagulant effect than UFH. Hirudin is a 65-amino-acid polypeptide, originally derived from the salivary gland of the medicinal leech Hirudo medicinalis. It is now prepared by recombinant technology. Recombinant hirudin has been modified into a number of available analogues. Currently, hirudin, lepirudin, and argatroban are currently FDA-approved for anticoagulation in patients with HIT. In the setting of AMI, unstable angina, or primary coronary intervention (PCI), hirudin reduced the incidence of death and reinfarction at 24 h, but not at 30 days postadmission. Although there were no significant differences in the incidence of serious or life-threatening hemorrhagic complications, hirudin was associated with a higher incidence of moderate bleeding.13 Currently, hirudin is approved only for patients with history of or at risk for HIT. Synthetic analogues of hirudin are currently being studied as alternatives to heparin for the treatment of unstable angina, post-PCI use, postsurgical DVT prevention, and as an adjunct to fibrinolytic therapy. Currently, bivalirudin and argatroban are approved for use in the catheterization laboratory as an anticoagulant during PCI. In addition to hirudin, lepirudin and argatroban are used for antithrombotic treatment in patients with HIT. Complications and Management The primary adverse effect of DTIs is bleeding and the majority of bleeding events occur at invasive sites. Because the half-life of hirudin and its analogues is relatively short (<2 h), and an antidote is not currently available, management of DTI-related hemorrhage may require only stopping the intravenous infusion and waiting, with coagulation factor replacement using FFP or prothrombin concentrates if bleeding persists. Antiplatelet Agents Aspirin and NSAIDs Pharmacology Aspirin irreversibly blocks cyclooxygenase, an enzyme that in the platelet catalyzes the conversion of arachidonic acid to thromboxane A2, and in the blood vessel wall promotes prostacyclin synthesis. The net effect of aspirin in ischemic arterial beds depends on the balance between thromboxane A2, a potent vasoconstrictor and platelet-aggregation agent, and prostacyclin, a vasodilator and platelet-aggregation inhibitor. An antithrombotic effect can be seen with doses as low as 30 mg. Because prostacyclin synthesis is stimulated at lower aspirin levels than is thromboxane A2 conversion, treatment plans often use low-dose strategies (e.g., 81 to 162 mg/d). For more rapid antiplatelet effect, a medium or higher initial dose (e.g., 162 to 325 mg) is indicated (see Table 224-1). Aspirin is quickly absorbed in the upper gastrointestinal tract, reaches peak blood concentrations in 15 to 20 min, and circulates with a half-life of 30 to 60 min. However, its antiplatelet effect is irreversible and lasts for the life span of the platelet (about 10 days). Side effects of aspirin use are mainly gastrointestinal and dose related, and may be reduced with concomitant use of antacids, enteric coating, and buffering agents. Aspirin should be avoided in patients with known hypersensitivity and used cautiously in those with bleeding disorders or severe hepatic disease. Active gastrointestinal hemorrhage (e.g., bleeding peptic ulcer) is a contraindication to aspirin use. However, in AMI and unstable angina with occult gastrointestinal bleeding (e.g., guaiac-positive stool), most experts favor aspirin use with careful monitoring. Non–enteric-coated aspirn should be considered when prompt onset of action is necessary, as in patients with ongoing chest pain. Aspirin therapy is also associated with a slightly increased risk of hemorrhagic stroke (12 per 10,000 over 3 years), but this risk is balanced by a tenfold reduction in the risk of myocardial infarction and a threefold reduction in the risk of ischemic stroke.14 Nonsteroidal anti-inflammatory agents reversibly inhibit platelet cyclooxygenase and inhibition of platelet aggregation usually lasts less than 24 h. The exception is piroxicam, which has a 2-day half-life. Complications and Management Upper gastrointestinal irritation is the most common side effect of aspirin therapy, while life-threatening gastrointestinal bleeding is uncommon.15 As noted earlier, intracranial hemorrhage, the most feared complication of anticoagulation and antithrombotic therapy, appears to occur rarely with aspirin alone.14 Some patients are markedly sensitive to aspirin, such that even low doses lead to markedly prolonged bleeding times and risk of severe clinical hemorrhage, particularly related to surgery or trauma. Uremic patients are especially sensitive to bleeding induced by aspirin. The combination of alcohol and aspirin can also prolong a patient's bleeding time (BT). Unfortunately, the BT is a poor test to confirm bleeding complications of aspirin. If aspirin-associated bleeding is suspected [e.g.,
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thromboembolism persistent oozing after tooth extraction despite normal platelet count (>100,000/ L) and coagulation studies], further workup should include obtaining a careful history for ingestion (significant unintentional ingestion may occur because some 300 over-the-counter medications contain aspirin), and confirmed with a salicylate level if needed. Management of acute aspirin-induced or NSAID-induced hemorrhage involves the transfusion of enough normal platelets to increase the platelet count by 50,000/ L. Because of the irreversible effect of aspirin on platelets, the hemostatic compromise might last for 4 to 5 days after aspirin has been discontinued, and platelet transfusions may have to be repeated daily, whereas NSAID-induced platelet dysfunction typically resolves within 1 day after halting use. Clopidogrel and Ticlopidine Pharmacology of Platelet Membrane Altering Agents During platelet aggregation, fibrinogen forms a bridge between adjacent platelets by binding to the glycoprotein platelet-surface receptor, labeled IIb-IIIa. A variety of agents that interfere with the platelet membrane and the glycoprotein (GP) IIb-IIIa receptor have been introduced into clinical practice during the past few years. Clopidogrel and ticlopidine selectively inhibit platelet aggregation induced by adenosine diphosphate (ADP). Specifically, they appear to irreversibly inhibit the binding of ADP to the receptor mediating inhibition of platelet adenylate cyclase, thereby deforming the region of the platelet membrane next to its fibrinogen receptor and rendering it ineffective. Clopidogrel has been approved for the treatment of unstable angina, NSTEMI, secondary prevention of AMI and CVA, and in established peripheral artery disease.16 Although clopidogrel is generally well tolerated, side effects include dyspepsia, rash, and diarrhea. Ticlopidine is associated with hematologic problems, such as neutropenia, idiopathic thrombocytopenic purpura, and, rarely, thrombotic thrombocytopenic purpura (TTP). Ticlopidinerelated TTP occurs most often during the first 2 weeks of therapy. Clopidogrel should be considered for administration in hospitalized patients with NSTEMI or unstable angina who have a history of ASA hypersensitivity or major gastrointestinal intolerance. Complications and Management TTP has rarely been reported, even after as little as 2 weeks of exposure. If quick reversal of pharmacologic effects is needed, platelet transfusion should be considered. Abciximab, Eptifibatide, and Tirofiban Pharmacology of Glycoprotein IIb-IIIa Receptor Inhibitors Damaged platelets activate several receptor sites, most notably the GP IIb-IIIa receptors. Once activated, a single fibrinogen molecule is capable of binding two GP IIb-IIIa receptor sites on adjacent platelets. Thus, GP IIb-IIIa receptors represent the final common pathway for platelet activation and aggregation. Three parenteral GP IIb-IIIa receptor inhibitors are currently available for the treatment of unstable angina, NSTEMI, and high-risk patients undergoing PCI. Abciximab (a monoclonal antibody), eptifibatide (a synthetic peptide), and tirofiban (a nonsynthetic peptide) inhibit platelet aggregation, prevent thrombosis, and may augment thrombolysis. These agents are administered as an initial loading-dose bolus for abciximab and eptifibatide, and as a 30-min infusion for tirofiban, followed by a constant intravenous infusion. Abciximab is a noncompetitive GP IIb-IIIa inhibitor with a much longer platelet effect than its plasma half-life of 10 min; platelet function will return to normal within 48 h after discontinuing the infusion. Eptifibatide is a competitive GP IIb-IIIa inhibitor with a plasma half-life of approximately 2.5 h. Tirofiban is also a competitive GP IIa-IIIb inhibitor with a plasma half-life of approximately 2 h. Platelet functional recovery after stopping either eptifibatide or tirofiban infusion is seen in 3 to 5 h. Improved outcome has been demonstrated in high risk unstable angina and NSTEMI patients with GP IIb-IIIa blockade who undergo PCI.17 Glycoprotein IIb-IIIa antagonists are recommended for such patients when catheterization and PCI are planned.18 Although a "time-dependent benefit window" for GP IIb-IIIa therapy has not been clearly established for unstable angina or NSTEMI, in patients undergoing PCI, a time-to-treatment benefit has been demonstrated with prompt initiation of eptifibatide and in the ED setting. The 2002 American College of Cardiologists (ACC)/American Heart Association (AHA) Guidelines state that the GP IIb-IIIa agent may "also be administered just prior to PCI."18 In institutions with ready access to a catheterization laboratory, emergency physicians can expedite definitive management by initiating aggressive medical therapy in consultation with interventional cardiologists. In institutions without an on-site catheterization laboratory, emergency physicians should initiate medical therapy and transfer arrangements in collaboration with the accepting interventional cardiologist. In patients not undergoing PCI, GP IIb-IIIa antagonists are appropriate for high-risk patients, but are not recommended for low-risk patient groups.18 Complications and Management Patients receiving GP IIb-IIIa inhibitors have increased risk for bleeding complications (particularly if heparin is also used and usually related to catheterization or coronary artery bypass surgery) but have no increased risk of intracranial hemorrhage. Treatment of major hemorrhage in patients on GP IIb-IIIa inhibitors requires red cell and platelet transfusions, and replacement of coagulation factors as needed. Fibrinolytics Although mechanisms vary, each fibrinolytic agent eventually converts plasminogen to plasmin, which then enzymatically breaks apart the fibrin component of thrombi. Currently approved fibrinolytic agents include streptokinase, anistreplase, alteplase, reteplase, and tenecteplase. Streptokinase and Anistreplase (First Generation) Streptokinase (SK), derived from -hemolytic streptococci, binds to and activates circulating plasminogen, converting it to plasmin, which in turn attacks fibrin, leading to thrombus dissolution. Circulating fibrinogen also undergoes plasmin-induced lysis, producing a state of "systemic fibrinolysis." SK is administered as a slow infusion (usually 1.0 to 1.5 million U IV over 60 min) and has a serum half-life of approximately 23 min, but in most patients systemic effects persist for up to 24 h. Because of the prolonged fibrinolytic state and increased risk of hemorrhage, anticoagulation with heparin is usually delayed following treatment with SK. Anistreplase, a modified active plasminogen-streptokinase complex, has an effect similar to that of SK, but its chief advantage is that it can be administered as a slow bolus (usually 30 mg IV over 5 min) and has a serum half-life of approximately 90 min. Anistreplase has similar benefits and adverse effects compared to SK. Both SK and anistreplase are antigenic, and allergic reactions occur in approximately 6 percent of patients treated with SK and subcutaneous heparin. Antibodies to SK develop approximately 5 days after treatment and persist for 6 months; retreatment
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thromboembolism with SK or anistreplase is not advised during this interval. In addition, SK or anistreplase should not be administered within 12 months of a streptococcal infection. Alteplase or Tissue Plasminogen Activator (Second Generation) Alteplase or tissue plasminogen activator (tPA) is a naturally occurring enzyme in vascular endothelial cells that directly cleaves a specific peptide bond in plasminogen, converting it to active plasmin, with subsequent fibrinolysis. Alteplase has binding sites for fibrin, which would suggest specificity for activity in the thrombus and less systemic fibrinolysis. Despite the in vitro clot specificity of alteplase, its clinical side-effect profile is comparable to that of other fibrinolytics. The serum half-life of alteplase is less than 5 min, and it produces a shorter fibrinolytic state than does SK. Heparin is commonly administered shortly after the completion of alteplase infusion. Unlike SK and anistreplase, alteplase is not antigenic; allergic reactions occur in fewer than 2 percent of patients treated with alteplase and intravenous heparin. Depending on the indication, alteplase is given as a weight-based dose via an intravenous infusion over 60 to 90 min. Reteplase and Tenecteplase (Third Generation) Both reteplase and tenecteplase (TNK) were created from modifications of the parent alteplase molecule, with the intent of improving both efficacy and safety. Reteplase is a deletion mutant of tPA in which the fibronectin finger (high-affinity fibrin binding), epidermal growth factor (EGF), and kringle-1 (receptor binding) regions of the wild-type tPA molecule have been deleted. These modifications prolong the half-life of reteplase to 18 min, nearly fourfold longer than alteplase, allowing for bolus administration of reteplase as opposed to infusion administration of alteplase. The double-bolus reteplase regimen results in superior coronary blood flow compared to the accelerated alteplase regimen, although mortality rates are similar. TNK resulted from creating amino acid substitutions in four different regions of the tPA molecule, with the intention of producing a molecule with an extended half-life, higher level of fibrin specificity, and superior potency. The long half-life of TNK (approximately 20 min) allows for single-weight tiered bolus dosing over 5 to 10 s. The specific amino acid substitutions also resulted in a molecule with 14fold greater fibrin specificity than alteplase in an effort to reduce systemic plasmin generation. Point mutations in the TNK molecule have resulted in plasminogen activator inhibitor-1 resistance 80 times greater than alteplase, thus allowing for longer association of TNK with the fibrin-rich clot. In addition, no increase in thrombin–antithrombin complex was seen following administration of TNK, in contrast to a fourfold increase following administration of streptokinase and a twofold increase after administration of alteplase.17 Despite theoretical advantages associated with genetic modification, neither reteplase nor tenecteplase demonstrate an absolute mortality benefit in AMI. However, bolus-dose fibrinolytics result in significantly fewer medication errors, when compared to more complicated regimens.19 Indications for Fibrinolytic Therapy Acute Myocardial Infarction The National Heart, Lung, and Blood Institute has established the principle that routine STEMI patients should receive emergency reperfusion therapy, either fibrinolytic therapy initiated within 30 min or PCI within 90 min after arrival in the emergency department. There are four general criteria for emergent fibrinolytic therapy in AMI: 1) clinical presentation consistent with AMI within 12 h of symptom onset; 2) an electrocardiogram showing ST-segment elevation in two or more contiguous leads or new-onset left bundle-branch block; 3) absence of contraindications (Table 224-5); and 4) absence of cardiogenic shock. PCI, if available within 60 to 90 min of presentation, is preferred over peripheral fibrinolytic therapy for AMI with cardiogenic shock. Important additional considerations, however, include patient age, location of the infarct, relative contraindications to fibrinolysis, and duration of symptoms within the 12-h criterion. Table 224-5 Contraindications to Fibrinolytic Therapy
Absolute Active or recent internal bleeding ( 14 d) CVA <2–6 months or hemorrhagic CVA Intracranial or intraspinal surgery or trauma <2 months Intracranial or intraspinal neoplasm, aneurysm, or arteriovenous malformation Known severe bleeding diathesis On anticoagulants (warfarin with PT >15 s, heparin with increased aPTT) Uncontrolled hypertension (i.e., blood pressure >185/100 mm Hg) Suspected aortic dissection or pericarditis Pregnancy Relative* Active peptic ulcer disease Cardiopulmonary resuscitation >10 min Hemorrhagic ophthalmic conditions Puncture of noncompressible vessel <10 d Advanced age >75 years Significant trauma or major surgery >2 weeks and <2 months Advanced kidney or liver disease
*Concurrent menses is not a contraindication. Abbreviations: aPTT = activated partial thromboplastin time; CVA = cerebrovascular accident; PT = prothrombin time. Patients who do not meet all four eligibility criteria (e.g., because symptoms have been present for >12 h or relative contraindications to fibrinolytic therapy are present) may still derive benefit from fibrinolytic therapy provided that no absolute
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thromboembolism contraindications are present and the differential diagnosis does not include disorders in which fibrinolytic therapy is harmful (e.g., aortic dissection). Under such circumstances, consultation with the physician who will assume continued definitive care of the patient (e.g., a cardiologist or internist) is reasonable and appropriate before initiating fibrinolysis. The rapid administration of fibrinolytic therapy is of greater importance than the specific agent used. Bolus-dose fibrinolytics have the added benefit of reducing medical errors. However, despite early studies that demonstrated improvement in patient survival, recent trials investigating newer fibrinolytic agents have not achieved significant improvement in 30-day mortality and stroke rates. Defining additional mortality benefit is the subject of much debate. Most clinicians in the United States accept a 1 percent absolute difference as clinically relevant; the level of benefit found favoring alteplase versus SK. Fibrinolytic studies underscore the important relationship between restoration of normal coronary flow and survival benefit. However, an additional 1 percent mortality benefit would require near-normal coronary blood flow [Thrombolysis in Myocardial Infarction (TIMI)-3 grade] rates after fibrinolytic therapy to approach 80 percent. Most new fibrinolytic agents are only capable of generating TIMI-3 flow rates of approximately 60 to 70 percent, suggesting that additional mortality reduction is unlikely with fibrinolytics alone. Prehospital fibrinolytic administration has a sound theoretical basis, given the critical relation between time to successful reperfusion and outcomes. Nonrandomized trials comparing prehospital administration of reteplase to hospital administration for STEMI have found the prehospital group is more likely to receive their first bolus within 30 min and achieve complete ST-segment resolution sooner.20 Although such studies have been underpowered to determine a mortality benefit, there is a trend for lower mortality at 7 days or hospital discharge favoring prehospital fibrinolytic therapy. A prehospital strategy of electrocardiography, confirmation of fibrinolytic eligibility and administration of bolus-dose lytic appears feasible in accelerating the time to reperfusion in patients with STEMI. Although prehospital fibrinolytic therapy for AMI remains investigational, in rural and remote communities, such therapy seems medically reasonable when excessive delays (>30 min) until arrival at the hospital may occur. Deep Venous Thrombosis or Pulmonary Embolism Although DVT and PE are a continuum of one disease, venous thromboembolism (VTE), management options are discussed separately. Therapy for VTE should start with an agent that has immediate anticoagulant effect (either UFH or LMWH) and it should be given at adequate dosage. Failure to reach the prescribed intensity of anticoagulation in the first 24 h of treatment is correlated with an increased risk of VTE recurrence during the next 3 months. DVT In a patient with DVT, the goals of therapy are the prevention of pulmonary embolism and the restoration of venous patency and valvular function in order to prevent the postphlebitic syndrome. Anticoagulation, with the dose adjusted for body weight, using intravenous UFH with aPTT monitoring or subcutaneous LMWH, are both suitable options. LMWH preparations are as safe and as effective as standard heparin for the treatment of acute DVT, with a lower incidence of bleeding complications. Alternatively, recent well-controlled studies demonstrated that selected patients with DVT may safely and effectively be treated entirely at home or after a brief hospitalization. Therapeutic anticoagulation with either agent along with initiation of a vitamin K antagonist (e.g., warfarin) on the first day of treatment is standard practice. The INR should be therapeutic (target INR 2.0 to 3.0) for 2 consecutive days before the discontinuation of the UFH or LMWH. The duration of warfarin therapy following an acute DVT is typically 3 months. The risks and benefits of fibrinolytic therapy in DVT remain uncertain. Systemic fibrinolytic therapy for DVT has shown some promise in reducing the incidence and morbidity of postphlebitic syndrome. Catheter-directed fibrinolysis has also shown some promise in the hands of highly skilled interventional radiologists. Controlled trials are lacking, and thus no formal guidelines exist regarding the use of fibrinolytic agents when treating patients with DVT. PE Antithrombotic drugs, mechanical devices, and fibrinolytics are all used to some extent in treating this life-threatening condition. The goals of treatment are to prevent death from the embolus and to prevent any further recurrence. Occasionally, empiric therapy may be initiated based on clinical suspicion alone before diagnostic testing. Both UFH as well as LMWH are indicated for the treatment of pulmonary embolism. A number of studies have found that LMWH is at least as effective and as safe as UFH in the treatment of PE. As with DVT, recent studies suggest that outpatient treatment of PE in a highly selective patient population is possible. Regardless of which heparin product is used, timely administration and adequate dosing are essential to good patient outcomes. Provided the patient is hemodynamically stable, adequate anticoagulation with UFH or LMWH, along with a vitamin K antagonist (e.g., warfarin), initiated during the first 24 h is standard practice. Warfarin is continued for a minimum of 3 months. The total duration of therapy is dependent upon the etiology of the thrombus. Thrombolytic agents provide a more rapid lysis of pulmonary emboli and reduction of pulmonary hypertension than heparin.21 Whether or not these advantages result in improved clinical outcomes and outweigh the increased risk of bleeding complications is controversial. No conclusive clinical outcome studies aimed at comparing thrombolysis with standard treatment in patients with pulmonary embolism are available. A recent meta-analysis concluded that in patients with pulmonary embolism, thrombolysis had a lower composite end point of death/reoccurrence than did heparin treatment.21 However, the risk of intracerebral hemorrhage and other serious bleeding complications were significantly higher in patients treated with thrombolytic therapy. Other opinions suggest that there was no evidence that thrombolytic therapy decreases the mortality or the rate of reoccurrence of PE.22 Advocates for the more liberal use of thrombolytic therapy suggest that in the presence of right ventricular strain as evidenced by echocardiography, patients may achieve better outcomes. As published in the American College of Chest Physicians (ACCP) guidelines, the use of thrombolytic agents in treating VTE is highly individualized.23 However, most authorities agree that thrombolytic therapy may play a role in patients with massive PE complicated by hemodynamic collapse. Currently approved fibrinolytic agents for PE include alteplase, streptokinase, and urokinase. The antigenicity and high incidence of bleeding complications associated with the 24-h infusion of SK make it a less-attractive alternative. Full anticoagulation with UFH or LMWH is not a contraindication to fibrinolysis for PE. Vena cava filter devices are indicated for patients with contraindications to anticoagulation therapy, patients who have failed anticoagulation therapy, and patients who are at high risk of mortality from recurrent pulmonary embolism. There are a number of different devices available and most are placed percutaneously. Complications include filter migration, thrombosis, and perforation of the inferior vena cava. Anticoagulation therapy is recommended whenever possible as an adjunctive therapy with filters to help prevent thrombosis of the filter and further DVT. Ischemic Stroke
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thromboembolism The use of fibrinolytics for acute ischemic stroke to restore cerebral blood flow and to improve neurologic outcome is controversial. Only alteplase has been shown to benefit carefully selected patients with acute ischemic stroke if given within 3 h of the onset of stroke symptoms. The benefit was greater if alteplase was given within 90 min from stroke onset as measured by 24-h and 3-month outcomes.24 Benefits are sustained up to 1 year in treated patients.25 Conversely, there is no reduction in mortality.25 One reason for this lack of mortality reduction is that alteplase increases the absolute risk of conversion to intracerebral hemorrhage by 6 percent, and the majority of these patients died.26 Currently, alteplase can be recommended only if the protocol used in the National Institutes of Neurological Disorders and Stroke Tissue Plasminogen Activator Stroke Trial is strictly followed. Physicians are advised to obtain informed consent from patients or their proxies in all cases. It is best to have an emergency department policy developed in cooperation with neurologists concerning the administration of alteplase for acute CVA. Contraindications to the use of alteplase for acute stroke include patients with rapidly improving neurologic signs or minor symptoms, significant pretreatment hypertension (blood pressure >185/110 mm Hg or requiring aggressive therapy to control), seizure at onset, or symptoms suggestive of subarachnoid hemorrhage. Complications and Management Compared with fibrinolytic therapy, PCI (angioplasty and/or stent placement) are the favored reperfusion strategies for high-risk patients presenting with STEMI. Unfortunately, not all patients have expeditious access to PCI. In such cases, thrombolytic therapy remains a good alternative for most patients. The most significant complications of fibrinolytic therapy are hemorrhagic, and the most catastrophic complication is intracranial hemorrhage, seen in at least 1 to 3 percent of patients.27 Fibrinolytics should not be given to any patient with an absolute contraindication (see Table 224-5). In patients with a relative contraindication, careful weighing of potential risks and benefits of fibrinolysis in consultation with the physician who will assume in-hospital care of the patient is indicated. Allergic reactions and anaphylaxis from SK and anistreplase should be treated with diphenhydramine 50 mg and methylprednisolone 125 mg IV. Hypotension occurs in up to 10 percent of patients treated with either SK or tPA, and is treated by slowing the fibrinolytic infusion rate and administering intravenous crystalloid, paying close attention to the patient's volume status. To minimize the bleeding risks associated with fibrinolytic therapy, the following precautions should be observed: 1) avoid all unnecessary needle sticks; 2) avoid any arterial punctures; 3) limit venous access to easily compressible sites (e.g., avoid central lines, especially the jugular or subclavian veins); and 4) avoid both nasogastric tubes and nasotracheal intubation. Careful monitoring of the patient is crucial. The hematocrit should be checked every 4 to 6 h after fibrinolytic therapy is initiated. A fall in hematocrit of greater than 2 percent should prompt a search for the source of blood loss. Most bleeding episodes (more than 70 percent) occur at vascular puncture sites, but intracranial, intrathoracic, retroperitoneal, gastrointestinal, genitourinary, or soft tissue extremity hemorrhage may occur. External bleeding at any site should be controlled with prolonged manual pressure. Significant bleeding, especially from an internal site, mandates discontinuation of the fibrinolytic agent, antiplatelet agent, and heparin. Volume replacement using NS or LR solution should be provided as necessary and supplemented with red blood cell transfusions if clinically indicated. The thrombin time, aPTT, platelet count, and fibrinogen level should be checked. Heparin administered within 4 h of the onset of bleeding can be reversed with protamine. Massive bleeding with hemodynamic compromise necessitates coagulation factor replacement in addition to the interventions recommended above. Ten units of cryoprecipitate (rich in fibrinogen) should be administered and the fibrinogen level rechecked. If the fibrinogen level is less than 100 mg/dL, the dose of cryoprecipitate should be repeated. If bleeding continues after cryoprecipitate or if bleeding persists despite a fibrinogen level above 100 mg/dL, 2 units of FFP should be given. If bleeding persists after appropriate cryoprecipitate and FFP treatments, a BT should be checked. If it is more than 9 min, 10 units of random donor platelets should be administered, followed by an antifibrinolytic agent (e.g., -aminocaproic acid or tranexamic acid); if the BT time is less than 9 min, platelets are unnecessary, but an antifibrinolytic agent should still be administered for continuing hemorrhage. Fibrinolytic-associated intracranial hemorrhage requires an aggressive response. Immediately discontinue the fibrinolytic agent, antiplatelet agent, and heparin. Administer protamine in the dose outlined above if the patient received heparin. The patient should also receive cryoprecipitate, FFP, platelet transfusion, and an antifibrinolytic agent (e.g., -aminocaproic acid or tranexamic acid). References 1. Ansell J, Hirsh J, Dalen J, et al: Managing oral anticoagulant therapy. Chest 119(Suppl 1):22S, 2001. 2. Crowther MA, Ginsberg JB, Kearon C, et al: A randomized trial comparing 5-mg and 10-mg warfarin loading doses. Arch Intern Med 159:46, 1999. [PMID: 9892329] 3. Hirsh J, Dalen J, Anderson DR, et al: Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest 119(Suppl 1):8S, 2001. 4. Glover JJ, Morrill GB: Conservative management of over anticoagulated patients. Chest 108:987, 1995. [PMID: 7555174] 5. Crowther MA, Douketis JD, Schnurr T, et al: Oral vitamin K lowers the international normalized ratio more rapidly than subcutaneous vitamin K in the treatment of warfarin-associated coagulopathy: A randomized controlled trial. Ann Intern Med 137:251, 2002. [PMID: 12186515] 6. Makris M, Greaves M, Phillips WS, et al: Emergency oral anticoagulant reversal: The relative efficacy of infusions of fresh frozen plasma and clotting factor concentrate on correction of the coagulopathy. Thromb Haemostat 77:477, 1997. [PMID: 9065997] 7. Levine MN, Raskob G, Landefeld S, Hirsh J: Hemorrhagic complications of anticoagulant treatment. Chest 119(Suppl 1):108S, 2001. 8. Olson JD, Arkin CF, Brandt JT, et al: College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy: Laboratory monitoring of unfractionated heparin therapy. Arch Pathol Lab Med 122:782, 1998. [PMID: 9740136] 9. Pineo GF, Hull RD: Unfractionated and low-molecular-weight heparin: Comparisons and current recommendations. Med Clin North Am 82:587, 1998. [PMID: 9646781] 10. Laposata M, Green D, Van Cott EM, et al: College of American Pathologists Conference XXXI on Laboratory Monitoring of Anticoagulant Therapy: The clinical use and laboratory monitoring of low-molecular-weight heparin, danaparoid, hirudin and related compounds, and argatroban. Arch Pathol Lab Med 122:799, 1998. [PMID: 9740137] 11. Cohen M, Antman EM, Gurfinkel EP, et al: The ESSENCE (Efficacy and Safety of Subcutaneous Enoxaparin in Non-Q-wave Coronary Events) and TIMI 11B Investigators: Enoxaparin in unstable angina/non-ST-segment elevation myocardial infarction: Treatment benefits in
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thromboembolism prespecified subgroups. J ThrombosisThrombolysis 12:199, 2001. [PMID: 11981102] 12. Hirsh J, Warkentin TE, Shaughnessy SG, et al: Heparin: Mechanism of action, pharmacokinetics, dosing considerations, monitoring, efficacy, and safety. Chest 119(1 Suppl):64S, 2001. 13. The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators: A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. New Engl J Med 335:775, 1996. 14. He J, Whelton PK, Vu B, Klag MJ: Aspirin and risk of hemorrhagic stroke: A meta-analysis of randomized controlled trials. JAMA 280:1930, 1998. [PMID: 9851479] 15. Hirsh J, Dalen JE, Fuster V, et al: Platelet-active drugs: The relationship among dose, effectiveness, and side effects. Chest 119(Suppl 1):39S, 2001. 16. The Clopidogrel in Unstable Angina to Prevent Recurrent Events (CURE) trial investigators: Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. New Engl J Med 345:494, 2001. 17. Cannon CP, Weintraub WS, Demopoulos LA, et al: Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb-IIIa inhibitor tirofiban. New Engl J Med 344:1879, 2001. [PMID: 11419424] 18. Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines for the management of patients with unstable angina and non-STsegment elevation myocardial infarction: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients with Unstable Angina). J Am Coll Cardiol 26:970, 2000. Updated March 2002, at http://www.acc.org and http://www.americanheart.org . 19. Cannon CP: Thrombolysis medication errors: Benefits of bolus thrombolytic agents. Am J Cardiol 85:17C, 2000. 20. Morrow DA, Antman EM, Sayah A, et al: Evaluation of the time saved by pre-hospital initiation of reteplase for ST-elevation MI: Results of the Early Retavase (ER-TIMI 19) Trial. J Am CollCardiol 40:71, 2002. [PMID: 12103258] 21. Agnelli G, Becattini C, Kirschstein T: Thrombolysis vs heparin in the treatment of pulmonary embolism: A clinical outcome-based meta-analysis. Arch Intern Med 162:2537, 2002. [PMID: 12456225] 22. Dalen JE: The uncertain role of thrombolytic therapy in the treatment of pulmonary embolism. Arch Intern Med 162:2521, 2002. [PMID: 12456222] 23. Hyers TM, Angelli G, Hull RD, et al: Antithrombotic therapy for venous thromboembolic disease. Chest 119(Suppl 1):176S, 2001. 24. Marler JR, Tilley BC, Lu M, et al: Earlier treatment associated with better outcome: The NINDS-TPA Stroke Study. Neurology 55:1649, 2002. 25. Kwiatkowski TG, Libman RB, Frankel M, et al: Effects of tissue plasminogen activator for acute ischemic stroke at one year. New Engl J Med 340:1781, 1999. [PMID: 10362821] 26. The NINDS-TPA Stroke Study group: Intracerebral hemorrhage after intravenous tPA therapy for ischemic stroke. Stroke 28:2109, 1997. 27. Levine MN, Goldhaber SZ, Gore JM, et al: Hemorrhagic complications of thrombolytic therapy in the treatment of myocardial infarction and venous thromboembolism. Chest 108(Suppl 4):291S, 1995.
critical care
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Prevention of Venous Thromboembolism in the ICU
Principles of Critical Care > Chapter 10. Preventing Morbidity in the ICU > Effective Prevention in the ICU: Adopt Effective BehaviorChange Strategies
Because of the significantly elevated risk of venous thromboembolism in obesity, we recommend an ag...
Principles of Critical Care > Chapter 109. The Obesity Epidemic of Critical Care > Minimizing Complications of Critical Illness
and Critical Care >
Other Problems in the Delivery
1-2 of 2 Results
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thromboembolism
Preventing Morbidity in the ICU Effective Prevention in the ICU: Adopt Effective Behavior-Change Strategies It is now well understood that knowing the research evidence about health care interventions that decrease rates of morbidity and mortality does not ensure that it is used in practice. The research evidence about effective behavior-change strategies can be extremely helpful to improve preventive care. The behavior-change strategies that are most likely to enhance the faithful application of diagnostic, preventive, and therapeutic interventions have been summarized in the Cochrane Collaboration Systematic Review by Bero and colleagues,13 which has been comprehensively updated by Grimshaw and associates.14 Although few studies in these reviews focused exclusively on preventive interventions, there are useful signals from this literature. For example, the Cochrane Review clearly shows that passive dissemination of information is generally ineffective; it seems necessary to use specific strategies to encourage implementation of research-based recommendations and to ensure changes in practice. The most effective strategies are interactive education rather than passive education, audit and feedback, reminders (manual or computerized), and involvement of local opinion leaders. To ensure that preventive care interventions are applied in practice, a behavioral program could be instituted that is specifically adapted to the ICU setting. A portfolio of behavior-change strategies may be desirable, some of which could be common and some of which may be different, to promote each preventive intervention. Further research on the relative effectiveness of different strategies specifically for preventive care and specifically for the ICU setting is needed. Studies on the cost effectiveness of behavioral-change strategies to promote prevention would also be useful. In the following sections of this chapter, we illustrate some behavior-change strategies using two examples in the ICU setting: prevention of venous thromboembolism and prevention of hyperglycemia. Prevention of Venous Thromboembolism in the ICU Venous thromboembolism (VTE) is a common complication of serious illness, conferring considerable morbidity and mortality in hospitalized patients. Patients with deep venous thrombosis (DVT) are at risk of subsequently developing pulmonary embolism (PE), which may be fatal if untreated. In the ICU setting, patients with DVT are significantly more likely to have PE, 15 and patients with DVT have a longer duration of mechanical ventilation (p = 0.02), ICU stay (p = 0.005), and hospitalization (p <0.001) than do patients without DVT.16 Critically ill patients can rarely communicate their symptoms, making it unlikely that patient self-reported symptoms will prompt intensivists to pursue the diagnosis of VTE; moreover, the physical examination is insensitive to detect DVT. Clinically unsuspected DVT and PE are frequently found at autopsy on critically ill patients. 17 In summary, VTE is a good example of an ICU-acquired morbidity that can be silent but potentially deadly.
The Obesity Epidemic and Critical Care Minimizing Complications of Critical Illness
Because of the significantly elevated risk of There are only two published randomized trials testing heparin for VTE prophylaxis in medical and surgical ICU patients. 18 , 19 venous One double-blind single-center trial allocated 119 medical-surgical ICU patients at least 40 years of age to unfractionated heparin 5000 U thromboembolism in obesity, we twice daily or placebo subcutaneous injections.18 Using serial fibrinogen leg scanning for 5 days, the rates of DVT were 13% in the recommend an heparin group and 29% in the placebo group (relative risk = 0.45, p <0.05). Rates of bleeding and PE were not reported. This trial aggressive demonstrated that unfractionated heparin is better than no prevention (the number of patients needed to prophylax with 5000 U twice approach to daily of subcutaneous heparin to prevent one DVT is four). A multicenter trial by Fraisse and colleagues randomized 223 patients with an prophylaxis. acute exacerbation of chronic obstructive pulmonary disease requiring mechanical ventilation for at least 2 days to 3800 or 5700 IU of the Unfortunately, data low-molecular-weight heparin nadroparin once daily or placebo. 19 Patients were screened with weekly duplex ultrasounds and after on this subject are clinical suspicion of DVT, and venography was attempted in all patients. Rates of DVT were 16% in the nadroparin group and 28% in the lacking, and a placebo group (relative risk = 0.67, p <0.05). A similar number of patients bled in each group (25 vs. 18 patients, respectively; p = 0.18). survey of surgeons Although patients were not screened for PE, no patients developed PE during the trial. This trial demonstrated that nadroparin is better who perform than no prevention (the number of patients needed to prophylax with nadroparin to prevent one DVT is eight). bariatric surgery showed wide Although there are only two published randomized trials of thromboprophylaxis in medical-surgical ICU patients, randomized trials variation in have been conducted in other populations for three decades and have clearly shown the effectiveness of anticoagulant VTE prophylaxis. practice. 28 Without Accordingly, anticoagulant thromboprophylaxis is universally recommended for critically ill patients except those with contraindications.20 good data to guide However, compliance with this recommendation for thromboprophylaxis is not what it should be. the clinician, we Preventing suggest the joint Morbidity use of pneumatic Compliance with Thromboprophylaxis in the ICU compression boots and increased-dose subcutaneous Several prospective single-center utilization reviews of VTE prophylaxis have provided evidence about the use of VTE prophylaxis in heparin (7500 U ICU practice. For example, thromboprophylaxis was prescribed in 33% of 152 medical ICU patients in one study 21 and in 61% of 100 twice per day). medical ICU patients in another.22 In contrast, in a medical-surgical ICU in which a clinical practice guideline was in place, VTE prophylaxis was prescribed for 86% of 209 patients. 23 In medical-surgical ICU patients, after excluding those receiving therapeutic anticoagulation and for whom heparin was contraindicated, only 63% of 96 received unfractionated heparin.24
In a multicenter 1-day cross-sectional utilization review of surgical ICU patients, unfractionated heparin was the predominant choice, and two methods of VTE prophylaxis were prescribed in 23% of patients. 25 Prophylaxis with unfractionated or low-molecularweight heparin was significantly less likely for postoperative ICU patients requiring mechanical ventilation than for patients weaned from mechanical ventilation later in their ICU course (odds ratio = 0.36). Use of intermittent pneumatic compression devices was significantly associated with current hemorrhage (odds ratio = 13.5) and risk of future hemorrhage (odds ratio = 19.3). In summary, the use of effective VTE prophylaxis ranges widely, according to the foregoing utilization reviews. One inference from this health services research is that insufficient attention is paid to thromboprophylaxis in the ICU setting. However, when prophylaxis is prescribed, clinicians appear to risk stratify, that is, patients with more VTE risk factors are more likely to receive prophylaxis than are patients with fewer risk factors. The dynamic competing risks of bleeding and thrombosis during critical illness underscore the individual risk:benefit ratios in critically ill patients. Two studies evaluating implementation strategies to enhance appropriate VTE prophylaxis are relevant to the ICU setting. One three-armed multicenter randomized trial of 3158 surgical patients requiring VTE prophylaxis evaluated the impact of education versus education plus quality improvement. 26 Both interventions significantly improved appropriate VTE prophylaxis rates compared to the control group. In a time series study of 1971 orthopedic patients, a computer-decision support system significantly increased the rate of appropriate VTE prophylaxis prescribing from 83% to 95%.27 Interestingly, each time that the computer-decision support was removed, practice patterns reverted to those observed previously. In a before-after single-center study, our group demonstrated how appropriate anticoagulant thromboprophylaxis increased from 65%24 to 95%28 after the introduction of a thromboprophylaxis practice guideline implemented by using interactive multidisciplinary educational in-services, ongoing verbal reminders to the ICU team, daily computerized nurse recordings of thromboprophylaxis, weekly graphic feedback to individual intensivists on prophylaxis adherence, and publically displayed graphic feedback on group performance. However, no randomized trials have formally tested individual behavior-change
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Most studies suggest that the risk of aspiration of gastric contents is increased in the obese patient due to increased intraabdominal pressure and the high volume and low pH of gastric contents in such patients. This has implications not only for intubation (see above) but also for routine nursing and feeding. We recommend that all morbidly obese patients be fed and nursed in the semiupright position.
thromboembolism strategies for thromboprophylaxis in the ICU, in contrast with this multimethod approach. Fortunately, published thromboprophylaxis rates for critically ill patients appear to be increasing over time. 1 Prevention of Hyperglycemia in the ICU The adverse consequences of acute hyperglycemia have been highlighted in numerous observational studies. A meta-analysis of 15 observational studies showed that, after myocardial infarction, diabetic patients with glucose values of 6.1 to 8.0 mmol/L had a fourfold higher risk of death than did patients without diabetes who had lower glucose values. 29 Among diabetic patients with glucose values of 10.0 to 11.0 mmol/L, the risk of death was increased twofold. After stroke, a meta-analysis of 32 observational studies among nondiabetic patients found that acute hyperglycemia with values of 6.1 to 8.0 mmol/L was associated with a threefold relative risk increase in hospital mortality and an increased risk of poor functional recovery in nondiabetic patients after stroke. 30 To test the hypothesis that outcomes could be improved in patients with lower blood glucose during acute illness, the Insulin Glucose Followed by Subcutaneous Insulin Treatment in Diabetic Patients with Acute Myocardial Infarction (DIGAMI) study randomized 620 patients with diabetes and myocardial infarction to two different intervention strategies. Patients were allocated to intensive metabolic treatment with insulin plus glucose infusion followed by multidose insulin treatment or to standard treatment. Investigators found a significantly lower mortality rate in the intensive treatment group at 1 year 31 and at 3 years. 32 In diabetic patients, the adverse consequences of chronic hyperglycemia are well known. The Diabetes Control and Complications Trial (DCCT), which enrolled 1441 patients with type 1 diabetes, demonstrated that patients who had intensive insulin management had significantly less retinopathy, nephropathy, and neuropathy than did those managed conventionally. 33 Similarly, the UK Prospective Diabetes Study (UKPDS) of 3867 patients with type 2 diabetes showed that intensive glucose control with oral hypoglycemic agents or insulin to achieve a target fasting glucose level below 6 mmol/L resulted in significantly fewer microvascular complications than did conventional management.34 In addition to the foregoing findings, emerging evidence suggests that acute hyperglycemia has adverse consequences for ICU patients. During critical illness, stress hyperglycemia occurs due to production of excessive counter-regulatory hormones (glucocorticoids, catecholamines, growth hormones, and glucagon ), effects of cytokines, insulin resistance, and pre-existing diabetes. Building on the results of the DCCT 33 and UKPDS 34 in diabetic patients and those of the DIGAMI trial in patients with and without diabetes, 31 a recent landmark randomized trial of 1548 critically ill patients demonstrated that patients allocated to a target of euglycemia (4.4 to 6.1 mmol/L) as compared with higher glucose values (10.0 to 11.1 mmol/L) had a significantly lower infectious morbidity rate, less renal failure, less polyneuropathy of the critically ill, and lower ICU and hospital mortality rates regardless of whether they had diabetes. 35
The Obesity Epidemic and Critical Care
Minimizing Complications of Critical Illness Because of the significantly elevated risk of venous thromboembolism in obesity, we recommend an aggressive approach to prophylaxis. Unfortunately, data on this subject are lacking, and a survey of surgeons who perform bariatric surgery showed wide variation in practice. 28 Without good data to guide the clinician, we suggest the joint use of pneumatic compression boots and increased-dose subcutaneous heparin (7500 U twice per day). Most studies suggest that the risk of aspiration of gastric contents is increased in the obese patient due to increased intraabdominal pressure and the high volume and low pH of gastric contents in such patients. This has implications not only for intubation (see above) but also for routine nursing and feeding. We recommend that all morbidly obese patients be fed and nursed in the semiupright position.
anderson oncology
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Thrombosis
Medical Oncology > Chapter 39. Oncologic Emergencies > Hematologic Emergencies
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thromboembolism Thrombosis Venous thromboembolism (VTE) is influenced by Virchow's triad: venous stasis, higher-than-normal coagulability, and intimal injury. Patients with cancer have a high risk of VTE, and up to 15% of patients will develop VTE because of hypercoagulability, the use of central venous catheters, and high stasis (35 ). Cancer patients can have increased serum viscosity due to dehydration or, less frequently, hyperviscosity syndrome (described previously). Stasis and intimal injury can be caused by numerous events—for example, tumor encroachment on blood vessels or indirect effects of cancer, such as spinal cord compression, brain metastasis, dehydration, or impaired ambulation. Some chemotherapeutic cancer agents can also induce VTE, among them tamoxifen , cisplatin , cyclophosphamide , methotrexate , and 5-FU (35 ). Symptoms of pulmonary embolism (PE) include chest pain, shortness of breath, palpitations, fever up to 102°F, and syncope in the case of massive PE. ECG findings can include T-wave inversion in the precordial leads, sinus tachycardia, right bundle branch block, or rightward movement of the QRS axis. Chest roentgenograms can be normal or might reveal a pleural effusion or elevation of the diaphragm on the involved side. Physical examination can reveal tachypnea, tachycardia, and leg edema or erythema in the case of associated deep vein thrombosis.
12 ).
Diagnosis of PE can be made by ventilation/perfusion scanning, spiral CT angiography, pulmonary angiography, or MRI (Fig. 39-
Hematologic Emergencies > Thrombosis >
Figure 39-12
Spiral CT angiogram in a patient with a saddle pulmonary embolism (arrow). AO = aorta; PA = main pulmonary artery. (Image courtesy of Dr. Joel Dunnington, M.D. Anderson Cancer Center.)
Ventilation perfusion scans are noninvasive and the results are useful in patients with a high probability of PE, which can be treated as VTE; normal results on ventilation/perfusion scans can rule out PE. Clinical suspicion based on the patient's risk factors and results of other tests can guide the clinician regarding the patient's pretest probability of PE. Patients with indeterminate result from ventilation/perfusion scans who are strongly suspected of having a PE can undergo further testing, such as spiral CT angiography, pulmonary angiography, or MRI. Spiral CT scanning and MRI can detect segmental PE but not necessarily subsegmental PE. Both of these tests are useful in that they give further information about the condition of the lung, such as whether pneumonia is present, tumor size, and impingement on the bronchial airways; this additional information is helpful in determining the cause of the patient's symptoms. Pulmonary angiography remains the gold standard in detecting PE, although it requires more dye than other contrast methods and a greater risk of renal complications. The alveolar-arterial gradient (A-a gradient) from an arterial blood gas (ABG) can serve to corroborate the diagnosis of PE, but a normal A-a gradient does not rule out a PE. The upper limit of normal of an A-a gradient is equal to patient age/4 + 4, but this value can also increase when the patient is supine. In the PIOPED study, ABGs were normal in 14% of patients with preexisting cardiopulmonary disease and in 38% of patients with no underlying cardiopulmonary disease despite the presence of pulmonary emboli (28,36) (Fig. 39-13 ).
Hematologic Emergencies > Thrombosis >
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thromboembolism Figure 39-13
Suggested algorithm for the evaluation of pulmonary embolism. IP = intermediate probability; LP = low probability; LE US = lower extremity ultrasound; LE venogram = lower extremity venogram; V/Q scan = ventilation perfusion scan; PE = pulmonary embolism; DVT = Deep venous thrombosis. (Adapted from Shannon VR, Ng A. Noninfectious pulmonary emergencies. In: Yeung SJ, Escalante CP, eds. Oncologic Emergencies. Hamilton, Ontario, Canada: BC Decker; 2002, with permission.)
Hematologic Emergencies > Thrombosis >
Figure 39-14
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thromboembolism
Diagnostic approach to patients with suspected acute deep venous thrombosis. DVT = deep venous thrombosis; IPG = impedance plethysmography; MRI = magnetic resonance imaging; US = ultrasonography. (Adapted from Gao S, Shannon VR. Vascular emergencies. In: Yeung SJ, Escalante CP, eds. Oncologic Emergencies. Hamilton, Ontario, Canada: BC Decker; 2002, with permission.)
The D-dimer test can also be used in the evaluation of VTE; normal results are associated with a significantly lower likelihood of VTE than high values. A normal D-dimer level does not rule out VTE, however (35 ). Because D-dimer is commonly high in patients with cancer, an elevated D-dimer is not useful in diagnosing VTE. First-line treatment for VTE consists of either unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH). LMWH has the advantage that factor Xa levels usually do not have to be monitored because protein binding is low. LMWH also has a longer half-life than UFH and thus can be given less frequently (once or twice per day). The LMWHs enoxaparin , tinzaparin, and dalteparin are all different and cannot be used interchangeably. Monitoring may be required for patients with obesity and renal insufficiency, because LMWH is cleared by the kidneys. When monitoring is necessary, the Xa level should be measured 4 h after the injection, with a target level ranging from 0.6 to 1.0 IU/mL for twice-daily dosing. For daily dosing, the Xa level should range between 1.9 and 2.0 IU/mL (37 ). For patients who will be transitioned to warfarin treatment, there should be an overlap of at least 5 days with LMWH. Levine and colleagues recently presented the results of a study involving VTE in cancer patients at the 44th American Society of Hematology Meeting. In their study, 672 cancer patients with VTE were randomized to dalteparin with oral anticoagulation versus dalteparin alone. The oral anticoagulation (OA) group were given warfarin and dalteparin 200 IU/kg subcutaneously every day for 5 to 7 days until the international normalized ratio (INR) reached 2 to 3. At that point, dalteparin was discontinued and the warfarin continued for 6 months. In the OA group, the goal INR was 2.5. The dalteparin group was given dalteparin 200 IU/kg subcutaneously every day for 1 month and then 150 IU/kg subcutaneously every day for the remaining 5 months. The patients in the dalteparin group had a lower rate of recurrent VTE at 6 months (8.8%) than the OA group (17.4%). There were no significant differences in major or minor bleeding between the two groups. The study investigators concluded that the occurrence of recurrent VTE can be decreased by the use of dalteparin rather than warfarin (38 ). Although VTE can often be treated on an outpatient basis, patients not eligible for outpatient treatment are those with active bleeding, major comorbid illnesses, a history of heparin -induced thrombocytopenia, hypertensive emergencies, major surgery or trauma within the previous 2 weeks, recent gastrointestinal bleeding, stroke or transient ischemic attack, severe renal dysfunction, or a platelet count below 100,000/ L (39 ). Figure 39-15 shows the dosing schedule.
Hematologic Emergencies > Thrombosis >
Figure 39-15
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thromboembolism
Heparin dosage schedule for venous thromboembolism.
Most patients are treated for at least 3 to 6 months. Patients from whom the central venous catheter has been removed can undergo repeat testing using such techniques as Doppler ultrasound or nuclear venous flow study to determine whether the clot has resolved, so that cessation of anticoagulation therapy may be considered. For patients with small clots at the distal tip, manifested by the inability of the central line to work, tissue plasminogen activator (t-PA) can be given carefully provided that there are no contraindications. Inferior vena cava (IVC) filters can be used for patients who cannot tolerate anticoagulation therapy. IVC filters do not decrease peripheral edema from deep venous thrombosis (DVT) and, in fact, can serve as a nidus for further clot formation. IVC filters can prevent life-threatening pulmonary emboli. Patients with massive pulmonary emboli may require thrombolysis or embolectomy. See Fig. 39-16 for a synopsis of the relative and absolute contraindications for thrombolytic therapy (40 ) and Fig. 39-17 for thrombolytic doses.
Hematologic Emergencies > Thrombosis >
Figure 39-16
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thromboembolism
Absolute and relative contraindications to thrombolysis. (Adapted from Shannon VR, Ng A. Noninfectious pulmonary emergencies. In: Yeung SJ, Escalante CP, eds. Oncologic Emergencies. Hamilton, Ontario, Canada: BC Decker; 2002, with permission.)
Hematologic Emergencies > Thrombosis >
Figure 39-17
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thromboembolism
Dosages of thrombolytics.
Patients with cancer and VTE should be treated indefinitely if the cancer remains active or for at least 3 to 6 months after resolution of the VTE if the cancer is no longer active (41,42). For patients who are treated with warfarin but who experience warfarin failure as evidenced by the recurrence or progression of clot formation, the INR range can be increased from 2 to 3, to 3 to 3.5, the patient can be switched to twice-daily UFH, or the patient can be switched to LMWH (42 ). Thrombectomy should be used only for patients with massive PE who are hemodynamically unstable and who either have contraindications for thrombolytic therapy or have previously failed thrombolytic therapy (35 ).
hazzard geriatrics
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Diagnosis
Hazzard's Geriatric Medicine and Gerontology, 6e > Chapter 105. Thrombosis
Natural History
Hazzard's Geriatric Medicine and Gerontology, 6e > Chapter 105. Thrombosis
Pathophysiology
Hazzard's Geriatric Medicine and Gerontology, 6e > Chapter 105. Thrombosis
Treatment of Venous Thromboembolism
Hazzard's Geriatric Medicine and Gerontology, 6e > Chapter 105. Thrombosis
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thromboembolism Incidence of VTE
Hazzard's Geriatric Medicine and Gerontology, 6e > Chapter 105. Thrombosis > Epidemiology
Risk Factors
Hazzard's Geriatric Medicine and Gerontology, 6e > Chapter 105. Thrombosis > Epidemiology
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harrison
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Chapter 59. Bleeding and Thrombosis
Harrison's Online
Pulmonary Hypertension Due to Thromboembolic Disease
Harrison's Online > Chapter 244. Pulmonary Hypertension
Renal Vein Thrombosis (RVT)
Harrison's Online > Chapter 280. Vascular Injury to the Kidney
Pulmonary Embolism and Chronic Pulmonary Hypertension
Harrison's Online > Chapter e19. Atlas of Electrocardiography > Atlas of Electrocardiography
Deep Venous Thrombosis and Pulmonary Embolism
Harrison's Online > Chapter 7. Medical Disorders during Pregnancy
Prophylaxis of Venous Thromboembolism
Harrison's Online > Chapter 8. Medical Evaluation of the Surgical Patient > Evaluation of Intermediateto High-Risk Patients
Streptokinase
Harrison's Online > Chapter 112. Antiplatelet, Anticoagulant, and Fibrinolytic Drugs > Fibrinolytic Drugs
Thromboembolic Disorders
Harrison's Online > Chapter 289. Inflammatory Bowel Disease > Extraintestinal Manifestations
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thromboembolism
Thromboembolism
Harrison's Online > Chapter 239. ST-Segment Elevation Myocardial Infarction > Complications and Their Management > Other Complications
Venous Thromboembolism
Harrison's Online > Chapter 342. The Menopause Transition and Postmenopausal Hormone Therapy > Menopause and Postmenopausal Hormone Therapy > Benefits and Risks of Postmenopausal Hormone Therapy > Definite Risks
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Vaughan & Asbury's General Ophthalmology, 17e
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Multisystem Autoimmune Diseases
Vaughan & Asbury's General Opthalmology > Chapter 15. Ocular Disorders Associated with Systemic Diseases
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pocket diagnostic tests | go | 1-3 of 3 Results
Pulmonary embolism: Diagnostic algorithm Diagnostic Tests > Differential Diagnosis and Diagnostic Algorithms Pulmonary Embolism: The Revised Geneva Score for Probability Assessment Diagnostic Tests > Differential Diagnosis and Diagnostic Algorithms Thrombosis, Venous Diagnostic Tests > Differential Diagnosis and Diagnostic Algorithms
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thromboembolism
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Pulmonary embolism: Diagnostic algorithm >
Figure 8–20.
PULMONARY EMBOLISM: Diagnostic approach. CT = computed tomography; DVT = deep venous thrombosis; PE = pulmonary embolism; Rx = anticoagulant therapy; / scan = ventilation-perfusion scan. (Modified from Ann Intern Med 2006;144:165.)
greenspan endocrinology
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Cushing's Syndrome
Greenspan's Basic & Clinical Endocrinology > Chapter 10. Glucocorticoids & Adrenal Androgens
Contraception
Greenspan's Basic & Clinical Endocrinology > Chapter 14. Female Reproductive Endocrinology & Infertility 1-2 of 2 Results
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thromboembolism
current rheumatology
1-4 of 4 Results
References
CURRENT Rheumatology Diagnosis & Treatment > Chapter 24. Antiphospholipid Antibody Syndrome
General Considerations
CURRENT Rheumatology Diagnosis & Treatment > Chapter 58. Osteonecrosis
Nonsteroidal Anti-Inflammatory Drugs
CURRENT Rheumatology Diagnosis & Treatment > Chapter 67. Medications
Systemic Lupus Erythematosus
CURRENT Rheumatology Diagnosis & Treatment > Chapter 14. Pregnancy & Rheumatic Diseases
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Schulman S, et al and the Duration of Anticoagulation Study Group. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Am J Med. 1998;104:332. (A prospective study proving the high risk of recurrent thrombosis in APS.) [PMID: 9576405]
Osteonecrosis
General Considerations Osteonecrosis is a generic term that refers to cell death in the two components of bone, both hematopoietic fat marrow and osteocytes. Other terms frequently used for this condition are "ischemic necrosis," "avascular necrosis," "aseptic necrosis," and "osteochondritis dissecans." ON, which represents an inability to supply adequate oxygen to underlying bone, is extremely uncommon in healthy individuals. The condition typically occurs only in the fatty marrow, which contains a sparse vascular supply. In contrast, hematopoietic marrow has a rich blood supply. The femoral head is the most vulnerable site for the development of ON. The site of necrosis is typically just below the weight-bearing articular surface of the bone, the anterolateral aspect of the femoral head. This is the site of greatest mechanical stress. Osteonecrosis is characterized by areas of dead trabecular bone and marrow extending to the subchondral plate. The anterolateral aspect of the femoral head, the principal weight-bearing region, is involved most often. In the adult, the involved segment never fully revascularizes. Once radiographic detection is possible, collapse of the femoral head is usually inevitable, at intervals ranging from weeks to years. Elderly persons seem to be at decreased risk for developing ON. In this age group, fat cells become smaller. The space between fat cells fills with a loose reticulum and mucoid fluid that is resistant to ischemic necrosis. This is termed gelatinous marrow, and even in the presence of increased intramedullary pressure, interstitial fluid is able to escape into the blood vessels, leaving the spaces free to absorb additional fluid. Osteonecrosis is not a discrete disease but represents the final common pathway of several conditions, most of which result in impairment of the blood supply to the bone. ON may occur in a variety of clinical settings, in association with defined diseases (eg, an infiltrative process such as Gaucher disease), medications (eg, glucocorticoids), physiologic or pathologic conditions (eg, pregnancy,
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thromboembolism thromboembolism, or trauma), or without identifiable predisposing factors (idiopathic). The true prevalence of ON is unknown, but it is estimated that there are approximately 10,000–20,000 new cases annually in the United States, and ON is the underlying diagnosis in approximately 10% of all total hip replacements. For the most part, ON affects the epiphyses of the long bones, such as the femoral and humeral heads, but other bones (eg, carpal and tarsal) can also be affected. The disease occurs more frequently in males than females, with the overall male:female ratio in the range of 8:1. The age distribution is wide, although most patients are younger than age 50 at the time of diagnosis. The average age of female cases exceeds that of males by almost 10 years.
nsaids Nonsteroidal Anti-Inflammatory Drugs Choice of NSAID A large number of NSAIDs are available in the United States. As a general rule, the NSAIDs are comparable in efficacy, but individual patients may exhibit different responses to particular NSAIDs. Physician and patient preferences, concerns regarding toxicity, and cost usually determine the choice of NSAID. See Table 67–1 for typical dosing ranges of selected NSAIDs in common use in the U.S. Traditional NSAIDs inhibit both COX-1 and COX-2. Although considered "nonselective," these nonetheless vary in their relative selectivity for COX-1 and COX-2 in vitro (N Engl J Med. 2001;345:433; J Clin Invest. 2006;116:4). Indeed, the in vitro selectivity of diclofenac, meloxicam, and nabumetone for COX-2 is comparable to that of celecoxib. On the other hand, indomethacin, ibuprofen, and naproxen display modest in vitro selectivity for COX-1. The clinical significance of differential selectivity for COX-1 and COX-2 by traditional NSAIDs remains to be determined. Selective COX-2 inhibitors (the "coxibs") were developed in an effort to reduce gastrointestinal toxicity, but an increase in adverse cardiovascular events (myocardial infarction and stroke) led to the withdrawal of two of these: rofecoxib and valdecoxib. Longer duration of therapy, higher dose, and the presence of cardiac risk factors appear to increase the risk of coxib-associated adverse cardiovascular events. The major underlying mechanism is thought to be inhibition of COX-2-mediated production of prostacyclin; loss of prostacyclin removes a vascular protective mechanism, thereby predisposing to thrombosis and accelerating atherogenesis (J Clin Invest. 2006;116:4). The inability of coxibs to inhibit platelets (which only express COX-1) also likely contributes to the increase in thromboembolism (Nat Rev Drug Discov. 2003;2:879). Celecoxib is the only coxib currently available in the United States. Low doses of celecoxib (total dose <200 mg per day) do not appear to be associated with increased cardiovascular risk in short-term studies, but safety data for long-term use are limited. The evidence that celecoxib has a favorable gastrointestinaltoxicity profile relative to traditional NSAIDs has been questioned (BMJ. 2002;324:1287).
current pulmonary medicine
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Chapter 19. Pulmonary Thromboembolism
CURRENT Diagnosis & Treatment in Pulmonary Medicine
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-------------------------------------Essentials of Diagnosis Clinicians should be aware of individual risk factors for development of pulmonary embolism. Pulmonary embolism should be considered in cases of unexplained hypoxemia. Limitations exist for all current diagnostic studies. All clinicians should have a diagnostic algorithm in cases of suspected pulmonary embolism. General Considerations
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thromboembolism Venous thromboembolism (VTE), a common medical problem, is the third most common vascular disease and carries a high morbidity and mortality. It is characterized by intravenous thrombus formation either as a deep venous thrombosis (DVT) in leg veins or as a pulmonary embolism (PE), a thrombus migrating to the lung circulation from proximal leg veins or the pelvis. Risk of venous thromboembolism rises with increasing age, up from 1:10,000 in childhood to 1:100 in the elderly. It is estimated that DVT occurs in 1 of 1000 adults and PE in 10–25% of these patients. Both conditions are difficult to diagnose due to their nonspecific symptoms and signs. As a result, many cases are recognized only postmortem or after a thrombus has migrated to the lung circulation. Therefore, it is extremely important to identify patients at risk to facilitate prompt diagnosis and management (Table 19–1). An algorithm can be instrumental in doing this. Because the thrombi originate in the legs, PE is potentially avoidable if preventive therapy, such as anticoagulation or compression stockings, is used in high-risk situations. Table 19–1. Risk Factors for Venous Thromboembolism.
Immobility Cancer Prior VTE Venous insufficiency Obesity Prolonged air travel Major surgery Hip Knee Abdominal Neurosurgery Pregnancy Congestive heart failure Myocardial infarction Fractures of the lower extremities Femoral catheters/other central venous catheters Hypercoagulable conditions (malignancy, oral contraceptives, Protein C and S deficiency, Factor V Leiden mutation, antithrombin III deficiency) Age Chronic respiratory failure
Clinical Findings Symptoms and Signs Presenting signs and symptoms for pulmonary embolism are nonspecific, which makes clinical diagnosis difficult. The most common presenting symptoms noted in the patients from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED) study who had angiographically confirmed PE were dyspnea, pleuritic chest pain, and tachypnea. The findings on physical examination included increased respiratory rate, rales, tachycardia, a loud second heart sound, deep venous thrombosis, temperature above 38.5°C, wheeze, Homan's sign (pain on palpation of the calf), pleural friction rub, an S3 gallop, and cyanosis. Syncope or hypotension may uncommonly be the presenting symptoms of pulmonary embolism and suggests severe hemodynamic compromise. The presence of the above clinical findings can heighten concern for PE but does not constitute a diagnosis. Although clinical symptoms and signs are nonspecific, clinical models using findings from history and physical examination help focus clinical suspicion for PE. Recent clinical models use weighted clinical scores to assign low, moderate, or high clinical probability of a PE. Some use clinic assessment plus a noninvasive diagnostic test, such as the d-dimer assay that measures active fibrinolysis. Wells reports an example of such a score for DVT tested prospectively on a large number of patients. This model, which includes nine findings from history and physical examination, weighs these features into a clinical score of low, moderate, or high likelihood of DVT. The features included are leg swelling, pain to palpation, heart rate greater than 100 beats/min, immobilization, surgery in the previous 4 weeks, prior PE or DVT, hemoptysis, malignancy, and likelihood of PE greater than likelihood of other diagnoses. A low probability clinical score coupled with a negative d-dimer assay gave a negative predictive value of 99.5% (CI 99.1–100%) for PE. Clinical tools such as this combined clinical/laboratory assessment protocol are useful in stratifying information obtained from the history and physical examination to decide on further diagnostic testing. Laboratory Findings Arterial Blood Gas (ABG) ABG is of limited use in assessment of pulmonary embolism. Although respiratory alkalosis and hypoxemia are common findings, they should not be used in isolation to detect PE. In the prospective PIOPED trial, 8–23% of patients with PE confirmed by angiography had normal alveolar–arterial (A–a) oxygen gradients and 7% had completely normal ABG results. Although ABG findings should not be used to confirm a diagnosis of PE, profound hypoxemia without clear explanation should raise suspicion for possible PE. D-Dimer D-dimer, a product of the fibrinolytic degradation of cross-linked fibrin, has emerged as a potentially useful serological marker in the assessment of PE. Its current use is to rule out pulmonary embolism in the appropriate clinical setting; sensitivity rates are in the mid90% range. Fibrinolytic markers including d-dimer are, however, elevated in many other medical disorders including cancer, hepatic and renal insufficiency, septicemia, stroke, and major trauma, thus limiting specificity in these situations. Five methods have been developed for detecting elevations in d-dimer: (1) enzyme-linked immunosorbent assay (ELISA) testing, which has the highest sensitivity but low specificity, (2) latex agglutination testing, which has improved specificity but lower sensitivity, (3) the immunofiltration assay, (4) an
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thromboembolism immunoturbidometric assay, and, more recently, (5) the SimpliRED d-dimer agglutination assay, which uses a biospecific antibody directed against d-dimers and red blood cells. ELISA appears to have a high negative predictive value (91–100%) but is limited by longer testing time and lack of widespread availability. Latex agglutination testing is more readily available and requires less time, but is limited by a negative predictive value between 67 and 97%. To interpret these studies, it is important to know which test is used by the local clinical laboratory. Currently, although a negative d-dimer may be used to prevent further testing in the setting of low pretest probability and low probability imaging, it does not provide full assurance of the absence of a PE. Imaging Studies Chest Radiograph Findings on chest x-ray are rarely diagnostic for pulmonary embolism. Radiographs may often look completely normal. When abnormal, radiographs show infiltrates, pleural effusion, or atelectasis. Less common abnormalities include unilateral enlargement of a pulmonary artery, and the Westermark sign, which is the asymmetry of lung markings due to absence of perfusion distal to a clot; the hemithorax without the thrombus appears denser. Hampton's hump describes a pleural-based wedge-shaped infiltrate/atelectasis from an infarct. Chest radiography is most useful in diagnosing other processes that may present with a similar clinical picture such as pneumonia or pneumothorax. Often, the presence of a chest film showing little abnormality for a patient with new onset hypoxemia is a clue to the presence of pulmonary vascular disease such as PE. Ventilation–Perfusion Scanning The ventilation-perfusion scan ( /Q) has been the most common diagnostic test for suspected pulmonary embolism. 99Tcradiolabeled albumin is injected intravenously into the pulmonary capillary bed followed by inhalation of a radioactive gas to assess ventilation. A diagnosis of pulmonary embolism is based on the pattern of ventilatory and perfusion defects with PE causing large segmental decrease in perfusion with preserved ventilation. Major disadvantages of this test are the limitations posed by the presence of comorbid lung disease and the test's lack of sensitivity for small clots. These result in underdiagnosis of PE. Therefore nondiagnostic or negative /Q scanning must be considered in each clinical risk setting: high, moderate, or low likelihood of PE. PIOPED data have indicated that ventilation–perfusion scanning has a high positive predictive value (96%) in the setting of a high pretest clinical suspicion and a high probability scan (Figure 19–1). However, a low probability scan with the same high clinical suspicion still has an associated 40% incidence of pulmonary embolism (Table 19–2). Scans appear to be of particular use when they are either normal or high probability rather than low or indeterminant probability; in PIOPED the majority (75%) were nondiagnostic. Figure 19–1.
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thromboembolism
High-probability ventilation/perfusion images (A, perfusion; B, ventilation) revealing several mismatched defects in the left lung. (Courtesy of Marcus Chen, MD, Department of Nuclear Medicine, University of Colorado Health Sciences Center.)
Table 19–2. /Q Scan Usefulness Varies with High, Uncertain, and Unlikely Clinical Estimates.
Clinical estimate of probability High (80–100%)
Uncertain (20–79%)
Unlikely (0–19%)
High
28/29 (96%)
70/80 (88%)
5/9 (56%)
Indeterminate
27/41 (66%)
66/236 (28%)
11/68 (16%)
Low
6/15 (40%)
30/191 (16%)
4/90 (4%)
Near normal/normal
0/5 (0%)
4/62 (6%)
1/61 (2%)
Total
61/90 (68%)
170/569 (30%)
21/228 (9%)
/Q scan
From ATS Consensus Statement (1999). Commonly, physicians need to choose a diagnostic test for pulmonary embolism for a patient with significant pulmonary disease such as chronic obstructive pulmonary disease (COPD). Data suggest that the positive predictive value of /Q scanning remains the same, but that the incidence of indeterminant scans is much higher among those with COPD due to underlying ventilation abnormalities. In the setting of a nondiagnostic study, examination of lower extremity for thrombus may be used to assist in reaching a diagnosis. Lower Extremity Doppler Because pulmonary thromboemboli originate primarily in the legs, lower extremity (LE) Doppler and ultrasound studies are an alternative strategy for diagnosing suspected venous thromboembolic events, particularly in the setting of nondiagnostic /Q scans. Venous ultrasonography is a noninvasive and relatively inexpensive test that is useful in identifying proximal venous thrombosis. Doppler examination entails placement of an external probe for flow assessment. Patients with negative LE Dopplers and nondiagnostic /Q scan may be followed with serial Doppler/ultrasound examinations. Other modalities used to examine the lower extremities include impedance plethysmography and contrast venography. Lower extremity imaging, especially if positive for clot, may complement other diagnostic tests, especially indeterminate /Q scanning, even without direct visualization of the lung circulation. Pulmonary Angiography Pulmonary angiography remains the gold standard for the diagnosis of pulmonary embolism. Diagnosis is based on pulmonary artery occlusion or the presence of intraluminal filling defects in two views. Other suggestive findings include asymmetrical blood flow, slow filling of the artery, and arterial cutoff. Pulmonary angiography is invasive; access is achieved via the femoral, basilic, or internal jugular vein. Angiography is reserved for a setting of high clinical suspicion when nondiagnostic testing is provided by the less invasive studies, since it has a higher complication rate due to the dye load and need for central vein catheter placement. It is important to
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thromboembolism recognize risks of angiography including bleeding risk and dye-induced nephropathy. Death has been reported in 0.2–0.5% of studies. Complications include arrhythmias and groin hematomas. Even high-risk patients, though, can safely undergo angiography if the platelet count is at least 75,000 L, coagulation studies are only minimally elevated, and adequate prestudy hydration is provided. Helical Computed Tomography (CT) Scan Recently, helical or spiral CT scanning has received attention as a primary diagnostic tool for acute pulmonary embolism. Helical CT scanning constructs a two-dimensional lung image over a brief period of time after injection of contrast dye. Defects in dye penetration of a vessel diagnostic of thrombus may be detected centrally or peripherally (Figure 19–2). Helical CT scanning has the advantage of being minimally invasive, similar to /Q scanning. To date, there is no consensus on the role of helical CT scanning in the diagnosis of acute PE. Prospective studies have reported sensitivities of 53–100% and specificities ranging from 81 to 100%. There are data in selected case series revealing a low incidence of PE among patients up to 3 months after a negative helical CT scan. However, studies have been limited by several features including small sample size, bias in patient selection, retrospective selection, presence or absence of comorbid conditions, and lack of angiography as the reference standard. Interobserver variation among radiologists remains a potential problem in scan interpretation. Although helical CT is effective in imaging main, lobar, and subsegmental emboli, it generally lacks resolution for detecting subsegmental (small) emboli. Some believe that it should be a first-line replacement for /Q scans and angiography, while others have suggested reserving it for selected patients in whom /Q scanning is nondiagnostic or unavailable. Currently, CT scanning appears useful in identifying central emboli, an area of weakness for /Q scans. It also identifies previously undetected parenchymal, pleural, and mediastinal abnormalities that could be alternate explanations for patient symptoms. A large multicenter trial is under way nationwide to assess the role of CT scanning prospectively. A promising extension of CT scanning is scanning of the pelvic and leg veins during the same injection protocol as CT of the chest to identify vena caval, iliac, or femoral venous thrombosis. Figure 19–2.
CT angiogram revealing right lower lobe intravascular filling defect with expansion consistent with acute thrombus. (Courtesy of Debra Dyer, MD, Department of Radiology, University of Colorado Health Sciences Center.) Magnetic Resonance Angiography Magnetic resonance angiography (MRA) is an alternative method for diagnosing pulmonary vascular disease. To date, only small studies have examined the role of MRA in the diagnosis of acute PE with reports of sensitivities as high as 86% in main arteries and as low as 50% in lobar arteries. Earlier reports were limited technically by lack of contrast enhancement. Current studies using contrast-enhanced methods report slightly better results for this unproven test. Electrocardiograms (ECGs) ECGs are of limited use in diagnosing acute PE. Most commonly, patients present with sinus tachycardia. Although patterns of right ventricular strain may be evident, these are often absent, especially for small emboli. Findings of right ventricular strain include right bundle branch block (RBBB), incomplete RBBB, T wave inversions in V1–V4 or III, S wave in I, Q wave in III, and S1Q3T3 complexes. In a
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thromboembolism prospective assessment of ECGs in patients with suspected pulmonary embolism, only sinus tachycardia [positive predictive value (PPV) 38%, negative predictive value (NPV) 81%] and incomplete RBBB (PPV 100%, NPV 77%) were significantly more frequent in patients with confirmed PE. Echocardiogram For the majority of patients, echocardiography adds little to diagnosis or treatment. In submassive PE, however, right ventricular electrocardiographic strain patterns vary with the severity of the pulmonary artery pressure estimated by echocardiogram. These patterns help estimate the extent of PE in clinically severe cases. Some authors have suggested that echocardiogram may identify right ventricular dysfunction in the suspected massive pulmonary embolism and guide a decision for use of thrombolytic therapy. Diagnostic Algorithm At present, there is no perfect algorithm for PE assessment. Experts have endorsed strategies such as the one outlined in Figure 19–3. Helical CT scans are playing an increasing role in diagnosis despite the lack of wide-based prospective testing. Their current use should probably be similar to the /Q scan with pursuance of low probability or negative results using a pulmonary angiogram as clinically indicated. Negative d-dimer assays may be added to a clinical algorithm to minimize further scanning in the low likelihood clinical settings. Figure 19–3.
Clinical presentation and suspicion for pulmonary embolism. D-dimer can be used at the time of presentation to help interpret /Q scan. Differential Diagnosis Given the frequently nonspecific symptoms observed in pulmonary embolism, multiple diagnoses are often considered. Chest radiograph is performed to rule out pneumonia, pleural effusion, pneumothorax, or congestive heart failure, all of which can have chest pain or shortness of breath. Cardiac ischemia presents with acute onset chest pressure or shortness of breath and can be initially assessed by electrocardiogram. Based on the previous clinical history, exacerbations of COPD, asthma, gastroesophageal reflux with aspiration, esophageal spasm, and unusual presentations of high-altitude pulmonary edema or drug reactions are considered. Very rarely, interstitial lung disease has an acute presentation. Treatment PE and DVT comprise a systemic disease with similar therapeutic strategies. Treatment options are growing due to new pharmaceutical developments and are outlined below.
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thromboembolism Unfractionated Heparin Heparin is considered by most to be first line therapy in confirmed PE, and low-molecular-weight heparin is currently first line therapy for DVT. Heparin acts by enhancing the effect of antithrombin III, which results in inactivation of thrombin (factor IIa), factor Xa, factor V, and factor VIII. Heparin is effective in reducing mortality among patients with PE. Initial dosing is best achieved via a weightbased nomogram using an initial bolus of 80 U/kg followed by a continuous infusion of 18 U/kg/h and monitored by following the activated partial thromboplastin time (PTT). Several retrospective and randomized trials have concluded that the risk of recurrent venous thromboembolism is reduced if the PTT is maintained at levels between 1.5 and 2.3 times normal. However, circulating factors such as heparin-binding proteins can decrease the effect of heparin. Therefore, some advocate monitoring of plasma heparin levels (goal of 0.2-0.4 IU/mL) in the treatment of acute thrombosis. It is important to avoid underanticoagulation as inadequate heparinization in the first 24 h heightens the risk of recurrent PE. The minimum duration of heparin administration in the setting of acute thrombosis appears to be 5 days. Oral warfarin should be started in this time window. Heparin may be discontinued 24–48 h after an international normalized ratio (INR) of >2.0 is reached on the PT test used to monitor warfarin effect. There is a 1% incidence of heparin-induced thrombocytopenia (HIT) with heparin use, which can lead to paradoxical arterial or venous thrombus formation (heparin-induced thrombocytopenia and thrombosis, HITT). In this setting in the presence of heparin, platelet factor 4/heparin complexes induce platelet aggregation. Reduction in platelet count is seen in the first 5–7 days of therapy and is unusual beyond 2 weeks. Because of this, the American College of Chest Physicians (ACCP) guidelines recommend checking a platelet count between Days 3 and 5 of therapy. Should the platelet count drop below 100,000/ L or by 50%, heparin should be discontinued and alternative therapy chosen. Diagnostic tests for heparin-induced antibodies are notoriously inaccurate and include a high rate of false negative results. Thus, clinical suspicion should drive cessation of heparin even when the assay is nondiagnostic. Other heparin-associated complications include bleeding and osteoporosis. Contraindications to anticoagulation include recent major bleeding including cerebral hemorrhage or gastrointestinal bleed. Heparin induces osteopenia, which poses problems for the postmenopausal or pregnant patient. Low-Molecular Weight Heparin Therapy for venous thromboembolic disease has recently expanded to include low-molecular-weight heparins (LMWH). Several options are available (Table 19–3). These molecules have a mean molecular weight of 4000–5000 Da, compared to unfractionated heparin, with a higher mean molecular weight of 15,000 Da. Advantages of LMWH are a subcutaneous route of administration, lack of need for laboratory monitoring or dose adjustment, and reduction in length of required hospitalization. Several randomized controlled trials have successfully compared the efficacy of LMWH to unfractionated heparin in the setting of acute thrombosis and concluded that LMWH appears to be at least as effective as unfractionated heparin in DVT and stable pulmonary embolism. However, ACCP guidelines have suggested these minimal requirements for use of LMWH, particularly in the outpatient setting: DVT or PE without evidence of hemodynamic instability, hypoxemia, absence of severe renal insufficiency, appropriate support for outpatient administration and surveillance, and low bleeding risk. Table 19–3. Low-Molecular-Weight Heparin and Heparin Treatment Dosing.
Unfractionated heparin
80 U/kg bolus and 18 U/kg/h intravenously
Enoxaparin (Lovenox)
1 mg/kg subcutaneously twice a day or 1.5 mg/kg subcutaneously daily
Dalteparin (Fragmine)
200 anti-Xa IU/kg subcutaneously daily
Tinzaparin
175 anti-Xa IU/kg daily
Nadroparin (Innohep)
86 anti-Xa IU/kg subcutaneously twice a day for 10 days
(Fraxiparin)
Alternate Anticoagulant Drugs For acute anticoagulation, there are new anticoagulant options under development including a pentasaccharide Fondaparinux that is a Factor x inhibitor with even smaller molecular size than LMWH, and possibly less toxicity. The direct thrombin inhibitors lepirudin, hirudin, and argatroban are currently available for use in HIT or HITT when heparin is contraindicated. There is also clinical experience with dextran and danaparoid for those patients who cannot use heparin or LMWH. Therapy with danaparoid is monitored by an antifactor xa assay. Warfarin Sodium (Coumadin) Coumadin is the common coumarin derivative used in the United States. Coumarins function by inhibiting several vitamin Kdependent proteins including factors II, VII, IX, and X and two anticoagulant factors: protein C and S. Overlap therapy with heparin in the setting of acute VTE is needed to avoid a paradoxical procoagulant effect in early warfarin therapy. Coumadin must be administered for several days in order to reach therapeutic levels. Therapy is monitored by checking the INR, which represents a standardization of the prothrombin time. Effective therapy for VTE is usually achieved with an INR of 2.0–3.0. Warfarin is potentially teratogenic and should not be used during pregnancy. Thrombolytic Therapy Although first used 30 years ago, thrombolytic therapy including streptokinase, urokinase, and tissue plasminogen activator followed by heparin therapy remains a limited part of treatment for PE (Table 19–4). This is due to the marginal improvement over heparin or LMWH alone, and the risk of intracerebral bleeding. Use in PE has been limited to the hemodynamically unstable patient. Recently, a trial of treatment of the hemodynamically stable patient with acute right heart failure demonstrated by echocardiogram has suggested that the bleeding risk can be lowered by changing the dose and duration of the thrombolytic agent. The role of thrombolytic treatment in improving outcome in PE still, however, remains controversial. Table 19–4. Thrombolytic Agents.
Streptokinase
250,000 IU load followed by 100,000 IU/h for 24 h
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thromboembolism Urokinase
4400 IU/kg body weight load followed by 2200 IU/kg/h for 12 h
Tissue plasminogen activator (tPA)
100 mg infusion over 2 h
Vena Caval Filters In clinical practice, vena caval interruption is accomplished by surgery or a placement of a filter. The purpose is to prevent embolization of venous thromboses to the lung when the risk of anticoagulation is high, such as for a person with a recent gastrointestinal bleed, or when anticoagulation in therapeutic doses has failed to prevent a pulmonary embolism. The data on use of vena caval filters are mixed. A randomized controlled trial in Europe compared filter use to no filter in 400 patients with DVT. Although acute risk of PE was lower for those receiving a filter (1.1% vs. 4.8%), outcomes at 2 years demonstrated a 1.87-fold increase in risk of recurrent DVT for persons with the filter. There was no difference in 2-year mortality between groups. Thus the frequent use of filters should probably be minimized, especially as sole treatment for pulmonary embolism. ACCP guidelines recommend the placement of filters in cases of acute thrombus when anticoagulation is contraindicated and cases in which there is recurrent thrombus despite adequate anticoagulation. Direct Vascular Infusion of Thrombolytic Agents/Embolectomy Data on the use of both direct thrombolytic infusion into the pulmonary circulation and embolectomy are limited. However, for patients with pulmonary embolism and hemodynamic instability who fail to respond to thrombolysis or have contraindications these options may be considered. Duration of Therapy For pulmonary embolism in the setting of an identified risk situation such as trauma, myocardial infarction, or surgery, total anticoagulation duration is recommended at 3–6 months. For patients with recurrent venous thrombosis, some experts would consider lifelong therapy if the risk of bleeding is not high. Duration of therapy for idiopathic venous thrombosis, defined as thrombosis without a recognizable clinical risk event, is at least 6 months, with longer duration or even life-long therapy recommended by some experts. Inclusion of genetic risk information in treatment decisions is not standardized, but it is likely that those with genetic risk factors may be those who present with VTE without recognizable risk factors. In a recent randomized trial, authors concluded that low-intensity anticoagulation with coumadin (INR 1.5 to 2.0) beyond standard duration of therapy is effective in preventing recurrent thromboembolism. Other Considerations Prophylaxis Clearly, prevention of thrombus is preferred to treatment, as the sequelae of PE include pulmonary hypertension, hypoxemia, and death. Identification of high-risk conditions or diseases should be pursued whenever possible. Causal factors for VTE can be determined for a majority of cases. The ACCP guidelines note conditions of high risk and make recommendations for prevention in surgical settings such as general surgery, hip and knee surgery, hip fracture, and neurosurgery. Medical conditions are less well studied but myocardial infarction, congestive heart failure, stroke, malignancy, pregnancy and the postpartum period, and intensive care unit illness also pose high risk. Oral contraceptive pills and hormone replacement therapy confer a mild increase in risk, which may be higher in those with underlying genetic risk factors. Risk of thrombosis also increases with age, obesity, and prolonged travel. Absolute criteria for preventive therapy for situations other than surgery are not straightforward. Prevention includes heparin, 5000 U subcutaneously twice a day, LMWH, and compressive pneumatic stockings. A combination of the anticoagulant with compression stockings may be better than one or the other alone in certain high-risk situations. Recommendations for surgical prophylaxis are outlined by the ACCP consensus conference on antithrombotic therapy as summarized in Table 19–5. Table 19–5. Prophylaxis Recommendations from ACCP Consensus Conference on Antithrombotic Therapy, 2001, Based on Thromboembolism Risk for Surgical Patients.
Risk
Proximal PE DVT
Prevention
Low risk
0.4%
0.2% None
2–4%
1– 2%
Low dose heparin (5000 U subcutaneously every 12 h), or LMWH, or elastic stockings, or pneumatic compression stockings
4–8%
2– 4%
Low dose heparin every 8 h, LMWH, or pneumatic compression stockings
10–20%
4–
LMWH, oral
Early mobilization Minor surgery for patients under age 40 and no other risk factors Moderate risk
Minor surgery with other risk factors: nonmajor surgery for patients ages 40–60 without risk factors, major surgery patients under age 40 without risk factors High risk
Nonmajor surgery in patients over age 60 or with risk factors; major surgery for patients over age 40 or with risk factors Highest risk
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thromboembolism 10%
anticoagulants, pneumatic compression + LMWH/low-dose heparin, or full dose heparin
Major surgery in patients over age 40 plus prior thrombosis, cancer, or identified hypercoagulable risk; hip or knee arthroplasty, hip fracture surgery, major trauma, spinal cord injury
Hypercoagulable/Genetic Risk Factor Assessment The growing knowledge of genetic risk factors for VTE has captured the imagination but outstrips knowledge of clinical application. Many identified risk factors involve the activated protein C endogenous anticoagulant system, including the factor V Leiden (FVL) mutation where FVL fails to bind to the activated protein C complex and switch off thrombosis. Genetic polymorphisms such as FVL lead to underactivity of this endogenous anticoagulant system, as do high levels of factor VIII and low levels of protein C or protein S. Other wellcharacterized procoagulant conditions associated with higher risk of venous thromboembolism include the antithrombin (AT) deficiency, formerly called AT III. High levels of homocysteine and the prothrombin 20210 G-A point mutation are moderate risk factors. Abnormalities of the fibrinolytic system that are not yet fully characterized likely enhance risk as well. These include high levels of or mutations in fibrinogen and the plasminogen activator inhibitor, PAI-1. Although there is much interest in the inherited genetic polymorphisms, acquired conditions often pose a hypercoagulable risk. The lupus anticoagulant, measured as an elevated anticardiolipin antibody, is a common example. There is growing recognition that hypercoagulability risks may be acquired rather than only inherited. Acquired inflammatory conditions, including malignancy, infection, and collagen vascular disease, may induce a hypercoagulable state and thrombus formation. Combinations of genetic and acquired risk may result in a synergistic increase in thrombosis risk. In addition to heightened risk from a genetic plus an acquired risk factor, two or more genetic risk factors also appear to act synergistically to increase risk of VTE. A genetic panel of tests is frequently ordered at the time of clinical diagnosis of PE. Assessment for a hypercoagulable state should be considered in persons younger than age 45 with thrombosis, for those with a positive family history, and/or in the setting of recurrent VTE. For genetic testing, the timing of sample accrual is not important, however, factor levels, antithrombin, and protein S and protein C activity are affected by disease and use of anticoagulant drugs. Patients may be inappropriately labeled protein C deficient, for example, if samples are taken during presentation with an acute clot. Optimal timing of samples is at least 3 weeks after stopping all anticoagulant medications. Although debatable, a standard hypercoagulable work-up should start with prothrombin time (PT), activated partial thromboplastin time (PTT), and anticardiolipin antibody (aCL) or lupus anticoagulant, using the latter to assess for antiphospholipid syndrome, which is relatively common in adults with unexplained thrombosis. For persons younger than age 45, with multiple recurrent thromboses or thrombosis in the absence of clinical risk factors, where there is a higher likelihood of inherited risk, a genetic work-up may be slightly more extensive and include antithrombin, protein C, protein S, and factor V Leiden. Good outcome data are, however, lacking for this recommendation. Suspected Pulmonary Embolism in Pregnancy In the evaluation of suspected pulmonary embolism, ventilation–perfusion scanning appears to be a safe diagnostic study and may be used in conjunction with lower extremity ultrasound in the setting of a nondiagnostic scan. Regarding therapy for acute venous thromboembolism, unfractionated heparin or LMWH should be utilized as warfarin clearly has teratogenic effects. Prognosis Approximately 1% of pulmonary emboli result in death. Patients may be left with debilitating symptoms of shortness of breath and chronic pulmonary hypertension, although most have resolution of the majority of their symptoms. Postphlebitic syndrome causes symptoms for approximately 20% of those with DVT. A person with a single PE or DVT in a high clinical risk setting may never have a recurrence. If an event is idiopathic or if there are multiple events, the clinical risk of recurrent thrombosis versus the risk of anticoagulant-induced bleeding should be weighed to see if there is reason for life-long anticoagulation therapy. Adcock DM, Fink L, Marlar RA: A laboratory approach to the evaluation of hereditary hypercoagulability. Am J Clin Pathol 1997;108:434. (One view of hypercoagulable assessment.) [PMID: 9322598] American Thoracic Society Committee on Venous Thromboembolism: The diagnostic approach to acute venous thromboembolism, Clinical Practice Guideline. Am J Respir Crit Care Med 1999;160:1043. (This is an extensive compilation of detailed information on diagnostic testing.) [PMID: 10471639] Chan WS et al: Suspected pulmonary embolism in pregnancy. Arch Intern Med 2002;162:1170. (This cohort study of 120 pregnant women undergoing evaluation for suspected pulmonary embolism addresses ventilation–perfusion scans and safety.) [PMID: 11530132] Dalen JE, Hirsh J, Guyatt G (eds): Sixth ACCP Consensus Conference on Antithrombotic Therapy. Chest 2001;119(Suppl): 1S. (This document is the consensus of experts and has an extensive bibliography and treatment recommendations.) Decousus H et al: A clinical trial of vena caval filters in the prevention of pulmonary embolism in patients with proximal deep-vein thrombosis. Prevention du Risque d'Embolie Pulmonaire par Interruption Cave Study Group. N Engl J Med 1998;338:409. (The only randomized trial using vena caval filters.) [PMID: 9459643] Goldstein N et al: The impact of the introduction of a rapid d-dimer assay on the diagnostic evaluation of suspected pulmonary embolism. Arch Intern Med 2001;161:567. (Randomized prospective trial examining the impact of a rapid d-dimer assay on diagnostic testing.) [PMID: 11252116] Ost D et al: The negative predictive value of spiral computed tomography for the diagnosis of pulmonary embolism in patients with nondiagnostic ventilation-perfusion scans. Am J Med 2001;110:16. (Results are reassuring but patient selection may have biased these results.) [PMID: 11152860] PIOPED Investigators: Value of the ventilation/perfusion scan in acute pulmonary embolism. Results of the prospective investigation of pulmonary embolism diagnosis (PIOPED). JAMA 1990;263:2753. (This is a comprehensive study comparing ventilation–perfusion scanning to the "gold standard" pulmonary angiography.) [PMID: 2332918] Rathbun S, Raskob G, Whitsett T: Sensitivity and specificity of helical computed tomography in the diagnosis of pulmonary embolism: a systematic review. Ann Intern Med 2000;132:227. (This is a review of the case series that use helical CT scanning for PE diagnosis. Many
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thromboembolism design flaws are revealed.) [PMID: 10651604] Ridker, P et al: Long-term, low intensity warfarin therapy for the prevention of recurrent venous thromboembolism. N Engl J Med 2003;348:1425 (Randomized trial that concludes that in cases of idiopathic venous thromboembolism, long-term, low-intensity warfarin therapy is beneficial.) [PMID: 126010175] Stein PD, Henry JW: Clinical characteristics of patients with acute pulmonary embolism stratified according to their presenting syndromes. Chest 1997;112:974. (Study evaluating presenting clinical symptoms.) [PMID: 9377961] Wells PS et al: Excluding pulmonary embolism at the bedside without diagnostic imaging: management of patients with suspected pulmonary embolism presenting to the emergency department by using a simple clinical model and d-dimer. Ann Intern Med 2001;135:98. (An excellent method of combining a clinical index with d-dimer levels to minimize use of ventilation–perfusion scanning.) [PMID: 11453709]
current pediatrics
1-3 of 3 Results
Pulmonary Embolism CURRENT Diagnosis & Treatment: Pediatrics > Chapter 18. Respiratory Tract & Mediastinum >
Pulmonary Circulation
Contraception CURRENT Diagnosis & Treatment: Pediatrics > Chapter 3. Adolescence >
Diseases of the
Gynecologic Disorders in Adolescence
Cerebrovascular Disease CURRENT Diagnosis & Treatment: Pediatrics > Chapter 23. Neurologic & Muscular Disorders >
the Nervous System in Infants & Children
Disorders Affecting
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--------------------------------
Pulmonary Embolism General Considerations
:
commonly in Although pulmonary embolism is apparently rare in children, the children with sickle cell anemia i n c i d e n c e i s p r o b a b l y u n d e r e s t i m a t e d because it is often not considered in as part of the acute chest the differential diagnosis of respiratory distress. syndrome It occurs most
and with
rheumatic fever, infective endocarditis, schistosomiasis, bone fracture, dehydration,
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thromboembolism
polycythemia, nephrotic syndrome, atrial fibrillation, and other conditions. A recent report suggests that a majority of children with pulmonary emboli referred for hematology evaluation have coagulation regulatory protein abnormalities and antiphospholipid antibodies. Emboli may be single or multiple, large or small, with clinical signs and symptoms dependent on the severity of pulmonary vascular obstruction.
Clinical Findings Symptoms and Signs Pulmonary embolism usually presents clinically as an acute onset of dyspnea and tachypnea. Heart palpitations or a sense of impending doom may be reported. Pleuritic chest pain and hemoptysis may be present (not common), along with splinting, cyanosis, and tachycardia. Massive emboli may be present with syncope and cardiac arrhythmias. Physical examination is usually normal (except for tachycardia and tachypnea) unless the embolism is associated with an underlying disorder. Mild hypoxemia, rales, focal wheezing, or a pleural friction rub may be found. Laboratory Findings and Imaging Radiographic findings may be normal, but a peripheral infiltrate, small pleural effusion, or elevated hemidiaphragm can be present. If the emboli are massive, differential blood flow and pulmonary artery enlargement may be appreciated. The electrocardiogram is usually normal unless the pulmonary embolus is massive. Echocardiography is useful in detecting the presence of a large proximal embolus. A negative D-dimer has a more than 95% negative predictive value for an embolus. Ventilation-perfusion scans show localized areas of ventilation without perfusion. Spiral CT with contrast may be helpful, but pulmonary angiography is the gold standard. Further evaluation may include Doppler ultrasound studies of the legs to search for deep venous thrombosis. Coagulation studies, including assessments of antithrombin III and protein C or S deficiencies or defective fibrinolysis may be indicated. Antiphospholipid antibodies and other coagulation regulatory proteins (proteins C and S, and factor V Leiden) should be checked, as abnormalities have been demonstrated in 70% of the hematology referrals in one pediatric institution.
Treatment
:
Current recommendations include
Acute treatment includes
heparin administration to maintain supplemental oxygen, sedation, and anticoagulation. an activated partial thromboplastin time that is 1.5 or more times the control value for the first 24 hours. Urokinase (2000–4000 units/kg for 36 hours) can be used to help dissolve the embolus. Tissue plasminogen activator is another option via central or peripheral administration.
These therapies should be followed by warfarin therapy for at least 6 weeks with an international normalized ratio (INR) greater than 2. In patients with identifiable deep venous thrombosis of the lower extremities and significant pulmonary emboli (with hemodynamic compromise despite anticoagulation), inferior vena caval interruption may be necessary. However, long-term prospective data regarding this latter therapy are lacking.
Bounameaux H: Review: ELISA D-dimer is sensitive but not specific in diagnosing pulmonary embolism in an ambulatory clinical setting. ACP J Club 2003;138:24. [PMID: 12511136]
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thromboembolism Kearon C: Duration of therapy for acute venous thromboembolism. Clin Chest Med 2003;24:63. [PMID: 12685057] Konstantinides S et al: Heparin plus alteplase compared with heparin alone in patients with submassive pulmonary embolism. N Engl J Med 2002;347:1143. [PMID: 12374874] Rahimtoola A et al: Acute pulmonary embolism: An update on diagnosis and management. Curr Probl Cardiology 2005;30:61. [PMID:
15650680]
Remy-Jardin M et al: Pulmonary embolus imaging with multislice CT. Radiol Clin North Am 2003;41:507. [PMID: 12797603]
Adolescence / contraception Oral & Cutaneous Contraceptives OCPs have a three-pronged mechanism of action: (1) suppression of ovulation; (2) thickening of the cervical mucus, thereby making sperm penetration more difficult; and (3) atrophy of the endometrium, which diminishes the chance of implantation. The latter two actions are progestin effects. Combination OCPs contain both estrogen and progestin. Ethinyl estradiol is the estrogen currently used in nearly all OCPs in the United States. A number of progestins are used in OCPs and differ in their estrogenic, antiestrogenic, and androgenic effects. As estrogen doses decreased in OCPs, the androgenic side effects of progestins became more apparent, leading to the development of two progestins (desogestrel and norgestimate) with lower androgenic potential. All of the lower androgenic pills improve acne and may especially benefit patients with polycystic ovary syndrome. Reports of increased risk of thromboembolism associated with the newer progestins are likely related to an excess of first-time users among desogestrel patients. Factor V Leiden has been identified as a risk factor for venous thrombosis; 5% of patients of European ancestry are carriers of factor V Leiden. Carriers have a 30-to 50-fold increased risk for thrombosis. Testing family members with a history of venous thrombosis for factor V Leiden and other conditions such as the prothrombin gene mutation, proteins C and S, and antithrombin III before prescribing estrogen-containing OCPs to the adolescent may prevent these complications. OCPs have many noncontraceptive benefits, including improvement of dysmenorrhea, menorrhagia, acne, and PMS; suppression of ovarian and breast cysts; and lower risk of anemia, pelvic inflammatory disease, and ectopic pregnancy. A pill containing 30–35 mg of ethinyl estradiol with norgestimate, desogestrel, or 0.5 mg norethindrone is recommended for most adolescents beginning OCPs. Ortho Evra is a combined estrogen-progesterone patch, which is worn 3 weeks out of every 4. It releases 150 mcg of norelgestromin and 20 mcg of ethinyl estradiol per day. Side effects are similar to those of combined OCPs. Reports of increased thrombotic events reinforce the importance of screening patients for risk factors for thrombosis (personal or family history of thrombosis) prior to prescription of the patch. Five percent of patients report having a patch come off. Two percent report skin irritation. Efficacy may be reduced in patients weighing more than 200 pounds. The patch is an attractive alternative to OCPs for adolescents who have difficulty remembering to take a pill every day, as compliance is increased. The failure rate for the patch is reported to be 1%. Progestin-only pills contain no estrogen. Their chief use is in women who experience unacceptable estrogen-related side effects with combination OCPs or who have a contraindication to estrogen-containing pills. Their lack of estrogen, however, is also responsible for the main side effect, less predictable menstrual patterns. For this reason, progestin-only pills are not often desirable for adolescents. Their mechanism of action relies on the progestin-mediated actions, and ovulation is suppressed in only 15–40% of cycles.
Neurologic & Muscular Disorders Cerebrovascular Disease Pediatric arterial ischemic stroke is subdivided into two categories: neonatal arterial ischemic stroke (neonatal stroke) and childhood arterial ischemic stroke (childhood stroke). Generally, neonatal stroke is defined as arterial ischemia occurring in a patient younger than age 28 days and older than 28 weeks' gestation. Childhood stroke is any stroke occurring in a patient between 28 days and 18 years old. Childhood Stroke Childhood stroke is emerging as a serious and increasingly recognized disorder, affecting 2–8:100,000 children. There are numerous adverse outcomes, which include death in 10%, neurologic deficits or seizures in 60–85%, and recurrent strokes in 20–35%. The initial approach to the patient should recognize that childhood stroke represents a neurologic emergency, for which promptness in diagnosis can affect treatment considerations and outcome. Unfortunately, most pediatric stroke is not recognized until 24–36 hours after onset; treatment considerations matter most in the first hours after stroke onset. When possible, all children who present with stroke should be transferred to a tertiary care center that specializes in pediatric stroke management. The evaluation should include a thorough history of prior illnesses, especially those associated with varicella (even in the prior 1–2 years) influenza, parvovirus B19, HIV, minor trauma to the head and neck, and familial clotting tendencies. A systematic search for evidence of cardiac, vascular, hematologic, or intracranial disorders should be undertaken (Table 23–17 ). Although many strokes are not associated with a single underlying systemic disorder, previously diagnosed congenital heart disease is the most common predisposing illness, followed by hematologic and neoplastic disorders. In many instances the origin is multifactorial, necessitating a thorough investigation even when the cause may seem obvious. As a result, the cause of childhood stroke is increasingly determined, whereas in past studies up to 30% remained idiopathic. This is particularly important when considering that recurrence risk may be as high as 35%. Disorders Affecting the Nervous System in Infants & Children > Cerebrovascular Disease > Childhood Stroke >
Table 23–17. Etiologic Risk Factors for Stroke.
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thromboembolism Cardiac disorders Cyanotic heart disease Valvular disease Rheumatic Endocarditis Cardiomyopathy Cardiac dysrhythmia Vascular occlusive disorders Arterial trauma (carotid dissections) Homocystinuria/homocystinemia Vasculitis Meningitis Polyarteritis nodosa Systemic lupus erythematosus Drug abuse (amphetamines) Varicella Mycoplasma Human immunodeficiency virus Fibromuscular dysplasia Moyamoya disease Diabetes Nephrotic syndrome Systemic hypertension Dural sinus and cerebral venous thrombosis Cortical venous thrombosis Hematologic disorders Iron deficiency anemia Polycythemia Thrombotic thrombocytopenia Thrombocytopenic purpura Hemoglobinopathies Sickle cell disease Coagulation defects Hemophilia Vitamin K deficiency Hypercoagulable states Prothrombin gene mutation Methylenetetrahydrofolate reductase mutation Lipoprotein (a) Factor V Leiden deficiency Antiphospholipid antibodies Hypercholesterolemia Hypertriglyceridemia Factor VIII elevation Pregnancy Systemic lupus erythematosus Use of oral contraceptives Antithrombin III deficiency Protein C and S deficiencies Leukemia Intracranial vascular anomalies Arteriovenous malformation Arterial aneurysm Carotid-cavernous fistula Transient cerebral arteriopathy
Clinical Findings Symptoms and Signs Manifestations of stroke in childhood vary according to the vascular distribution to the brain structure that is involved. Because
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thromboembolism many conditions leading to childhood stroke result in emboli, multifocal neurologic involvement is common. Children may present with acute hemiplegia similarly to stroke in adults. Symptoms of unilateral weakness, sensory disturbance, dysarthria, and dysphagia may develop over a period of minutes, but at times progressive worsening of symptoms may evolve over several hours. Bilateral hemispheric involvement may lead to a depressed level of consciousness. The patient may also demonstrate disturbances of mood and behavior and experience focal or multifocal seizures. Physical examination of the patient is aimed not only at identifying the specific deficits related to impaired cerebral blood flow, but also at seeking evidence for any predisposing disorder. Retinal hemorrhages, splinter hemorrhages in the nail beds, cardiac murmurs, rash, neurocutaneous stigmata, and signs of trauma are especially important findings. Laboratory Findings and Ancillary Testing In the acute phase, certain investigations should be carried out emergently with consideration of treatment options. This should include complete blood count, erythrocyte sedimentation rate, basic chemistries, blood urea nitrogen, creatinine, prothrombin time/partial thromboplastin time, chest radiography, electrocardiography, urine toxicology, and imaging (see following section). Subsequent studies can be carried out systemically, with particular attention paid to disorders involving the heart, blood vessels, platelets, red cells, hemoglobin, and coagulation proteins. Twenty to 50% of all pediatric stroke patients will have a prothrombotic state. Additional laboratory tests for systemic disorders such as vasculitis, mitochondrial disorders, and metabolic disorders are sometimes indicated. Examination of CSF is indicated in patients with fever, nuchal rigidity, or obtundation when the diagnosis of intracranial infection requires exclusion. Lumbar puncture may be deferred until a neuroimaging scan (excluding brain abscess or a space-occupying lesion that might contraindicate lumbar puncture) has been obtained. In the absence of infection and frank intracranial subarachnoid hemorrhage, CSF examination is rarely helpful in defining the cause of the cerebrovascular disorder. When seizures are prominent, an EEG may be used as an adjunct in the patient's evaluation. An EEG and sequential EEG monitoring may help in patients with severely depressed consciousness. Electrocardiography and echocardiography are useful both in the diagnostic approach to the patient and in ongoing monitoring and management, particularly when hypotension or cardiac arrhythmias complicate the clinical course. Imaging CT and MRI scans of the brain are helpful in defining the extent of cerebral involvement with ischemia or hemorrhage. CT scans may be normal within the first 12–24 hours of an ischemic stroke and may need to be repeated. CT scan early after the onset of neurologic deficits is valuable in excluding intracranial hemorrhage. This information may be helpful in the early stages of management and in the decision to treat with anticoagulants. State-of-the-art management of stroke in the adult population omits CT scanning but proceeds directly to urgent MRI, MRA , and diffusion-weighted imaging since these modalities are sensitive to acute stroke in the initial 3 hours, when intravenous thrombolytics might be considered. Increasingly, MRI with diffusion-weighed imaging is becoming the standard of care in diagnosing pediatric stroke. Vascular imaging is an important part of pediatric stroke management and may include CTA, MRA , or conventional angiography. In studies in which both MRA and cerebral angiography have been used, up to 80% of patients with ischemic stroke have demonstrated a vascular abnormality. Vascular imaging is helpful in diagnosing disorders such as transient cerebral arteriopathy, arteriopathy associated with sickle cell disease, moyamoya disease, arterial dissection, aneurysm, fibromuscular dysplasia, and chronic inflammatory vasculitis. Recent studies have demonstrated that patients with vascular abnormalities on MRA or conventional angiography have a much greater recurrence risk than patients with normal vessels. When vessel imaging is performed, all major vessels should be studied from the aortic arch. If evidence of fibromuscular dysplasia is present in the intracranial or extracranial vessels, renal arteriography is indicated. Differential Diagnosis Patients with an acute onset of neurologic deficits must be evaluated for other disorders that can cause focal neurologic deficits. Hypoglycemia, prolonged focal seizures, a prolonged postictal paresis (Todd paralysis), acute disseminated encephalomyelitis, meningitis, encephalitis, and brain abscess should all be considered. Migraine with focal neurologic deficits may be difficult to differentiate initially from ischemic stroke. Occasionally the onset of a neurodegenerative disorder (eg, adrenoleukodystrophy or mitochondrial disorder) may begin with the abrupt onset of seizures and focal neurologic deficits. The possibility of drug abuse (particularly cocaine) and other toxic exposures must be investigated diligently in any patient with acute mental status changes. Treatment The initial management of stroke in a child is aimed at providing support for pulmonary, cardiovascular, and renal function. Patients should be administered oxygen. Typically, maintenance fluids without added glucose are indicated to augment vascular volume. Specific treatment of stroke, including blood pressure management, fluid management, and anticoagulation measures, depends partly on the underlying pathogenesis. Meningitis or varicella infections should be treated. Sickle cell patients require specialists in hematology to perform urgent exchange transfusion and most patients will require chronic transfusions after hospital discharge. Moyamoya is usually treated with surgical revascularization. In most idiopathic cases of childhood stroke without hemorrhage, anticoagulation or aspirin therapy is indicated. The Royal College of Physicians Pediatric Stroke Working Group recommends aspirin, 5 mg/kg daily, as soon as the diagnosis is made. Aspirin use appears safe and has not been associated with Reye syndrome in pediatric stroke patients. Other groups, such as the American College of Chest Physicians, recommend initial treatment with anticoagulants, such as low-molecular-weight heparin or unfractionated heparin, for 5–7 days (while excluding cardiac sources and dissection) and then switching to aspirin (3–5 mg/d). In some situations, such as arterial dissection, stuttering stroke, emboli, and consumptive coagulopathies, emergent heparinization is usually indicated. In adults with cerebrovascular thrombosis, thrombolytic agents (tissue plasminogen activator) used systemically or delivered directly to a vascular thrombotic lesion using interventional radiologic techniques has been shown to improve outcome. Although case reports exist, studies in children have not been completed. Given the time-lag to diagnosis and the lack of evidence in children, tissue plasminogen activator is currently used in less than 2% of U.S. children with stroke. Long-term management requires intensive rehabilitation efforts and therapy aimed at improving the child's language, educational, and psychological performance. Length of treatment with various agents, such as low-molecular-weight heparin and aspirin, is still being studied and depends on the etiology. Constraint therapy may be particularly helpful in cases of hemiparesis. Multidisciplinary stroke teams are the best resource for making these decisions. Prognosis The outcome of stroke in infants and children is variable. Roughly 40% may have minimal or no deficits, 30% are moderately affected, and 30% are severely affected. Underlying predisposing conditions and the vascular territory involved all play a role in dictating the outcome for an individual patient. When the stroke involves extremely large portions of one hemisphere or large portions of both
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thromboembolism hemispheres and cerebral edema develops, the patient's level of consciousness may deteriorate rapidly, and death may occur within the first few days. Some patients may achieve almost complete recovery of neurologic function within several days if the cerebral territory is small. Seizures, either focal or generalized, may occur in 30–50% of patients at some point in the course of their cerebrovascular disorder. Recurrence is 20–35%, and is more prominent in some conditions, such as protein C deficiency, lipoprotein (a) abnormalities and arteriopathies. Chronic problems with learning, behavior, and activity are common. Long-term follow-up with a multidisciplinary stroke team is indicated. Neonatal Stroke Neonatal stroke is more common than childhood stroke, affecting 1:4000 children. Neonatal stroke has two distinct presentations: acute and delayed. Most patients with an acute presentation develop neonatal seizures during the first week of life, usually in association with a perinatal event. The seizures in acute neonatal stroke are often focal motor seizures of the contralateral arm and leg. The presentation is stereotypical because of the predilection of the stroke to occur in the middle cerebral artery. The presence of diffusionweighted abnormalities on an MRI scan confirms an acute perinatal stroke during the first week of life. Others patients present with delayed symptoms, typically with an evolving hemiparesis at an average of 4–8 months. Acute treatment of a neonatal stroke is usually limited to neonates with seizures. Unless an embolic source is identified, aspirin and anticoagulation are usually deferred. Management is based on supportive care, identification of comorbid conditions, and treatment of seizures. In acute neonatal stroke, treatable causes of the stroke such as infection, cardiac embolus, metabolic derangement, and dissection must be ruled out. In appropriate cases, echocardiography, MRA , and lumbar puncture are indicated. Supportive management focuses on general measures, such as normalizing glucose levels, monitoring blood pressure, and optimizing oxygenation. Long-term management of neonatal stroke usually starts with identifying risk factors, which might include prothrombotic states, cardiac disease, drugs, and dehydration. Although prothrombotic abnormalities with the best evidence of association are factor V Leiden, protein C deficiency, and lipoprotein (a), many neurologists perform an extensive hematologic workup. Maternal risk factors such as infertility, antiphospholipid antibodies, placental infection, premature rupture of membranes, and cocaine exposure are all independently associated with neonatal stroke. The prognosis for children who sustain neonatal strokes is generally better than for children or adults with strokes, presumably because of the plasticity of the neonatal brain. Twenty to 40% of patients who experience neonatal strokes are neurologically normal. Motor impairment affects about 40% of patient and is predominantly hemiplegic cerebral palsy. In acute presentations, MRI can be predictive of motor impairment, as descending corticospinal tract diffusion-weighted MRI signal is associated with a higher incidence of hemiplegia. Language delays, behavioral abnormalities, and cognitive deficits are seen in 20–30% of infants who experience neonatal strokes. Patients are also at an increased risk for seizures. Stroke recurs in 3% of neonates and is usually associated with a prothrombotic abnormality or an underlying illness, such as cardiac malformation or infection. Given the low incidence of recurrence, long-term management is largely rehabilitative, including constraint therapies. Barnes C et al: Prothrombotic abnormalities in childhood ischaemic stroke. Thromb Res 2005;1. [PMID: 16039697] deVeber G: In pursuit of evidence-based treatments for paediatric stroke: The UK and Chest guidelines. Lancet Neurol 2005;7:432. [PMID: 15963446] Duran R et al: Factor V Leiden mutation and other thrombophilia markers in childhood ischemic stroke. Clinical and applied thrombosis/hemostasis. Clin Appl Thromb Hemost 2005;11:83. [PMID: 15678277] Friefeld S et al: Health-related quality of life and its relationship to neurological outcome in child survivors of stroke. CNS Spectr 2004;6:465. [PMID: 15162094] Fullerton H et al: Risk of recurrent childhood arterial ischemic stroke in a population-based cohort: The importance of cerebrovascular imaging. Pediatrics 2007;119:3. [PMID: 17332202] Gabis L et al: Time lag to diagnosis of stroke in children. Pediatrics 2002;110:924. [PMID: 12415031] Ganesan V et al: Clinical guidelines for the management of childhood stroke. Hosp Med 2005;1:4. [PMID: 15686158] Ganesan V et al: Investigation of risk factors in children with arterial ischemic stroke. Ann Neurol 2003;53:167. [PMID: 12557282] Janjua N et al: Thrombolysis for ischemic stroke in children data from the nationwide inpatient sample. Stroke 2007;38. [PMID:
17431210]
Kirton A et al: Cerebral palsy secondary to perinatal ischemic stroke. Clin Perinatol 2006;367 [PMID: 16765730] Kirton A et al: Quantified corticospinal tract diffusion restriction predicts neonatal stroke outcome. Stroke 2007;38:3. [PMID: 17272775] Kurnik K et al: Recurrent thromboembolism in infants and children suffering from symptomatic neonatal arterial stroke. Stroke 2003;34:2887. [PMID: 14631084] Lee J et al: Maternal and infant characteristics associated with perinatal arterial stroke in the infant. JAMA 2005;293:723. [PMID:
15701914]
Lee J et al: Predictors of outcome in perinatal arterial stroke: A population-based study. Ann Neurology 2005;58:303. [PMID: 16010659] Lee M et al: Stroke prevention trial in sickle cell anemia (STOP): Extended follow-up and final results for the STOP Study Investigators. Blood 2006;108:847. [PMID: 16861341] Lynch J et al: Pediatric stroke: What do we know and what do we need to know? Semin Neurol 2005;4:410. [PMID: 16341997] Monagle et al: Antithrombotic therapy in children: The seventh ACCP conference on antithrombotic and thrombolytic therapy. Chest 2004;126:645. [PMID: 15383489] Nelson K et al: Stroke in newborn infants. Lancet Neurol 2004;3:150. [PMID: 14980530] Sebire G et al: Toward the definition of cerebral arteriopathies of childhood. Curr Opin Pediatr 2004;16:617. [PMID: 15548922] Shellhaas R et al: Mimics of childhood stroke: Characteristics of a prospective cohort. Pediatrics 2006;118:704. [PMID: 16882826] Sofronas M et al: Pediatric stroke initiatives and preliminary studies: What is known and what is needed? Pediatr Neurol 2006;34:439. [PMID: 16765821]
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Taub E et al: Pediatric CI therapy for stroke-induced hemiparesis in young children. Dev Neurorehabil 2007;10:3. [PMID: 17608322] Zahuranec DB et al: Is it time for a large, collaborative study of pediatric stroke? Stroke 2005;36:1825. [PMID: 16100029]
current otolaryngology
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Prognosis & Surgery-Related Complications CURRENT Diagnosis & Treatment in Otolaryngology > Chapter 61.
Neuroma)
Vestibular Schwannoma (Acoustic
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----------------------------------------Vestibular Schwannoma (Acoustic Neuroma)
Postoperative Complications
:
Postoperative hemorrhage manifests as neurologic and cardiovascular deterioration and requires evacuation.
Postoperative complications include hemorrhage, stroke, venous
Studies have shown that, postoperatively, low-molecularweight heparin in addition to compression stockings and intermittent t h r o m b o e m b o l i s m , t h e s y n d r o m e o f inappropriate antidiuretic hormone pneumatic compression devices may further reduce the risk of thromboembolism in high-risk patients (eg, elderly and obese (SIADH), CSF leak, and meningitis. patients) without increasing the risk of intracranial bleeding.
The most common complication is CSF leak. Most of these leaks resolve with conservative care, which includes placing wound sutures at the leak site, replacing the mastoid dressing, DECREASING INTRACRANIAL
PRESSURE WITH ACETAZOLAMIDE (DIAMOX) ,
fluid
restriction, and bed rest.
CSF leak occurs in 5–10% of cases either via the wound or via a pneumatic pathway to the eustachian tube.
Some patients also require a lumbar subarachnoid drain (LSAD), and a very few patients need surgical reexploration. A related complication is meningitis.
Meningitis occurs in 2–10% of patients and may be aseptic, bacterial, or due to CSF leak and arachnoid irritation from the fat graft (lipoid).
The distinction between aseptic and bacterial meningitis is necessary because THE TREATMENT FOR ASEPTIC
MENINGITIS IS A STEROID TAPER
and antibiotics for
bacterial meningitis. Delayed meningitis should be considered bacterial and likely due to a CSF leak.
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current orthopedics
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Immediate Management of Musculoskeletal Trauma CURRENT Diagnosis & Treatment in Orthopedics > Chapter 3.
Postoperative Care CURRENT Diagnosis & Treatment in Orthopedics > Chapter 2.
Surgery
Musculoskeletal Trauma Surgery
General Considerations in Orthopedic
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-----------------------------------Musculoskeletal Trauma Surgery
Pulmonary Embolism and Deep Venous Thrombosis
The trauma patient is at risk Although ARDS and atelectasis are seen in the early postoperative for PE, and the patient with period, pulmonary embolism (PE) is spinal cord injury even more so. u n c o m m o n s o o n e r t h a n 5 d a y s a f t e r t h e onset of immobilization or bed rest.
Population based studies have demonstrated recent trauma to be associated with a 13-fold increased risk of venous thromboembolism.
Young multiple-trauma patients without prophylaxis have been shown to have a 1–2% incidence of fatal PE, which appears to decrease with a variety of prophylactic measures. Other groups of patients at risk include the elderly (>70 years), the obese, those with a history of prior venous thromboembolism, major surgery of the abdomen, pelvis or extremities, and fractures of the pelvis, hip or leg, and those with malignancy. Although it is uncommon, even a young (<30 years) healthy person can develop deep venous thrombosis (DVT) and be at risk for PE after a long car or airplane trip in which the legs are dependent. Oral contraceptive and smoking use may also increase the risk for a young healthy patient.
Geerts and colleagues examined the incidence of DVT and PE in trauma patients in a prospective series with venography. They found patients to be at significantly increased risk if they had suffered a pelvis or long bone fracture with greater than 5 days immobilization in bed, were obese, had a preexisting coagulopathy or an Injury Severity Score (ISS) greater than 8. Overall, they reported an incidence of 58% with 18% proximal DVT in patients without prophylaxis.
The authors noted that fatal PE was the most common yet preventable form of
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death in the hospitalized trauma patient.
Clinically significant PE usually arise from the large veins proximal to the knee.
Patients at high risk for PE are those with DVT in the lower extremities, and pelvic veins.
Prevention of DVT in the venous system in this area reduces the risk of PE.
Various strategies used to accomplish this include drug therapy with LOW-DOSE HEPARIN, LOW-MOLECULAR-WEIGHT HEPARIN, PENTASACCHARIDE, OR SODIUM WARFARIN; AND MECHANICAL PROPHYLAXIS
1.
2.
with
intermittent pneumatic compression devices or inferior vena cava filters in the high risk patients with contraindications for pharmacologic prophylaxis.
Clinical diagnosis of DVT is unreliable. Prevention appears to be the best strategy as even routine surveillance screening in a trauma populations is cost-ineffective and does not appear to lower the overall rate of PE.
Pulmonary embolism is suspected in the orthopedic patient suffering an onset of tachypnea and dyspnea usually more than 5 days after an inciting event.
Definitive diagnosis is made with venography, duplex ultrasound scanning, impedance plethysmography, or CT or MRI venography.
The patient frequently reports chest pain and can often point to the painful area. Hemoptysis may also be present. On physical examination, tachycardia, cyanosis, and pleural friction rub can be noted.
Arterial blood gas studies demonstrate hypoxemia, although this is a nonspecific finding. Use of the d-dimer is unreliable in the early trauma patient but may be useful later in the recovery period. Definitive diagnosis is best made with pulmonary angiogram. Perfusion ventilation scanning is less invasive and may help determine whether there is a high or low probability of pulmonary embolus. Spiral CT is becoming useful in diagnosis of PE.
The natural history of treated PE is gradual lysis of the emboli, with the return of flow through the pulmonary arterial tree. The natural history of proximal DVT involves recanalization and arborization to bypass the clot.
Treatment involves pulmonary support and heparin therapy.
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thromboembolism Patients may suffer from
postphlebitic syndrome
characterized by chronically painful swelling in the extremity
current nephrology ang hypertension
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Percutaneous Thrombectomy
CURRENT Diagnosis & Treatment: Nephrology & Hypertension > Chapter 57. Interventional Nephrology: Endovascular Procedures > Core Endovascular Procedures
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current gastroenterology
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Mesenteric Artery Embolism & Thrombosis
CURRENT Diagnosis & Treatment: Gastroenterology, Hepatology, & Endoscopy > Chapter 6. Mesenteric Ischemia >
Acute Mesenteric Ischemia
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--------------------------------------------
Mesenteric Ischemia
Essential Concepts Acute mesenteric ischemia (AMI) is a medical and surgical emergency. Delay in diagnosis is associated with high mortality. Patients often present with
findings.
abdominal pain out of proportion to physical examination
Clinical suspicion of AMI necessitates
EARLY RADIOLOGIC EVALUATION (COMPUTED TOMOGRAPHIC
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[CT] ANGIOGRAPHY, CONVENTIONAL ANGIOGRAPHY) OR EXPLORATORY SURGERY IN PATIENTS WITH PERITONEAL SIGNS.
Chronic intestinal ischemia is a clinical diagnosis; patients report classic symptoms (eg, abdominal angina) and have radiographic findings showing
arteries.
severe stenoses or occlusion of two or more mesenteric
Colonic ischemia is rarely life-threatening and
usually resolves with supportive care
.
Etiology & Pathogenesis
Intestinal ischemia is caused by a reduction in intestinal blood flow, most commonly as a result of OCCLUSION, VASOSPASM, OR HYPOPERFUSION
of the mesenteric circulation.
It is categorized as acute or chronic, depending on the rapidity and the extent to which blood flow is compromised and whether it is episodic or constant, as might occur in chronic mesenteric ischemia.
Ischemia can involve the small intestine or colon. Acute small intestinal ischemia is a medical and surgical emergency that requires prompt diagnosis and a coordinated, interdisciplinary approach.
By contrast, a c u t e c o l o n i c i s c h e m i a ( i e , i s c h e m i c c o l i t i s ) i s r a r e l y a n e m e r g e n t c ondition.
Acute intestinal ischemia can be further categorized as arterial versus venous, embolic versus thrombotic, and occlusive versus nonocclusive.
Other causes of bowel ischemia include strangulating obstructions (adhesions, hernias, metastatic malignancy, intussusceptions) and vasculitis (systemic lupus erythematosus, polyarteritis nodosa).
Splanchnic Circulation: Anatomy & Physiology The vascular supply to the intestines includes the celiac artery, the superior mesenteric artery (SMA), and the inferior mesenteric artery (IMA) (Figure 6–1). The celiac axis supplies blood to the stomach and duodenum.
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thromboembolism The SMA supplies the small bowel from the distal duodenum to the mid-transverse colon. The inferior mesenteric artery supplies the transverse colon to the rectum. Anastomoses exist between branches of the major vessels and if one artery is occluded some flow may be maintained via a patent collateral vessel. Figure 6–1.
Distribution of blood supply to the small intestine and colon from the celiac artery, superior mesenteric artery (SMA), inferior mesenteric artery (IMA), and internal iliac artery (IIA).
(Reproduced, with permission, from Kasper DL, Braunwald E, Fauci AS, et al (editors). Harrison's Principles of Internal Medicine, 17th ed. McGraw-Hill, 2008.)
When a major vessel is occluded, collateral pathways open immediately in response to a fall in arterial pressure distal to the obstruction. The superior and inferior pancreaticoduodenal vessels are collaterals that connect the celiac axis to the SMA. The phrenic artery connects the aorta to the celiac axis.
The marginal artery of Drummond and the arc of Riolan are collaterals that connect the SMA and the IMA.
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The internal iliac arteries provide collaterals to the rectum. Griffith point in the splenic flexure and Sudek point in the rectosigmoid area are watershed areas within the colonic blood supply and common locations for ischemia.
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The splanchnic circulation receives 25% of the cardiac output under basal conditions and 35% or more postprandially. Approximately 70% of splanchnic inflow goes to the mucosa, which is the most metabolically active area of the gut.
The villus tips are the most vulnerable to ischemic injury. Intestinal blood flow is under complex regulation controlled primarily by
resistance arterioles and precapillary sphincters.
Several vasoactive substances influence intestinal perfusion.
Catecholamines, angiotensin II, and vasopressin whereas
all can cause vasoconstriction,
vasoactive intestinal peptide causes vasodilation.
Products of ischemia such as acidosis, hypoxemia, and hyperkalemia have been shown to cause vasodilation.
Ischemic damage is caused by both hypoxia and reperfusion injury. Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia. American Gastrointestinal Association. Gastroenterology. 2000;118:954– 968. [PMID: 10784596] Kirkpatrick ID, Kroeker MA, Greenberg HM. Biphasic CT with mesenteric CT angiography is the evaluation of acute mesenteric ischemia: initial experience. Radiology. 2003;229:91–98. [PMID: 12944600]
Acute Mesenteric Ischemia : Essentials of Diagnosis
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thromboembolism Maintain a high index of clinical suspicion.
>50 years who present with sudden onset of severe abdominal pain lasting >2 hours , especially if a history of cardiovascular disease (congestive heart failure, Consider
in patients
myocardial infarction, arrhythmia) is present. Consider in patients with ABDOMINAL PAIN OUT OF PROPORTION TO PHYSICAL FINDINGS.
Angiography is the diagnostic procedure of choice and is potentially therapeutic.
General Considerations due to
The incidence of AMI has increased over the past 20 years longer life expectancies, increased awareness of ischemic syndromes, and
Acute mesenteric ischemia (AMI) remains a challenging diagnosis with a mortality rate exceeding 50%.
enhanced diagnostic and therapeutic techniques.
The various causes of AMI include
SMA embolism (50%), SMA thrombosis (15–20%), nonocclusive mesenteric ischemia (NOMI; 20–25%), and mesenteric venous thrombosis (5–10%).
Mesenteric Artery Embolism & Thrombosis
:
Embolism to the SMA is most frequently due to a dislodged thrombus originating from the left atrium, left ventricle, or cardiac valves. One third of patients have a history of a prior embolic event and 20% have synchronous emboli. The onset of symptoms is abrupt and dramatic. SMA thrombosis usually occurs at the origin of the vessel, which is frequently an area of severe atherosclerotic narrowing.
Acute thrombosis usually occurs in a patient with underlying chronic intestinal ischemia.
This process is analogous to plaque
rupture in acute coronary syndromes.
Approximately 50% of patients have a history of chronic mesenteric ischemia, and the acute event occurs after closure of a collateral vessel.
Clinical Findings :
On examination the abdomen may be soft and either nontender or
Patients with AMI present with severe, acute, unremitting abdominal pain strikingly out of proportion to the
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minimally tender. Distention is often the first sign .
initial physical findings.
Later findings may include signs of peritonitis, especially if infarction or gangrene has occurred.
Associated symptoms may include nausea, emesis, and
transient diarrhea due to
urgent bowel evacuation. Occult blood is found in the stool in 50–75% of cases.
:
Laboratory Findings
Leukocytosis with a white blood cell count greater than 15,000/ L is found in 75% of patients.
However, most patients with early intestinal ischemia laboratory findings.
do not have abnormal
Lactic acidosis, hemoconcentration, and raised serum aminotransferase levels are usually late
findings indicative of intestinal infarction.
Imaging Studies :
Historically, standard radiologic imaging has not been useful in diagnosing AMI, because most of the reported "classic" findings (eg, bowel edema, pneumatosis intestinalis, portal venous gas) are not seen until late in the course of the illness. Plain films of the abdomen are usually normal, and the utility of these studies is to exclude other acute abdominal processes such as perforation or obstruction. Mesenteric angiography has been the gold standard for making the diagnosis of AMI; however, recent studies have demonstrated that CT scans may have an overall sensitivity of 80% for AMI, thanks to technical advances, including spiral CT, rapid intravenous bolus injection of contrast, and multidetector-row CT (MDCT) with threedimensional reconstruction. CT findings may be either more specific or nonspecific.
More specific findings include
thromboembolism in mesenteric vessels, portal venous gas, bowel wall intramural gas or pneumatosis, lack of bowel wall enhancement, and signs of ischemia in other organs.
Less specific signs include
diffuse bowel wall thickening, striking vascular engorgement, dilated fluid-filled loops of bowel, and mesenteric edema (Figure 6–2).
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thromboembolism Figure 6–2.
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CT scan findings of intestinal ischemia. A and B: Small bowel thickening. C: Small intestinal pneumatosis. D: Portal venous gas. (Courtesy of Koenraad Mortele, MD.)
Initial evaluation should include radiographic imaging to exclude other causes of acute abdominal pain such as perforation or obstruction.
MDCT can provide detailed information about the mesenteric vessels and small bowel and is
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particularly sensitive in the diagnosis of mesenteric venous thrombosis.
Angiography
Angiography is important in both diagnosis and management of AMI and remains the gold standard for evaluation of patients with suspected AMI and no peritoneal signs. It is the mainstay of diagnosis and treatment for both occlusive and NOMI.
It can be both diagnostic and therapeutic. Placement of a catheter into the SMA allows visualization of obstructing lesions and facilitates interventions such as
infusion of vasodilators into the SMA, angioplasty, stenting, or infusion of thrombolytics (Figure 6–3). Figure 6–3.
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A: Volume-rendered three-dimensional CT scan showing narrowing of the celiac trunk (arrowhead) and occlusion of the proximal SMA (arrow). B: Conventional angiogram showing SMA occlusion (arrow). (Reproduced, with permission, from Kirkpatrick Kroeker MA, Greenberg HM. Biphasic CT with mesenteric CT angiography is the evaluation of acute mesenteric ischemia: initial experience. Radiology. 2003;229:94.)
Treatment
The goal of treatment in AMI is to restore intestinal blood flow as rapidly as possible. However, initial management must include
hemodynamic resuscitation and correction of precipitating causes of AMI such as arrhythmias, congestive heart failure, or volume depletion.
Patients require aggressive hemodynamic monitoring and support, correction of fluid and electrolyte abnormalities, and treatment with broad-spectrum antibiotics.
Patients with peritoneal signs or clinical suspicion of perforation or gangrene require
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thromboembolism emergent laparotomy, after hemodynamic stabilization, to immediately restore mesenteric blood flow and resect nonviable bowel.
Patients
who are hemodynamically stable with no peritoneal signs
should undergo angiography to diagnose obstructive lesions and begin treatment with vasodilators, such as papaverine, which when infused directly into mesenteric vessels can help increase blood flow by reversing vasospasm.
Once an obstructing lesion is confirmed with angiography, patients can undergo either surgical revascularization (through aortomesenteric bypass grafting, embolectomy, or thromboendarterectomy) or endovascular revascularization (using techniques such as balloon dilation and angioplasty with or without stenting, or catheter-directed thrombolytic therapy, in selected cases).
The American Gastroenterological Association algorithm for diagnosis and management of acute intestinal ischemia is presented in Figure 6–4. Figure 6–4.
Algorithm for diagnosis and management of acute intestinal ischemia. DVT, deep venous thrombosis; SMA, superior mesenteric artery. (Reproduced, with permission, from American Gastroenterological Association Medical Position Statement: guidelines on intestinal ischemia. Gastroenterology. 2000;118:951.) Oldenburg WA, Lau LL, Rodenberg TJ, et al. Acute mesenteric ischemia: a clinical review. Arch Intern Med. 2004;164:1054–1062. [PMID: 15159262] Segatto E, Mortelé K, Ji H, et al. Acute small bowel ischemia: CT imaging findings. Semin Ultrasound CT MR. 2003;24:364–376. [PMID: 14620718] Wiesner W, Khurana B, Ji H, et al. CT of acute bowel ischemia. Radiology. 2003;226:635–650. [PMID: 12601205]
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Mesenteric Venous Thrombosis : Essentials of Diagnosis : Acute form—maintain a high index of suspicion in patients with recent onset of acute abdominal pain associated with a predisposing condition (ie, heritable or acquired hypercoagulable states). Diagnosed with 90% sensitivity by contrast CT, MDCT, or vascular angiography.
General Considerations :
Mesenteric venous thrombosis (MVT) accounts for 5–10% of all cases of AMI. The conditions responsible for the development of MVT can be identified in over 80% of cases, and risk factors are summarized in Table 6–1.
The clinical presentation of MVT can be
acute, characterized by the sudden onset of symptoms; subacute, in which symptoms occur for days or weeks without bowel infarction; or chronic, involving portal or splenic vein thrombosis and stigmata of portal hypertension with or without variceal bleeding.
Table 6–1. Causes of mesenteric venous thrombosis.
1. Hypercoagulable states a. Heritable disorder of coagulation (1) Factor V Leiden–resistance to activated protein C (2) Prothrombin gene mutation—A20210 b. Acquired hypercoagulable states (1) Paroxysmal nocturnal hemoglobinuria (2) Myeloproliferative disorders c. Deficiencies of anticoagulant proteins (1) Protein C and protein S (2) Antithrombin d. Acquired hypercoagulable states (1) Neoplasms (2) Oral contraceptives (3) Pregnancy
2. Inflammatory disorders a. Pancreatitis b. Intra-abdominal sepsis
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3. Cirrhosis and portal hypertension
Pathogenesis : MVT leads to resistance to mesenteric venous blood flow and intestinal ischemia, with
resultant bowel wall edema, fluid efflux into the bowel lumen, and systemic hypotension.
As a consequence of venous congestion, arterial inflow is diminished, which can lead to bowel ischemia and, ultimately, infarction.
The extent of the venous collateral circulation is a key variable influencing whether submucosal hemorrhage or bowel infarction will develop following MVT.
Clinical Findings : Symptoms and Signs As noted, the presentation of MVT can be
acute, subacute, or chronic.
Symptoms of acute MVT usually begin a few days to a few weeks (mean, 7 days) before presentation and in 25% of patients have been present for 30 days before admission.
Nausea, vomiting, and diarrhea are common, and over 50% of patients have occult blood in the stool. Examination findings include fever (50%), abdominal distention with mild to moderate tenderness and signs of dehydration, and hypotension (25%). Hematochezia, found in 15% of patients, usually signifies severe ischemia or bowel infarction.
Fever, guarding, rebound tenderness, lactic acidosis, and increased transaminases are late findings that may be associated with bowel infarction.
In the subacute form of MVT, symptoms such as abdominal pain can be present for several weeks along with an unremarkable physical examination.
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Patients with chronic MVT may not have experienced abdominal pain and The latter can be manifested by stigmata of portal hypertension, varices hematemesis or fecal (esophageal, gastric, intestinal), and blood loss.
often present with
splenomegaly or bleeding from varices.
Over 50% of patients with MVT have a personal or family history of deep venous thrombosis or pulmonary embolism. MVT should be suspected in patients with pain out of proportion to physical findings, especially if there is a personal or family history of such coagulation abnormalities.
Imaging Studies : The gold standard for the diagnosis of MVT is CT scan with intravenous contrast. Classical findings with a sensitivity of greater than 90% include a dilated superior mesenteric vein with a clot or filling defect in the lumen (Figure 6–5). It should be noted, however, that CT may be less reliable in early thrombosis if small vessels are involved. Portal venous gas, air in the small bowel, or free intraperitoneal air usually indicates intestinal infarction. Figure 6–5.
Acute superior mesenteric vein thrombosis; arrow points to a large thrombus in the proximal superior mesenteric vein. (Courtesy of David Stockwell, MD.) Treatment The treatment of acute MVT depends on whether intestinal infarction has occurred or is strongly suspected. For example, persistent peritoneal findings such as guarding or rebound tenderness should raise suspicion for gut infarction and warrant laparotomy (see Figure 6– 4). By contrast, in patients with clinical and radiologic evidence of MVT, but no infarction, and with good mesenteric blood flow demonstrated by angiography, conservative management can be attempted using anticoagulation therapy (ie, heparin). Anticoagulation is usually continued for 6 months or longer if coagulation abnormalities preceded MVT. Few data are available regarding long-term follow-up or the need for treatment after 6 months. Use of thrombolytics such as streptokinase, urokinase, and tissue plasminogen activator has not been studied in a large group of patients; however, catheter-directed thrombolysis has been performed in some cases. When there is suspicion of bowel infarction, laparotomy is required to restore mesenteric blood flow and resect gangrenous bowel segment(s). In cases in which there is extensive ischemic damage, massive intestinal resection followed by long-term parenteral nutrition may be required. Amitrano L, Brancaccio V, Guardascione MA, et al. High prevalence of thrombophilic genotypes in patients with acute mesenteric vein
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thromboembolism thrombosis. Am J Gastroenterol. 2001;96:146–149. [PMID: 11197244] Kumar S, Sarr MG, Kamath PS. Mesenteric venous thrombosis. N Engl J Med. 2001;345:1683–1688. [PMID: 11759648]
Nonocclusive Mesenteric Ischemia : Essentials of Diagnosis Accounts for ~20% of cases of AMI and results from intense mesenteric vasoconstriction, leading to splanchnic hypoperfusion. Maintain a high index of clinical suspicion. Suspect in patients with diffuse atherosclerotic disease under conditions of hemodynamic stress (hypotension), in the setting of vasoconstrictive agents (vasopressin, cocaine), and in patients with vasculitis (eg, systemic lupus erythematosus, polyarteritis nodosa). Angiography may be both diagnostic and therapeutic. Clinical Findings Signs and symptoms of NOMI may be similar to those of AMI. Patients who develop NOMI are typically elderly with diffuse vascular disease, but NOMI can also be seen in patients with vasculitis or who are on vasoconstricting medications. Predisposing factors include conditions such as myocardial infarction with decreased cardiac output, congestive heart failure, cardiac arrhythmias, sepsis, dehydration, and shock; medications such as diuretics, digoxin, and adrenergic agonists; and therapies such as dialysis. Vasopressin and angiotensin are the most likely mediators of the marked vasoconstriction. NOMI has also been reported after cocaine use. The mortality rate from NOMI is high for several reasons, including advanced patient age, comorbidities, and difficulty in making the diagnosis and reversing ischemia once it has started. When NOMI is suspected, angiography is the gold standard for diagnosis and management (Figure 6–6). Figure 6–6.
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Angiogram of the superior mesenteric artery in a patient with nonocclusive mesenteric ischemia (NOMI). A: Initial angiogram demonstrating diffuse vasoconstriction in setting of hypotensive shock. B: Angiogram after 48 hours of papaverine infusion, showing dilation. (Reproduced, with permission, from Boley SJ, Brandt LJ. Mesenteric ischemia. In: Baum S (editor). Abram's Angiography, 4th ed. Little, Brown, 1997:1627.) Treatment Treatment of NOMI includes hemodynamic resuscitation, antibiotics, and intra-arterial infusion of papaverine, a smooth muscle dilator, which reverses vasoconstriction and restores mesenteric blood flow. Bassiouny HS. Nonocclusive mesenteric ischemia. Surg Clin North Am. 1997;97:319–326. [PMID: 9146715] Brandt LJ, Boley SJ. AGA technical review on intestinal ischemia. American Gastrointestinal Association. Gastroenterology. 2000;118:954– 968. [PMID: 10784596]
Prognosis in Patients with AMI Survival of patients with AMI depends on early diagnosis and treatment. Reviewing outcomes of 21 patients with SMA embolism, Lobo Martínez and colleagues found intestinal viability was 100% in patients whose symptoms had lasted less than 12 hours, 56% when symptoms lasted 12–24 hours, and only 18% when symptoms lasted more than 24 hours. Survival was 90% in the setting of early angiography in patients with no peritonitis; however, among patients in whom intestinal infarction had already occurred, mortality was 80%. In summarizing data from 3692 patients with AMI from 1966–2002, Schoots and colleagues found that while overall survival has improved over the past four decades, in-hospital mortality remains high at 88% for SMA thrombosis, 86% for NOMI, 70% for SMA embolism, and 44% for SMV thrombosis. To recapitulate, mortality rates from AMI are 70–90% if diagnosis is delayed and intestinal gangrene develops. In patients with angiographically proven AMI who do not have peritonitis, survival rates now approach 90%. Early diagnosis and prompt intervention with angiography, or surgery, or both, are of critical importance for improving outcomes for patients with AMI.
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thromboembolism Lobo Martínez E, Meroño Carvajosa E, Sacco O, et al. [Embolectomy in mesenteric ischemia.] Rev Esp. Enferm Dig. 1993;83:351–354. [PMID: 8318278] Schoots IG, Koffeman GI, Legemate DA, et al. Systemic review of survival after acute mesenteric ischaemia according to disease aetiology. Br J Surg. 2004;91:17–27. [PMID: 14716789]
Chronic Mesenteric Ischemia : Essentials of Diagnosis Post-prandial abdominal pain, avoidance of eating (which triggers pain), weight loss, abdominal bruit (50% of patients). Angiography shows involvement of at least two of three major splanchnic blood vessels. General Considerations Chronic mesenteric ischemia (CMI) is the result of reduced blood flow due to atherosclerotic narrowing of at least two of three major vessels (ie, celiac axis, SMA, or IMA). Usually, an adequate collateral circulation has developed that prevents intestinal infarction. However, acute on chronic mesenteric ischemia and infarction can develop suddenly if thrombosis or embolism occurs in a severely narrowed artery. Clinical Findings Symptoms and Signs The classic diagnostic triad for CMI consists of post-prandial abdominal pain, weight loss, and an abdominal bruit. Pain from abdominal angina is typically recurrent, dull, crampy, epigastric, and periumbilical, occurring 10–30 minutes after meals and lasting 1–3 hours. Because eating consistently triggers pain, food fear causes patients to eat progressively less, resulting in weight loss and often cachexia. Most patients have a history of peripheral vascular disease (PVD). It is important to note that some patients with PVD develop abdominal angina after undergoing surgical repair of peripheral vascular lesions because of so-called steal syndrome (ie, increased blood flow to the extremities and away from the mesenteric circulation). Physical examination of CMI patients usually reveals a soft abdomen without tenderness during episodes of pain, hence the classic description of pain disproportionate to physical findings. As many as 50% of CMI patients have an epigastric bruit, especially postprandially, and nausea, emesis, and early satiety are common associated symptoms. The average duration of symptoms prior to diagnosis is 1 year. Diagnosis is often difficult because of the vague nature of complaints, absence of physical findings, and lack of an accurate noninvasive test. Imaging Studies Angiography is the diagnostic test of choice for CMI; however, the diagnosis of CMI remains a clinical rather than an anatomic one. Angiograms in patients with CMI typically demonstrate high-grade stenosis in at least two vessels. CT angiography, magnetic resonance angiography, and Doppler ultrasound measuring mesenteric blood flow are noninvasive imaging modalities. However, it is important to correlate angiographic findings with symptoms, because some individuals who have complete occlusion of all three major mesenteric arteries may remain asymptomatic because of collateral blood flow. Although there have been preliminary reports of "stress tests" for abdominal angina, at present there is no functional test with high sensitivity or specificity for confirming a clinical diagnosis of CMI. Treatment Once the diagnosis of CMI is made based on symptoms and high-grade stenosis or occlusion of two or more mesenteric arteries, the goal is to restore mesenteric arterial flow. Although surgical revascularization using aortomesenteric grafting is the gold standard, recent studies suggest that endovascular therapy using percutaneous angioplasty with or without stenting may be effective in treating CMI, albeit with a higher risk of symptom recurrence. Otte JA, Geelkerken RH, Oostveen E. Clinical impact of gastric exercise tonometry on diagnosis and management of chronic gastrointestinal ischemia. Clin Gastroenterol Hepatol. 2005; 3:660–666. [PMID: 16206498]
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Essentials of Diagnosis Typically, sudden onset of left lower quadrant pain followed by hematochezia within 24 hours. Diagnosed by colonoscopy or imaging studies (CT, barium enema). Bleeding is not massive and transfusion only rarely required. General Considerations Colonic ischemia, also referred to as ischemic colitis, is the most frequent form of mesenteric ischemia, accounting for 75% of all intestinal ischemia and affecting primarily the elderly. It is estimated that colonic ischemia accounts for 1 in 2000 hospital admissions. Findings of colonic ischemia are seen in one of every 100 colonoscopies and may be misdiagnosed as inflammatory bowel disease or infectious colitis (Plate 3). Colonic ischemia has been described in several clinical settings (Table 6–2), although in many instances no specific cause can be identified. Many cases are initially misdiagnosed as inflammatory bowel disease or infectious colitis, especially in individuals younger than age 50 years. The risk of colonic ischemia appears to be highest for patients who have recently undergone cardiovascular surgery, and these patients may experience more severe episodes. Plate 3.
MD.)
Endoscopic appearance of colonic ischemia. (Courtesy of David Stockwell,
Table 6–2. Risk factors for colonic ischemia.
Precipitants of colonic ischemia Hypotension Congestive heart failure Cardiopulmonary bypass Dialysis Aortoiliac surgery Cholesterol emboli Dehydration Precipitants in patients <50 years Vasculitis (eg, systemic lupus erythematosus) Hypercoagulable states (factor V Leiden), phospholipid antibody syndrome Sickle cell crisis Long-distance running Medications (estrogens, danazol, vasoconstrictors [pseudoephedrine, sumatriptan], gold, psychotropic drugs, alosetron, antihypertensives, diuretics)
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thromboembolism Cocaine Infections resulting in hemorrhagic colitis (Shigella, Escherichia coli O157:H7, Campylobacter, Klebsiella oxytoca [especially with use of penicillin derivative], Clostridium difficile [10% hemorrhagic colitis])
Pathogenesis Ischemic injury to the colon usually occurs as a consequence of a sudden and transient reduction in blood flow, resulting in a lowflow state. In the majority of cases a specific occluding anatomic lesion cannot be identified. Although it may occur anywhere, colonic ischemia most commonly affects the so-called watershed areas with a limited collateral blood supply, such as the splenic flexure and left colon (Figure 6–7). Ischemia is usually mucosal and rarely transmural; consequently, gangrenous colitis and colonic strictures are infrequent. Eighty-five percent of cases of colonic ischemia resolve spontaneously within 2 weeks. Figure 6–7.
Distribution of colonic ischemia in 250 cases. (Reproduced, with permission, from Brandt L, Boley SJ. Colonic ischemia. Surg Clin North Am 1992;72:212. Copyright Elsevier.) Clinical Findings Symptoms and Signs Patients with colonic ischemia usually present with abrupt onset of crampy left lower quadrant abdominal pain, and mild to moderate rectal bleeding or bloody diarrhea within the first 24 hours. Over 90% of patients are older than 60 years. Cardiovascular disease is common, and frequent precipitating factors include hypotension, cardiovascular surgery (coronary artery bypass grafting, aortic aneurism repair), dialysis, and dehydration. Physical examination reveals mild to moderate abdominal tenderness over the affected bowel, most often left-sided. In contrast to patients with AMI, those with colonic ischemia do not usually appear acutely ill. Bleeding is usually mild, and patients rarely require blood transfusion. Peritoneal signs, if present, would suggest perforation or peritonitis. Ischemic colitis is usually a singular event, and only 5% of patients develop a recurrence. The diagnosis is usually established on the basis of clinical history, physical examination, and endoscopic or radiologic studies. Although most patients who develop colonic ischemia are elderly, the condition can also occur in younger patients. For patients who are younger than age 50, several precipitants of colonic ischemia should be considered (see Table 6–2). In young women, the triad of smoking, use of oral contraceptives, and carriage of the factor V Leiden mutation may be associated with increased risk of colonic ischemia. Recent reports indicate that giving penicillin derivatives to patients who harbor Klebsiella oxytoca may precipitate hemorrhagic colitis. Diagnostic Tests Diagnostic modalities include flexible sigmoidoscopy or colonoscopy, plain films of the abdomen, and CT scan. Colonoscopy with biopsies makes the definitive diagnosis; however, endoscopy should be avoided in patients with significant abdominal pain or distention because air insufflation may precipitate perforation in cases of severe ischemia. Endoscopic findings frequently include petechial bleeding, pale mucosa, and, in more severe cases, hemorrhagic ulceration (see Plate 3), and biopsy specimens show characteristic findings. Plain
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thromboembolism films of the abdomen are usually nondiagnostic, but thumbprinting representing submucosal hemorrhage and edema may be seen in 20– 25% of cases. The use of plain films has been largely superseded by the ready availability and accuracy of CT scans. CT scans can demonstrate wall thickening, mucosal and submucosal hemorrhage, and pericolic fat stranding, and occasionally bowel wall pneumatosis (Figure 6–8). Figure 6–8.
CT scans demonstrating findings in colonic ischemia. A: Colonic thickening. B: Pneumatosis. (Courtesy of Koenraad Mortele, MD.) Angiography is usually not necessary in the evaluation of colonic ischemia; however, it should be considered if the clinical findings raise concern for concomitant small bowel ischemia or infarction. Stool studies should be performed to exclude infections such as Escherichia coli O157:H7, Campylobacter enteritis, Klebsiella oxytoca, Shigella, or Clostridium difficile, which can be associated with hemorrhagic colitis. Treatment Patients with colonic ischemia are usually placed on bowel rest. Patients should be followed with serial abdominal examinations and monitored for bleeding, fever, leukocytosis, and electrolyte abnormalities. Although there are no controlled randomized trials proving the effectiveness of antibiotics in reducing morbidity and mortality, broad-spectrum intravenous antibiotics are recommended. Any medications that can cause vasoconstriction and promote ischemia should be withdrawn (ie, digitalis, glycosides, vasopressin, and diuretics). Marked colonic distention is treated with rectal tubes and nasogastric decompression if necessary. There is no role for anticoagulation or corticosteroids. Prognosis is favorable, and most patients improve within a few days and demonstrate clinical and radiologic resolution within 2 weeks. Indications for surgery include peritoneal signs suggesting perforation, gangrenous colitis, massive bleeding, toxic megacolon, and recurrent sepsis. Long-term complications, including persistent recurrent colitis and colonic structures, are infrequent but may require resection of the affected colonic segment.
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In contrast to small bowel ischemia, colonic ischemia is rarely life threatening. However, the development of colonic ischemia in the setting of recent cardiovascular surgery deserves special mention, as the natural history of colonic ischemia in these patients may be more severe. Prolonged colonic ischemia, such as can occur in patients with ruptured abdominal aortic aneurysms or prolonged aortic cross-clamp time, can lead to acute gangrenous colitis and transmural infarction of the colon. Although emergent operative intervention may be necessary in the setting of sepsis and peritoneal signs, most cases of colonic ischemia resolve with conservative management. Hogenauer C, Langner C, Beubler E, et al. Klebsiella oxytoca as a causative organism of antibiotic-associated hemorrhagic colitis. N Engl J Med. 2006;355:2418–2426. [PMID: 17151365]
current family medicine
1-1 of 1 Results
Embolic Disease
CURRENT Diagnosis & Treatment in Family Medicine > Chapter 26. Respiratory Problems > Noninfectious Respiratory Problems
1-1 of 1 Results
---------------------------------------------
Embolic Disease Essentials of Diagnosis
Dyspnea. Hypoxia. Pleuritic pain.
General Considerations However, embolization of other materials including air, fat, and amniotic fluid also can obstruct the pulmonary vasculature. The symptoms of pulmonary embolism range from mild, intermittent shortness of breath or death.
Pulmonary embolism usually results from the mobilization of blood clots from thromboses in the lower extremities or pelvis.
pleuritic chest pain to complete circulatory collapse and
The most common source of embolism is the disruption of thrombi formed in the deep veins. Mortality in untreated cases is 30% but can be reduced to 2% with prompt recognition and appropriate management. Recurrent pulmonary embolism carries a very high mortality in the range of 45–50%.
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Risk factors for pulmonary embolism include venous stasis, trauma, abnormalities in the deep veins, and hypercoagulable states.
Hypercoagulability occurs with some cancers as well as with inherited conditions such as factor V Leiden mutation that results in resistance to the anticoagulant effects of protein C. Other congenital hypercoagulation disorders include protein C deficiency, protein S deficiency, and antithrombin III deficiency.
Hypercoagulation states also exist with the use of certain medications. Use of estrogens either as part of hormone replacement therapy or for contraception increases the risk by a factor of three. The effects of these drugs are compounded in patients with factor V Leiden mutation. In addition, smoking appears to be an independent risk factor for deep vein thrombosis and pulmonary embolism.
Prevention
Because pulmonary emboli usually arise from lower extremity thromboses, prophylactic anticoagulation can be used to reduce the incidence of these thrombi in high-risk individuals. Both low-molecular-weight heparin products and unfractionated heparin are effective in preventing deep venous thrombosis.
In addition to preventing initial thrombi, the pulmonary embolism can be reduced through the use of a vena-caval filter in patients with known thrombi and contraindications to long-term anticoagulation. The long-term impact of intravenacaval (IVC) filters has not been studied extensively. One study showed a complication rate, such as thrombi trapped in the filter or the filter tilting, malpositioning, or migrating, in nearly 50% of those who survived 3 years. However, given the high mortality rates from recurrent pulmonary embolism, the complication rates from long-term IVC filter insertion appear to be a worthwhile trade-off in high-risk patients.
Clinical Findings
Patients with pulmonary emboli usually exhibit
dyspnea and hypoxia, and often have pleuritic chest pain.
However, other than hypoxia, most routine studies including chest radiographs may be normal. Suspicious signs of embolism on a chest radiograph include a wedge-shaped infiltrate resulting from
lobar infarction, new pleural effusion, or both.
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Confirmation of a pulmonary embolism is based on either demonstrating obstruction of vascular flow through pulmonary angiography, finding a mismatch of perfusion and ventilation, or visualization of a clot on spiral (helical) computed tomography (CT) scanning. Although pulmonary angiography is considered the gold standard, because of its invasiveness spiral CT and ventilation-perfusion scan are usually employed to make the diagnosis. Of the noninvasive tests available, spiral CT has the best sensitivity for detecting pulmonary artery thrombi (95–100%), although it is not as useful in identifying subsegmental emboli. D-Dimer testing has been evaluated as a serum marker for pulmonary embolism or deep vein thrombosis. The presence of D-dimer is not specific for thrombotic disease because D-dimer also rises in other conditions such as
recent surgery, congestive heart failure, myocardial infarction, and pneumonia. Although the presence of D-dimer is not useful in diagnosing thrombosis or embolism, the negative predictive value of the absence of D-dimer is very high (97–99%), so this test can be useful in ruling out embolism.
Treatment Options for management of the patients with an acute pulmonary embolism include
anticoagulation to prevent further embolism from occurring, clot lysis with thrombolytic agents, or surgical removal of the clot.
Patients without life-threatening embolism can be managed with acute anticoagulation with heparin followed by long-term maintenance on warfarin. Heparin may be administered either as unfractionated heparin or as low-molecular-weight heparin. Unfractionated heparin is generally administered intravenously with the dosage rate titrated to produce a suitable anticoagulation state. The use of a weight-based nomogram for loading and maintenance dosing can improve the time to achieve adequate anticoagulation and reduce the risks of bleeding.
The drawbacks of unfractionated heparin include the need for hospitalization to monitor coagulation status and administer the intravenous drug plus the possibility of thrombocytopenia associated with the use of this agent. In contrast, low-molecular-weight heparin can be administered as a daily intramuscular dose without titration or frequent anticoagulation monitoring. As a result, low-molecular-weight heparin therapy usually can be provided in the patient's home.
To achieve long-term anticoagulation, warfarin should be started promptly at a dose of 5 mg/day. Starting with a higher dose of warfarin does not appear to achieve oral anticoagulation any faster or reduce the days that heparin is needed. Heparin can be discontinued when a prothrombin time indicates that the international normalized ratio (INR) has reached 2.0–3.0.
The duration of anticoagulation for pulmonary embolism depends on whether the precipitating event is known and reversible or whether the cause is unknown.
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In situations in which the thrombosis and embolism are the result of an acute event such as an injury or surgery, treatment for 6 months is recommended. If the risk factor associated with the embolic event is not reversible, such as cancer or coagulation disorder, then lifetime anticoagulation is advisable. When a risk factor or event causing the embolism is not known, so-called idiopathic embolism, treatment with anticoagulants for 6 months is indicated.
The use of thrombolytic agents for pulmonary embolism is usually reserved for patients with extensive embolism who show hemodynamic instability. Thrombolytic agents available for use in this situation include urokinase, streptokinase, tissue plasminogen activator (tPA), and reteplase. Embolectomy is rarely performed and is reserved for patients in whom embolism is rapidly diagnosed and a very large embolism is suspected that completely occludes the pulmonary arteries. In most situations, this is treated as a "last ditch" effort to save the patient.
Prevention Table 26–8. Strategies to Prevent Venous Thromboembolism.
Condition or Procedure
Prophylaxis
General surgery
Unfractionated heparin, 5000 units two or three times a day Enoxaparin, 40 mg/day subcutaneously Dalteparin, 2500 or 5000 units/day subcutaneously Nadroparin, 3100 units/day subcutaneously Tinzaparin, 3500 units/day subcutaneously, with or without graduated-compression stockings
Total hip replacement
Warfarin (target INR, 2.5)
Intermittent pneumatic compression Enoxaparin, 30 mg subcutaneously twice daily Danaparoid, 750 units subcutaneously twice daily
Total knee replacement
Enoxaparin, 30 mg subcutaneously twice daily Ardeparin, 50 units/kg subcutaneously twice daily
General medical condition requiring hospitalization
Condition requiring hospitalization in the intensive care unit
Graduated-compression stockings, intermittent pneumatic compression, or unfractionated heparin, 5000 units two or three times daily
Graduated-compression stockings and intermittent pneumatic compression, with or without unfractionated heparin, 5000 units two
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thromboembolism or three times daily
Pregnancy in high-risk patient1
Dalteparin, 5000 units/day subcutaneously Enoxaparin, 40 mg/day subcutaneously
1High risk includes patients with previous pulmonary embolism or deep venous thrombosis. Reprodiced with permission from Goldhaber SZ: Pulmonary embolism. New Engl J Med 1998;339:93.
Piazza G, Goldhaber SZ: Acute pulmonary embolism: Part I: Epidemiology and diagnosis. Circulation 2006;114:e28. [PMID: 16831989] Piazza G, Goldhaber SZ: Acute pulmonary embolism: Part II: Treatment and prophylaxis. Circulation 2006;114:e42. [PMID: 16847156] Takagi H, Umemoto T: An algorithm for managing suspected pulmonary embolism. JAMA 2006;295:2603. [PMID: 16772621]
current cardiology
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Chapter 26. Pulmonary Embolic Disease
CURRENT Diagnosis & Treatment in Cardiology
Thrombotic Diseases
CURRENT Diagnosis & Treatment in Cardiology > Chapter 33. Connective Tissue Diseases & the Heart >
Systemic Lupus Erythematosus
Thromboembolic Disease
CURRENT Diagnosis & Treatment in Cardiology > Chapter 31. Cardiovascular Disease in Pregnancy > Etiology & Symptomatology >
Pulmonary Hypertension
Thrombosis and Thromboembolism
CURRENT Diagnosis & Treatment in Cardiology > Chapter 31. Cardiovascular Disease in Pregnancy > Treatment > Pharmacologic Treatment
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Pulmonary Embolic Disease
Essentials of Diagnosis
Otherwise unexplained dyspnea, tachypnea, or chest pain. Clinical, ECG, or echocardiographic evidence of acute cor pulmonale. Positive chest CT angiography scan with contrast. High-probability ventilation-perfusion lung scan or high-probability perfusion lung scan with a normal chest radiograph. Positive venous ultrasound of the legs with a convincing clinical history and suggestive lung scan. Diagnostic contrast pulmonary angiogram.
Etiology "Primary" PE occurs in the absence of surgery or trauma. Patients with this condition often have an underlying hypercoagulable state, although a specific thrombophilic condition may not be identified. A common scenario is a clinically silent tendency toward thrombosis, which is precipitated by a stressor such as prolonged immobilization, oral contraceptives, pregnancy, or hormone replacement therapy. Recently, there has been an increased appreciation of the risks of VTE among patients with medical illnesses, including cancer (which itself may be associated with a hypercoagulable state), congestive heart failure, and chronic obstructive pulmonary disease.
Table 26–1. Thrombophilic Risk Factors for Venous Thromboembolism.
Common Factor V Leiden Prothrombin gene mutation Anticardiolipin antibodies (including lupus
anticoagulant ) as a feature of the antiphospholipid antibody
syndrome
Hyperhomocysteinemia (usually due to folate deficiency)
Uncommon
Antithrombin III deficiency Protein C deficiency Protein S deficiency Mutations of cystathionine -synthase or methylene tetrahydrofolate reductase (MTHFR) High concentrations of Factors VIII or XI (or both)
Hormone replacement therapy also predisposes to VTE. In 1996, three separate large data sets implicated hormone replacement therapy as doubling, tripling, or even quadrupling the risk of VTE. As with oral contraceptives, the risk of VTE peaks during the first year of hormone replacement therapy.
Gerhardt A et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med. 2000 Feb 10;342(6):374–80. [PMID: 10666427]
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Miles JS et al. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol. 2001 Jan;37(1):215–8. [PMID: 11153741] Nguyen A. Prothrombin G20210A polymorphism and thrombophilia. Mayo Clin Proc. 2000 Jun;75(6):595–604. [PMID: 10852421] Wicki J et al. Predicting adverse outcome in patients with acute pulmonary embolism: a risk score. Thromb Haemost. 2000 Oct;84(4):548– 52. [PMID: 11057848]
clinical findings : Pulmonary Embolic Disease > Clinical Findings >
Figure 26–1.
Strategy for diagnosing pulmonary embolism. CT, computed tomographic scan; CXR, chest xray film; PAgram, pulmonary angiogram; PE, pulmonary embolism; U/S, ultrasound.
Clinical Scoring Systems >
Table 26–2. Ottawa Scoring System.
Signs or Symptoms
Points
Clinical signs and symptoms of DVT (minimum of leg swelling and pain with palpation of the deep veins)
3.0
An alternative diagnosis is less likely than PE
3.0
Heart rate greater than 100 bpm
1.5
Immobilization or surgery in the previous 4 weeks
1.5
Previous DVT or PE
1.5
Hemoptysis
1.0
Malignancy (on treatment, treated in the last 6 months or palliative)
1.0
DVT, deep veinous thrombosis; PE, pulmonary embolism. Reprinted, with permission, from: Wells PS et al. Thromb Haemost. 2000;83:416.
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Table 26–3. Geneva Diagnostic Scoring System–Multivariate Predictors of Pulmonary Embolism and Development of the Clinical Score.
Variable
Logistic Regression Coefficients
Adjusted Odds Ratio (95% CI)
P
Point Score
60–79
0.6
1.9 (1.3–2.7)
.002
+1
80
1.0
2.8 (1.8–4.4)
< .001
+2
1.1
3.0 (2.1–4.4)
< .001
+2
Recent surgery 1.5
4.6 (2.6–8.3)
< .001
+3
Pulse rate > 100/min
0.5
1.6 (1.1–2.2)
.008
+1
1.1
2.9 (1.9–4.4)
< .001
+2
0.6
1.9 (1.1–3.2)
.02
+1
2.0
7.2 (3.2–15.8) < .001
Age, years
Previous PE or DVT
PaCO2 mm Hg < 36 mm Hg 36–40 mm Hg PaO2 mm Hg < 50 50–59
+4
1.4
3.9 < (2.2– .001 6.8)
60–72
1.0
2.6 (1.6–4.2)
< .001
+2
73–82
0.6
1.8 (1.1–2.9)
.03
+1
0.7
1.9 (1.3–2.9)
.001
+1
Elevation of 0.5 hemidiaphragm
1.6 (1.1–2.4)
.02
+1
+3
Chest radiograph Platelike atelectasis
DVT, deep venous thrombosis; PE, pulmonary embolism. Adapted, with permission, from Wicki J, et al. Arch Intern Med. 2001;161:92.
prevention
:
Pharmacologic Prevention >
Table 26–5. FDA–Approved Low–Molecular Weight Regimens for Orthopedic and General Surgery Prophylaxis.
Indication
Drug and Dose
Duration
Timing of Initial Dose
Hip replacement Enoxaparin 30 mg ("USA-style") with q12h or 40 mg enoxaparin q24h
14 days
12–24 h postoperatively, providing that hemostasis has been achieved
Hip replacement Enoxaparin 40 mg ("European-style") q24h with enoxaparin
14 days
12 h ± 3 h preoperatively
Hip replacement with dalteparin (option #1)
Dalteparin 2500
14 days
First dose within 2 h preoperatively; second dose at least 6 h after the first dose, usually on the evening of the day of surgery; omit second dose on the day of surgery if surgery is done in the evening
Hip replacement with dalteparin (option #2)
Dalteparin 5000
14 days
First dose on the preoperative evening; second dose on the evening of the day of surgery (unless surgery is done in the evening)
units preoperatively and first dose postoperatively, followed by 5000 units q24h units q24h
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thromboembolism Enoxaparin 40 mg An
Extended hip prophylaxis
q24h
General surgery with enoxaparin
q24h
After the initial hip replacement additional 3 prophylaxis regimen has been completed weeks after initial hip replacement prophylaxis
Enoxaparin 40 mg
12 days
2 h preoperatively
General surgery Dalteparin 2500 units q24h with dalteparin (moderate risk for venous thromboembolism)
5–10 days
1–2 h preoperatively
General surgery Dalteparin 5000 with dalteparin units q24h (high risk for venous thromboembolism: option #1)
5–10 days
Preoperative evening
General surgery with dalteparin (high risk for venous thromboembolism: option #2)
5–10 days
First dose 1–2 h preoperatively; second dose 12 h later
Dalteparin 2500
units preoperatively and first dose postoperatively, followed by 5000 units q24h
Risk Stratification
:
Table 26–6. Geneva Point Score to Assess Pulmonary Embolism Prognosis.
Variable
Point Score
Cancer
+2
Heart failure
+1
Prior DVT
+1
Hypotension
+2
Hypoxemia
+1
DVT on ultrasound
+1
DVT, deep venous thrombosis. Modified, with permission, from Wicki J et al. Thromb Haemost. 2000;84:548.
Treatment
:
> Heparin >
Table 26–8. Unfractionated Heparin Weight–Based Nomogram for Acute Venous Thromboembolism.
PTT
Repeat Bolus Stop Infusion (min) Rate Change
Repeat PTT (h)
< 35
70 units/kg1
0
Increase 3 units/kg/h
6
35–59
35 units/kg2
0
Increase 2 units/kg/h
6
60–80 target 0
0
No change
6
81–100
0
0
Decrease 2 units/kg/h 6
> 100
0
60
Decrease 3 units/kg/h 6
1Maximum bolus 10,000 units. 2Maximum bolus 5000 units.
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thromboembolism PTT, activated partial thromboplastin time; measured in seconds.
Low-Molecular-Weight Heparin >
Table 26–9. Comparison of Unfractionated Heparin versus Low–Molecular–Weight Heparin.
Characteristic
UFH
LMWH
Molecular weight (average in daltons)
15,000
5000
Ratio of anti-Xa to anti-IIa (thrombin) activity
1
> 1
Metabolism
Hepatic
Renal
Bioavailability
Fair
Excellent
Frequency of subcutaneous administration X2–X3/day
X1–X2/day
Frequency of heparin -induced thrombocytopenia
1–2%
0.1–0.2%
Osteoporosis after prolonged exposure
Rare
Very rare
Laboratory assay of anticoagulant effect
Activated partial thromboplastin Anti-Xa level time
Reversal of anticoagulant effect
Protamine
Protamine
Spinal or epidural anesthesia
OK
Heed the FDA warning
FDA, Food and Drug Administration.
Table 26–10. FDA-Approved Low-Molecular-Weight Heparins for the Initial Treatment of DVT (with or without Asymptomatic PE).
Enoxaparin 1 mg/kg twice daily Enoxaparin 1.5 mg/kg once daily Tinzaparin 175 units/kg once daily DVT, deep venous thrombosis; FDA, Food and Drug Administration; PE, pulmonary embolism.
Table 26–11. Low–Molecular–Weight Heparin Weight–Based Nomogram for Enoxaparin in the Presence of Renal Insufficiency or Marked Obesity.
Renal Insufficiency Creatinine Clearance (mL/min)
Enoxaparin Dose
Anti–Xa Monitoring (Heparin Level)1
> 70
1 mg/kg q12h
None
35–69
0.75 mg/kg q12h
3–6 h after the third injection
< 35
1 mg/kg q24h
3–6 h after the third injection
Obese Weight
Enoxaparin Anti–Xa
< 100 kg
Dose
Monitoring (Heparin Level)1
1 mg/kg q12h
None
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thromboembolism 100–130 kg
1 mg/kg q12h
3–6 h after the first injection
> 130 kg
130 mg q12h 3–6 h after the first injection
1Therapeutic level is 0.5–1.0 units/mL.
Table 26–12. Pulmonary Embolism Patients at High Risk (in the Absence of Systemic Arterial Hypotension and Cardiogenic Shock).
Physical findings of right ventricular dysfunction (eg, distended neck veins, accentuated P2, tricuspid regurgitation murmur) Electrocardiographic manifestations of right ventricular strain (eg, new right bundle branch block, new T-wave inversion in leads V1– V4) Right ventricular dilatation and hypokinesis or akinesis on echocardiogram Patent foramen ovale Free-floating right-heart thrombi Doppler echocardiographic pulmonary arterial systolic pressure > 50 mm Hg Elevated troponin level Age > 70 years Cancer Congestive heart failure Chronic obstructive pulmonary disease
Connective Tissue Diseases & the Heart
Systemic Lupus Erythematosus
Thrombotic Diseases
:
General Considerations
:
Deep venous thrombosis, pulmonary embolism, and peripheral or cerebral arterial thrombosis are common in SLE patients. Acute coronary thrombosis in the absence of angiographic CAD has also been reported. Patients with SLE are subject to intracardiac thrombosis and cerebral or systemic thromboembolism independently of or exacerbated by aPL.
Both arterial and venous thrombotic events have been associated with aPL.
Current data support that SLE cerebrovascular disease is commonly associated and likely causally related to cardioembolism from Libman-Sacks endocarditis.
In recent series, mitral or aortic valve vegetations were two to four times more common and strong independent predictors of focal ischemic brain injury on MRI;
and nonfocal neurologic dysfunction, such as cognitive dysfunction, acute confusional state, or seizures.
In fact, microembolic events during
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stroke or TIA;
transcranial Doppler echocardiography are common in patients with cerebral ischemic events.
Symptoms and Signs : Although acute pleuritic chest pain and tachycardia could be related to the presence of pericarditis, pleuritis, or pneumonitis, they should prompt the suspicion of pulmonary embolism and DVT.
Focal and nonfocal transient or permanent neurologic deficits are commonly due to cardioembolism from valvular or myocardial disease and rarely due to vasculitis or cerebritis.
Laboratory Findings :
Antiphospolipid antibodies are highly associated with venous or arterial thrombotic events. However, these antibodies can be present in SLE patients without thrombosis and infrequently in patients who do not have SLE.
Treatment
Therefore, routine measurement of aPL to identify patients at high thrombotic risk and as a basis for prophylactic anticoagulant therapy is still undefined.
:
Specific Antiinflammatory Therapy Corticosteroids or immunosuppressive agents may be beneficial in patients with active SLE and noninfective vegetations with or without thrombosis or thromboembolism.
Other Therapy Anticoagulation with warfarin is the therapy of choice in patients with DVT, pulmonary embolism, and in those with noninfective valve vegetations and stroke or TIA or cerebral infarcts on MRI.
Cardiovascular Disease in Pregnancy Etiology & Symptomatology > Pulmonary Hypertension Thromboembolic Disease
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Venous Venous thromboembolic disease thromboembolism affects ims oar t al el iatdyi ndgu rcianug s ep r oe fg nma no cr by i daint dy a n d postpartum pregnant women five times more frequently than nonpregnant women. It is estimated to complicate 2 in 1000 pregnancies.
The diagnosis is complicated by symptoms similar to usual pregnancy symptoms such as shortness of breath, tachycardia, and leg swelling. The immediate postpartum period risk for pulmonary embolism is 15 times greater than during the pregnancy. Risk factors for venous includes
thromboembolism
As many as up to 33% of deep venous thrombosis may occur in the first trimester, although the risk is highest postpartum (five times higher than during the pregnancy).
age > 35 years, weight > 165 lbs, a family or personal history of deep venous thrombosis or pulmonary embolism, varicose veins, smoking, or any known hypercoagulable state as well as multiple previous pregnancies.
Pulmonary embolism will occur in 15–24% of patients with untreated deep venous thrombosis and may be fatal in 15%.
pulmonary embolism.
Diagnosis of deep venous thrombosis should be made with compression ultrasound or impedance plethysmography.
Magnetic resonance imaging (MRI) can be performed to diagnose iliac thrombosis.
The diagnosis of pulmonary embolism is complicated by the need to avoid radiation in the pregnant patient. However, ventilation-perfusion scannning is considered safe throughout pregnancy and should be the first step in the diagnosis of a
To further decrease radiation, consideration should be given to performing perfusion scan alone. If there is no defect, then pulmonary embolism would be very unlikely.
The gold standard for pulmonary embolism is pulmonary angiogram. Except in the first trimester, pulmonary angiogram exposes the fetus to less radiation than a helical CT scan.
An echocardiogram may support the diagnosis of acute embolus by demonstrating right heart enlargement without hypertrophy and elevated pulmonary artery pressure. Hypokinesis with relative sparing of the right ventricular apex may be seen.
If unfractionated heparin is used, a target activated partial prothrombin time level should be 2.0–2.5.
The main treatment for deep venous thrombosis during pregnancy consists of heparin, although warfarin
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If an LMWH is used, the patient should c a n b e g i v e n a f t e r t h e f i r s t t r i m e s t e r until 35 gestation weeks. be monitored with anti-Xa levels.
Pulmonary embolism, if stable, should be treated with intravenous heparin for at least 5 days. Oral anticoagulation should be continued for 6 months thereafter.
In unstable pulmonary embolism, consideration to thrombolysis and embolectomy should be given. An inferior vena caval filter may also be needed. Heit JA et al. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med. 2005 Nov 15;143(10):697–706. [PMID: 16287790] Stone SE et al. Pulmonary embolism during and after pregnancy. Crit Care Med. 2005 Oct;33(10 Suppl):S294–300. [PMID: 16215350]
pocket monkey
1-13 of 13 Results
Dextran 40 (Rheomacrodex)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Bevacizumab (Avastin)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Esterified Estrogens (Estratab, Menest)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Esterified Estrogens + Methyltestosterone (Estratest, Estratest HS)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Estradiol (Estrace)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Estradiol Cypionate & Medroxyprogesterone Acetate (Lunelle)
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thromboembolism Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Estrogen, Conjugated (Premarin)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Estrogen, Conjugated + Medroxyprogesterone (Prempro, Premphase)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Estrogen, Conjugated Synthetic (Cenestin)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Levonorgestrel Implant (Norplant)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Megestrol Acetate (Megace)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Norgestrel (Ovrette)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
Raloxifene (Evista)
Clinician's Pocket Reference > Chapter 22. Commonly Used Medications > Generic Drug Data
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current neurology
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Organ Transplantation
Clinical Neurology > Chapter 1. Disorders of Cognitive Function > Acute Confusional States > Organ System Failure
Treatment
Clinical Neurology > Chapter 9. Stroke > Focal Cerebral Ischemia
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thromboembolism
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stroke
:
Focal Cerebral Ischemia > Treatment
Table 9–5. Recommended Treatment of Cerebrovascular Disease.1
Condition
Antiplatelet Agents2
Anticoagulants3
Thrombolytics4
Revascularization5
–
–
±
±
+
–
–
Extracranial carotid source
+
±
–
+
Intracranial or vertebrobasilar source
+
±
–
–
Stroke-inevolution
+
±
–
–
±
+
+
–
Extracranial carotid source
+
±
+
+
Intracranial or vertebrobasilar source
+
±
+
–
Asymptomatic carotid bruit or stenosis
+
Transient ischemic attack
source
Cardiac
Completed stroke6
source
Cardiac
1+, probably effective; ±, less evidence for efficacy or similarly effective but associated with greater risk; –, ineffective or efficacy untested. 2Aspirin , 30–1300 (typically 81) mg orally daily (but optimal dose uncertain); aspirin/extended release dipyridamole, 25 mg/200 mg orally twice daily; ticlopidine , 250 mg orally twice daily; or clopidogrel , 75 mg orally daily. 3Heparin, given by continuous intravenous infusion to achieve an activated partial thromboplastin time (aPTT) = 1.5–2.0 times control, followed by warfarin , given orally daily to achieve an international normalized ratio (INR) = 2.0–3.0, except in patients with mechanical heart valves, in whom the INR target is higher. 4Recombinant tissue plasminogen activator (rt-PA), 0.9 mg/kg intravenously over 1 hour, begun within 4.5 hours of the onset of symptoms (contraindicated in hemorrhagic stroke). 5For 50–99% stenosis, assuming a low (<2%) risk of perioperative death or disabling stroke. 6For prophylaxis against subsequent events in another vascular territory, or in the same territory in the case of completed stroke involving less than the entire area supplied by the affected vessel (partial stroke), or for dissolution of the existing thrombus (thrombolytics).
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thromboembolism
Asymptomatic Carotid Bruit or Stenosis
Carotid artery stenosis is also common, and can be demonstrated by ultrasonography in as many as 30% of men older than 75 years
Carotid bruits are commonly detected during routine examinations of asymptomatic patients, with a frequency that reaches 7% for those who are older than 65 years.
Because the natural history of carotid artery stenosis is variable, the relationship of
asymptomatic bruit or stenosis
to an individual's risk for stroke is difficult to assess.
In large studies, severe stenosis is associated with increased stroke risk (2.5% per year for ipsilateral stroke with 75% stenosis), but the risk of contralateral stroke is increased as well, and the risk of myocardial ischemia in these patients is even higher. with lesser degrees of stenosis or at increased surgical risk.
Moreover, carotid endarterectomy, which has been advocated in this setting, carries significant perioperative risk of stroke or death, and this risk varies widely across institutions. Although asymptomatic patients with high-grade carotid stenosis have appeared to benefit from endarterectomy in some studies, this effect was dependent on an extremely low surgical morbidity and mortality rate.
For these reasons, antiplatelet and HMG-CoA reductase inhibitor (statin) therapy (see below) is a
reasonable approach for asymptomatic patients presenting
Transient Ischemic Attack
Because TIAs can indicate an impending stroke and because it may be possible to prevent such an event by appropriate treatment, TIAs must be accurately and promptly diagnosed and treatment instituted (Table 9–5 ).
Antiplatelet therapy—
Of the various medical treatments proposed for stroke prophylaxis in patients with noncardiogenic TIAs, antiplatelet agents appear to have the best benefit-to-risk ratio. The rationale for this approach is that embolism from platelet-fibrin thrombi on arterial surfaces may be responsible for many cases of TIA and stroke.
interferes with platelet function by irreversibly inhibiting the enzyme cyclooxygenase-1, which catalyzes the synthesis of thromboxane A2, an eicosanoid with procoagulant and platelet-aggregating properties. Aspirin
Clopidogrel and ticlopidine irreversibly inhibit the binding of adenosine diphosphate (ADP) to its platelet receptor and block activation of the ADP-mediated glycoprotein GPIIb/IIIa complex.
Dipyridamole increases concentrations of adenosine and cyclic adenosine monophosphate (cAMP), which decreases platelet activation. Dipyridamole may also inhibit the formation of thromboxane A2.
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thromboembolism Aspirin , when administered to patients with
TIAs or minor stroke (defined as little or no neurologic
deficit after 1 week),
has been shown to reduce the incidence of subsequent TIAs, stroke, or death in several studies. Although most studies have focused on noncardiogenic TIA or stroke, aspirin is also beneficial for
In some cases (e.g., patients with artificial heart valves), the combination of aspirin and anticoagulation may be more effective than anticoagulation alone.
preventing recurrent cerebral ischemia caused by cardiac emboli.
A sex-related difference in benefit favoring men has been observed, but only inconsistently. Administration of low-dose aspirin (325 mg orally every other day) to men age 40 years and
does not reduce the risk of stroke , although
older without a history of TIA or stroke
Doses of aspirin between 30 and 1300 mg orally daily appear to be effective, and daily oral administration of 325 mg of aspirin is probably used most often in North America.
it decreases the incidence of myocardial infarction.
In contrast,
this strategy did reduce stroke risk in women older than 60 years.
Adverse effects of aspirin include
dyspepsia, nausea, abdominal pain, diarrhea, skin rash, peptic ulcer, gastritis, and gastrointestinal bleeding.
Ticlopidine (250 mg orally twice daily), another antiplatelet agent , may be somewhat more effective than aspirin in preventing stroke and reducing
mortality IN PATIENTS WITH TIAS OR MILD STROKE . However, ticlopidine is more expensive than aspirin and appears to be associated with such side effects as diarrhea, skin rash, and occasional cases of severe but reversible neutropenia.
Clopidogrel (75 mg orally daily), which inhibits platelet aggregation by binding irreversibly to ADP receptors on the platelet surface, also has been shown to reduce the incidence of ischemic stroke, myocardial infarction, or death from
IN PATIENTS WITH RECENT ISCHEMIC STROKE, MYOCARDIAL INFARCTION, OR SYMPTOMATIC PERIPHERAL ARTERIAL DISEASE. other vascular causes
Diarrhea and skin rash were more common than with aspirin , but neutropenia and thrombocytopenia occurred at the same rate. Thrombotic thrombocytopenic purpura (see Chapter 1 ) has complicated clopidogrel treatment in some patients.
Some experts recommend the use of a combination of
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aspirin (25 mg) and
extended-release dipyridamole (200 mg),
Other antiplatelet drugs such as sulfinpyrazone and dipyridamole are commonly used to treat thrombotic vascular disease.
taken twice daily to prevent stroke
IN PATIENTS WITH PRIOR TIA OR STROKE.
Glycoprotein IIb/IIIa antagonists are also under investigation as platelet aggregation inhibitors.
Anticoagulation— Anticoagulation is indicated for patients with TIAs caused by cardiac embolus or a hypercoagulable state and is typically continued indefinitely or for as long as the cause of embolization (e.g., atrial fibrillation or prosthetic heart valve) persists. The value of anticoagulation for TIAs from arterial thrombosis is uncertain. Unfractionated heparin is the drug of choice for acute anticoagulation, whereas warfarin is used for long-term therapy. Heparin is usually administered by continuous intravenous infusion at 1000–2000 units/h. The activated partial thromboplastin time (aPTT) is measured at least daily, and the dose of heparin is adjusted to maintain the aPTT at about 1.5–2.5 times the pretreatment value. Low-molecular-weight heparin (LMWH) is often used as a bridging therapy in patients switching from intravenous heparin to warfarin . It is also commonly used to bridge patients at high risk for recurrent thromboembolism on temporary interruption of warfarin therapy for invasive procedures. LMWH requires dose adjustment in patients with renal insufficiency.
Warfarin (the usual maintenance dose is 5–15 mg/d orally) can be started simultaneously with heparin therapy. About 2 days after the prothrombin time (PT) reaches international normalized ratio (INR) = 2.0–3.0 (typically about 5 days after the onset of therapy), heparin can be discontinued. The PT or INR should be measured at least every 2 weeks and the dose of warfarin adjusted to maintain INR = 2.0–3.0. For mechanical prosthetic heart valves, the recommended target INR is 2.5–3.5. Enthusiasm for the use of anticoagulant therapy should be tempered by an appreciation of its potential hazards. The risk of intracranial hemorrhage is greatest in hypertensive patients and those older than 65 years of age.
Carotid endarterectomy— Carotid endarterectomy involves the surgical removal of thrombus from a stenotic common or internal carotid artery in the neck. In patients with anterior-circulation TIAs and moderate (50–70%) or high-grade (70–99%) carotid stenosis on the side appropriate to account for the symptoms, the combination of endarterectomy and aspirin is superior to aspirin alone in preventing stroke. Endarterectomy has no place in the treatment of vertebrobasilar TIAs or those related to intracranial arterial disease or complete carotid occlusion. The value of carotid endarterectomy for minimally stenotic but ulcerated carotid lesions is uncertain. The operative mortality rate for carotid endarterectomy has ranged from 1 to 5% or more.
Angioplasty and intraluminal stents—
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thromboembolism
Transluminal angioplasty of the carotid and vertebral arteries and surgical placement of tubular metal stents to maintain lumen patency in stenotic cerebral arteries are under investigation. However, a recent study in patients with symptomatic or severe asymptomatic carotid stenosis showed no difference in outcome between carotid stenting with an antiembolic device and endarterectomy.
Extracranial–intracranial bypass— Many patients with TIAs referable to the carotid circulation have stenoses in intracranial portions of the artery not accessible through the neck, or they exhibit tandem lesions in both the extracranial and intracranial cerebral circulations. Because carotid endarterectomy does not correct these problems, an alternative approach has been explored involving anastomosis of the extracranial (temporal artery) and intracranial (middle cerebral artery) circulations distal to the stenosis. The bulk of current evidence suggests that this bypass procedure is ineffective, but it is being reinvestigated in a subpopulation of patients with increased oxygen extraction in the ipsilateral hemisphere.
Conclusions—In experienced hands, carotid endarterectomy can be a safe procedure that reduces the risk of subsequent TIAs or stroke in symptomatic patients. Noninvasive vascular imaging should be used with these patients to define surgically accessible moderate to high-grade (50–99%) stenotic lesions. Medical treatment with aspirin should be instituted with both nonsurgical and postoperative patients. For patients who continue to have TIAs despite optimization of risk factor management, aspirin, and HMG Co-A reductase inhibitor (statin) treatment, clopidogrel , or a sustained release dipyridamole-aspirin combination should be considered. The utility of warfarin in this setting has not been established. In addition to the above measures, such contributory risk factors as hypertension, diabetes, and hyperlipidemia should be treated. Cigarette smoking and heavy alcohol use should be discontinued. Patients should be encouraged to modify their diets to conform to AHA guidelines and to increase their physical activity.
Stroke in Evolution
The optimal treatment for stroke in evolution is uncertain. The
onset of aspirin's antiplatelet effect is delayed
after oral administration, and
endarterectomy also involves considerable delay in treatment.
Anticoagulation with heparin can be considered, particularly in cases of high-grade, large-vessel stenosis or occlusion,
although the efficacy of this approach has not been proven.
In general, the risk of hemorrhagic transformation, a particular concern with large infarcts, must be weighed against the short-term risk of recurrent embolization.
Thrombolytic therapy is
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Thrombolytic agents such as tissue plasminogen activator (t- PA) must be administered in the hyperacute phase of stroke (<4.5 hours after onset), often before the evolution is completed.
appropriate for patients with stable or worsening deficits, but should generally be withheld if deficits are rapidly improving.
Completed Stroke Intravenous thrombolytic therapy—Tissue plasminogen activator (t-PA) is a serine protease that maps to chromosome 8 (8p12) in humans and catalyzes the conversion of plasminogen to plasmin. This accounts for its ability to lyse fibrin-containing clots such as those found in cerebrovascular thrombotic lesions. Some but not all controlled
clinical data suggest that the intravenous administration of recombinant t-PA (rt-PA) within 4.5 hours of the onset of symptoms reduces disability and mortality from ischemic stroke (technically, from TIA, since stroke is defined by a deficit that persists for at least 24 hours). The drug is administered at a dose of 0.9 mg/kg, up to a maximum total dose of 90 mg; 10% of the dose is given as an intravenous bolus and the remainder as a continuous intravenous infusion over 60 minutes.
The efficacy of rt-PA given more than 4.5 hours after symptoms begin, of other thrombolytic agents such as urokinase, or of intra-arterial administration of these agents is under investigation.
The lack of proven benefit when rtThe major complication of rt -PA PA is given after 3 hours, the risk of treatment is hemorrhage, which may bleeding complications, and the affect the brain or other tissues. importance of a correct diagnosis when treatment is potentially dangerous dictate that rt-PA not be given in certain settings.
It is important that the time of onset of symptoms can be established with confidence. The CT scan should not already show evidence of a large ischemic stroke or of hemorrhage. Patients whose coagulation function has been compromised by the administration of warfarin or heparin or by thrombocytopenia (platelet count <100,000/mm3) should
not receive rt-PA,
nor should those who are at increased risk of hemorrhage because of seizures at the onset of symptoms, prior intracranial hemorrhage, another intracranial disorder (including stroke or trauma) within 3 months, a major surgical procedure within 14 days, bleeding from the gastrointestinal or urinary tract within 21 days, or marked hypertension (systolic blood pressure >185 mmHg or diastolic blood pressure >110 mmHg).
To avoid treating TIAs that are already resolving or other conditions unlikely to respond to rt- PA, or for which the risk exceeds likely benefit, patients whose deficits are improving rapidly and spontaneously,
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patients with mild and isolated deficits, and those with blood glucose concentrations consistent with a hypo- or hyperglycemic origin of symptoms <50 mg/dL or >400 mg/dL)
should be excluded.
Within the first 24 hours after administration of rt-PA, anticoagulants and antiplatelet agents should not be given, blood pressure should be carefully monitored, and
Patients receiving rt -PA for stroke should be managed in facilities in which the capacity exists to diagnose stroke with a high degree of certainty and to manage bleeding complications.
arterial puncture and placement of central venous lines, bladder catheters, and nasogastric tubes should be avoided.
Intra-arterial thrombolytic therapy—Intra-arterial administration of
urokinase ,
prourokinase, or rt-TPA has also been investigated for the acute treatment of stroke . Early results with this approach suggest that prourokinase, and perhaps the other thrombolytic agents, given together with low-dose intravenous heparin, may be beneficial for patients with middle cerebral artery distribution stroke who can be treated within 3–6 hours of the onset of symptoms. Even less is known about the benefit of intra-arterial thrombolytic therapy for vertebrobasilar stroke, and about the comparative efficacy of intravenous and intra-arterial thrombolysis. The MERCI catheter, a clot retrieval device, is effective in recanalizing large intracranial vessels within 8 hours of occlusion . Mechanical embolectomy is under investigation to determine whether it improves stroke outcome.
Antiplatelet agents—As noted above in discussing the treatment of TIAs, antiplatelet therapy is recommended for secondary stroke prevention unless a high-risk cardioembolic source warrants anticoagulation with warfarin . The regimen is as described in the section on treatment of TIA.
Anticoagulation—Anticoagulation has not been shown to be useful in most cases of completed stroke. An exception is where a persistent source of cardiac embolus is present; anticoagulation is then indicated to prevent subsequent embolic strokes, although it does not affect the course of the stroke that has already occurred. R e c e n t e v i d e n c e i n d i c a t e s t h a t a l t h o u g h
immediate anticoagulation of such patients may result in hemorrhage into the infarct, this rarely affects the ultimate outcome adversely unless the infarct is massive.
Where there is a particularly high risk of recurrent embolization soon after an embolic stroke, as is the case in patients with mechanical prosthetic heart valves, anticoagulation should not be delayed. Heparin and warfarin are administered as described in the section on treatment of TIA.
Surgery—The indications for surgical treatment of completed stroke are extremely limited. When patients deteriorate as a consequence of brainstem compression following cerebellar infarction,
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thromboembolism posterior fossa decompression with evacuation of infarcted cerebellar tissue can be lifesaving.
Antihypertensive agents—Although hypertension contributes to the pathogenesis of stroke and many patients with acute stroke have elevated blood pressures, attempts to reduce the blood pressure acutely in stroke patients can have disastrous results, since the blood supply to ischemic but as yet uninfarcted brain tissue may be further compromised. Therefore, aggressive blood pressure reduction
In the usual course of events, the blood pressure declines spontaneously over a period of hours to a few days.
is not recommended.
Antiedema agents—Antiedema agents such as mannitol and corticosteroids have not been shown to be of benefit for cytotoxic edema (cellular swelling) associated with cerebral infarction.
Neuroprotective agents—A variety of drugs with diverse pharmacologic actions have been proposed as neuroprotective agents that might reduce ischemic brain injury by decreasing cerebral metabolism or interfering with the cytotoxic mechanisms triggered by ischemia. These include barbiturates, opioid antagonists (naloxone ), voltage-gated calcium channel antagonists (nimodipine ), excitatory amino acid receptor antagonists, trophic factors, gangliosides, lipid peroxidation inhibitors (tirilazad), and free radical scavengers (NXY-059). Thus far, however, clinical trials with these agents have been unsuccessful.
Prevention of stroke recurrence—Antiplatelet therapy (discussed above for TIAs) is also recommended for secondary stroke prevention unless a high-risk cardioembolic source warrants anticoagulation with warfarin . Long-term antihypertensive therapy can also reduce the risk of recurrent stroke, and angiotensin converting enzyme inhibitors may be especially effective for this purpose. Statins such as atorvastatin (80 mg/d) likewise appear to lower the risk of stroke in patients with prior stroke or TIA.
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