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Disorders of Hemostasis, Thrombosis, & Antithrombotic Therapy Patrick F. Fogarty, MD Tracy Minichiello, MD
In assessing patients for defects of hemostasis, the clinical context must be considered carefully (Table 14–1). Heritable defects are suggested by bleeding that begins in infancy or childhood, is recurrent, and occurs at multiple anatomic sites, although many other patterns of presentation are possible. Acquired disorders of hemostasis more typically are associated with bleeding that begins later in life and may be relatable to introduction of medications (eg, agents that affect platelet activity) or to onset of underlying medical conditions (such as renal failure or myelodysplasia), or may be idiopathic. Importantly, however, a sufficient hemostatic challenge (such as major trauma) may produce excessive bleeding even in individuals with completely normal hemostasis. Fogarty PF et al. Disorders of Hemostasis I: Coagulation. In: Rodgers GP et al (editors). The Bethesda Handbook of Clinical Hematology. Philadelphia: Lippincott Williams and Wilkins, 2010.
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PLATELET DISORDERS
Thrombocytopenia The causes of thrombocytopenia are shown in Table 14–2. The age of the patient and presence of any comorbid conditions may help direct the diagnostic work-up. The risk of spontaneous bleeding (including petechial hemorrhage and bruising) does not typically increase appreciably until the platelet count falls below 10,000– 20,000/mcL, although patients with dysfunctional platelets may bleed with higher platelet counts. Suggested platelet counts to prevent spontaneous bleeding or to provide adequate hemostasis around the time of invasive procedures are found in Table 14–3.
Decreased Platelet Production 1. Bone Marrow Failure
``
Essentials of diagnosis
Bone marrow failure states may be congenital or acquired. `` Most congenital marrow failure disorders present in childhood. ``
``General Considerations Congenital conditions that cause thrombocytopenia include amegakaryocytic thrombocytopenia, the thrombocytopeniaabsent radius (TAR) syndrome, and Wiskott-Aldrich syndrome; these disorders usually feature isolated thrombocytopenia, whereas patients with Fanconi anemia and dyskeratosis congenita typically have depressions in other blood cell counts as well. Acquired causes of bone marrow failure leading to thrombocytopenia include acquired aplastic anemia, myelodysplastic syndrome (MDS), and acquired amegakaryocytic thrombocytopenia. Unlike aplastic anemia, MDS is more common among older patients.
``Clinical Findings Acquired aplastic anemia typically presents with reductions in multiple blood cell lines; a bone marrow biopsy subsequently reveals hypocellularity. Myelodysplasia may also present as cytopenias with variable marrow cellularity, at times mimicking aplastic anemia; however, the presence of macrocytosis, ringed sideroblasts on iron staining of the bone marrow aspirate, dysplasia of hematopoietic
Table 14–1. Evaluation of the bleeding patient. Necessary Component of Evaluation
Table 14–2. Causes of thrombocytopenia. Decreased production of platelets Congenital bone marrow failure (eg, Fanconi anemia, WiskottAldrich syndrome) Acquired bone marrow failure (eg, aplastic anemia, myelodysplasia) Exposure to chemotherapy, irradiation Marrow infiltration (neoplastic, infectious) Nutritional (deficiency of vitamin B12, folate, iron; alcohol) Increased destruction of platelets Immune thrombocytopenia (including hepatitis C virus- and HIV-related,1 and drug-induced) Heparin-induced thrombocytopenia Thrombotic microangiopathy Disseminated intravascular coagulation Posttransfusion purpura Neonatal alloimmune thrombocytopenia Mechanical (aortic valvular dysfunction; extracorporeal bypass) von Willebrand disease, type 2B Hemophagocytosis Increased sequestration of platelets Hypersplenism (eg, related to cirrhosis, myeloproliferative disorders, lymphoma) Other conditions causing thrombocytopenia Gestational thrombocytopenia Bernard-Soulier syndrome, gray platelet syndrome, May-Hegglin anomaly Pseudothrombocytopenia
Diagnostic Correlate
Location Mucocutaneous (bruises, petechiae, gingival, nosebleeds)
Likely qualitative/quantitative platelet defects
Joints, soft tissue
Likely disorders of coagulation factors
Onset Infancy/childhood
Suggests heritable condition
Adulthood
Suggests milder heritable condition or acquired defect of hemostasis (eg, ITP, medication-related)
Clinical context Postsurgical
Anatomic/surgical defect must be ruled out
Pregnancy
vWD, HELLP syndrome, ITP, acquired factor VIII inhibitor
Sepsis
May indicate DIC
Patient taking anticoagulants
Rule out excessive anticoagulation
Personal history1 Absent
Suggests acquired rather than congenital defect, or anatomic/ surgical defect (if applicable)
Present
Suggests established acquired defect or congenital disorder
Family history Absent Present
Suggests acquired defect or no defect of hemostasis May signify hemophilia A or B, vWD, other heritable bleeding disorders
1 Includes evaluation of prior spontaneous bleeding, as well as excessive bleeding with circumcision, menses, dental extractions, trauma, minor procedures (eg, endoscopy, biopsies) and major procedures (surgery). DIC, disseminated intravascular coagulation; HELLP, hemolysis, elevated liver enzymes, low platelets; ITP, immune thrombocytopenia; vWD, von Willebrand disease.
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1 HIV-related thrombocytopenia as well as disorders such as some cases of immune thrombocytopenia and cyclic thrombocytopenia may feature both decreased production and increased clearance of platelets.
``Treatment A. Congenital Conditions Treatment is varied but may include blood product support, blood cell growth factors, androgens, and (some cases) allogeneic hematopoietic progenitor cell transplantation.
B. Acquired Conditions Patients with severe aplastic anemia are treated with allogeneic hematopoietic progenitor cell transplantation, which
Table 14–3. Desired platelet count ranges. elements, or cytogenetic abnormalities (especially monosomy 5 or 7, and trisomy 8) are more suggestive of MDS. Thrombocytopenia in patients with MDS is usually mild to moderate, rather than severe.
Clinical Scenario
``Differential Diagnosis Adult patients with acquired amegakaryocytic thrombocytopenia have isolated thrombocytopenia and reduced or absent megakaryocytes in the bone marrow, which (along with failure to respond to immunomodulatory regimens typically administered in immune thrombocytopenia [ITP]) distinguishes them from patients with ITP.
Platelet count (/mcL)
Prevention of spontaneous mucocutaneous bleeding
> 10,000–20,000
Insertion of central venous catheters
> 20,000–50,0001
Administration of therapeutic anticoagulation
> 30,000–50,000
Minor surgery and selected invasive procedures2 > 50,000–80,000 Major surgery 1
> 80,000–100,000
A platelet target within the higher range of the reference is required for tunneled catheters. 2 Such as endoscopy with biopsy.
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is the preferred therapy for patients younger than age 40 who have an HLA-matched sibling donor (see Chapter 13), or with immunosuppression, which is the preferred therapy for older patients and those who lack an HLA-matched sibling donor. Treatment of thrombocytopenia due to MDS, if clinically significant bleeding is present or if the risk of bleeding is high, is limited to chronic transfusion of platelets in most instances (Table 14–3). Newer immunomodulatory agents such as lenalidomide do not produce increases in the platelet count in most patients. Use of the thrombopoietin receptor agonists, eltrombopag and romiplostim, is not recommended in patients with MDS due to the potential for accelerated development of leukemia. Akhtari M. When to treat myelodysplastic syndromes. Oncology (Williston Park). 2011 May;25(6):480–6. [PMID: 21717901] Guinan EC. Diagnosis and management of aplastic anemia. Hematology Am Soc Hematol Educ Program. 2011;2011:76–81. [PMID: 22160015]
2. Bone Marrow Infiltration Replacement of the normal bone marrow elements by leukemic cells, myeloma, lymphoma, or other tumors or by infections (such as mycobacterial disease or ehrlichiosis) may cause thrombocytopenia; however, abnormalities in other blood cell lines are also usually present. These entities are easily diagnosed after examining the bone marrow biopsy and aspirate or determining the infecting organism from an aspirate specimen. Treatment of thrombocytopenia is directed at eradication of the underlying infiltrative disorder, but platelet transfusion may be required if clinically significant bleeding is present.
3. Chemotherapy & Irradiation Chemotherapeutic agents and irradiation may lead to thrombocytopenia by direct toxicity to megakaryocytes, hematopoietic progenitor cells, or both. The severity and duration of chemotherapy-induced depressions in the platelet count are determined by the specific regimen used, although the platelet count typically resolves more slowly following a chemotherapeutic insult than does neutropenia or anemia, especially if multiple cycles of treatment have been given. Until recovery occurs, patients may be supported with transfused platelets if bleeding is present or the risk of bleeding is high (Table 14–3). Clinical trials to determine the role of the platelet growth factors eltrombopag and romiplostim in the treatment of chemotherapyinduced thrombocytopenia are ongoing.
4. Nutritional Deficiencies Thrombocytopenia, typically in concert with anemia, may be observed when a deficiency of folate (that may accompany alcoholism) or vitamin B12 is present (concomitant neurologic findings are common). In addition, thrombocytopenia rarely can occur in very severe iron deficiency. Replacing the deficient vitamin or mineral results in improvement in the platelet count.
5. Cyclic Thrombocytopenia Cyclic thrombocytopenia is a very rare disorder that produces cyclic oscillations of the platelet count, usually with a periodicity of 3–6 weeks. The exact pathophysiologic mechanisms responsible for the condition may vary from patient to patient. Severe thrombocytopenia and bleeding typically occur at the platelet nadir. Oral contraceptive medications, androgens, azathioprine, and thrombopoietic growth factors have been used successfully in the management of cyclic thrombocytopenia. Masoodi I et al. Hemorrhagic manifestation of megaloblastic anemia: report of two cases and literature review. Blood Coagul Fibrinolysis. 2011 Apr;22(3):234–5. [PMID: 21297452]
Increased Platelet Destruction 1. Immune Thrombocytopenia
``
Essentials of diagnosis
Isolated thrombocytopenia. Assess for any new causative medications and HIV and hepatitis C infections. `` ITP is a diagnosis of exclusion. `` ``
``General Considerations ITP is an autoimmune condition in which pathogenic antibodies bind platelets, resulting in accelerated platelet clearance. Contrary to the historical view of the disorder, it is now recognized that many patients with ITP also lack appropriate compensatory platelet production. The disorder is primary and idiopathic in most adult patients, although it can be associated with connective tissue disease (such as lupus), lymphoproliferative disease (such as lymphoma), medications (see below), and infections (such as hepatitis C virus and HIV infections). Targets of antiplatelet antibodies include glycoproteins IIb/IIIa and Ib/IX on the platelet membrane, although antibodies are demonstrable in only two-thirds of patients. In addition to production of antiplatelet antibodies, HIV and hepatitis C virus may lead to thrombocytopenia through additional mechanisms (for instance, by direct suppression of platelet production [HIV] and cirrhosis-related splenomegaly [hepatitis C virus]).
``Clinical Findings A. Symptoms and Signs Mucocutaneous bleeding manifestations may be present, depending on the platelet count. Spontaneous bruising, nosebleeds, gingival bleeding, or other types of hemorrhage generally do not occur until the platelet count has fallen below 20,000–30,000/mcL. Individuals with secondary ITP (such as due to collagen vascular disease, HIV or HCV
Disorders of Hemostasis, Thrombosis infection, or lymphoproliferative malignancy) may have additional disease-specific findings.
B. Laboratory Findings Typically, patients have isolated thrombocytopenia. If bleeding has occurred, anemia may also be present. Hepatitis virus B and C and HIV infections should be excluded by serologic testing. Bone marrow should be examined in patients with unexplained cytopenias, in patients older than 60 years, or in those who did not respond to primary ITP-specific therapy. Megakaryocyte abnormalities and hypocellularity or hypercellularity are not characteristic of ITP. If there are clinical findings suggestive of a lymphoproliferative malignancy, a CT scan should be performed. In the absence of such findings, otherwise asymptomatic patients with unexplained isolated thrombocytopenia of recent onset may be considered to have ITP.
``Treatment Only individuals with platelet counts < 20,000–30,000/mcL or those with significant bleeding should be treated; the
Prednisone, 1 mg/kg/d orally for 7–10 days followed by rapid taper INITIAL or TREATMENT Dexamethasone, 40 mg/d orally for 4 days monthly for 6 months
RELAPSED OR PERSISTENT ITP
±
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remainder may be monitored serially for progression. The mainstay of initial treatment of new-onset primary ITP is a short course of corticosteroids with or without intravenous immunoglobulin (IVIG) or anti-D (WinRho) (Figure 14–1). Responses are generally seen within 3–5 days of initiating treatment. Platelet transfusions may be given concomitantly if active bleeding is present. Although over two-thirds of patients with ITP respond to initial treatment, most relapse following reduction of the corticosteroid dose. Patients with a persistent platelet count < 30,000/mcL or clinically significant bleeding are appropriate candidates for second-line treatments (Figure 14–1). These treatments are chosen empirically, bearing in mind potential toxicities and the patient’s preference. Anti-D (WinRho) or IVIG temporarily increases platelet counts (duration, 3 weeks or longer), although serial anti-D treatment (platelet counts < 30,000/mcL) may allow adult patients to delay or avoid splenectomy. The monoclonal anti-B cell antibody rituximab leads to initial responses in about 50% of adults with corticosteroid-refractory chronic ITP, decreasing to 20% at 5 years. The thrombopoietin receptor agonists, romiplostim (administered subcutaneously weekly) and
IVIG, 1 g/kg/d intravenously for 2 days or anti-D, 75 mcg/kg intravenously for 1 dose1
±
Platelets, if bleeding
Prednisone, 1 mg/kg/d orally for 7–10 days followed by rapid taper or Dexamethasone, 40 mg/d orally for 4 days monthly for 6 months
and Rituximab, 375 mg/m2 intravenously weekly for 4 weeks
or
anti-D, 75 mcg/kg intravenously serially as or needed for platelets 1 < 30,000/mcL
IVIG, 1 g/kg/d intravenously for 2 days serially as needed for platelets < 30,000/mcL
or
Thrombopoietin receptor agonist (see text)
or Splenectomy (laparoscopic)
PERSISTENT OR WORSENING ITP
Trial of additional agent(s) above or Mycophenolate mofetil • Azathioprine/danazol • Cyclosporine • Chemotherapy 2 Enrollment in clinical trial • Autologous transplantation
or Splenectomy (laparoscopic) 1 2
Use in nonsplenectomized, Rh blood type-positive, nonanemic patients only. Both lymphoma-type chemotherapy and single-agent vincristine have been used successfully in refractory cases of ITP.
s Figure 14–1. Management of immune thrombocytopenia (ITP).
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eltrombopag (taken orally daily), are approved for use in adult patients with chronic ITP who have not responded durably to corticosteroids, IVIG, or splenectomy and must be taken indefinitely to maintain the platelet response. Splenectomy has a durable response rate of over 60% and may be considered for cases of severe thrombocytopenia that fail to respond durably to initial treatment or are refractory to second-line agents; patients should receive pneumococcal, Haemophilus influenzae type b, and meningococcal vaccination at least 2 weeks before the procedure. If available, laparoscopic splenectomy is preferred. Additional treatments for ITP are found in Figure 14–1. The goal of management of pregnancy-associated ITP is a platelet count of 10,000–30,000/mcL in the first trimester, > 30,000/mcL during the second or third trimester, and > 50,000/mcL prior to cesarean section or vaginal delivery. Moderate-dose oral prednisone or intermittent infusions of IVIG are standard. Splenectomy is reserved for failure to respond to these therapies and may be performed in the first or second trimester. The safety of platelet growth factors in pregnancy has not been formally evaluated. For thrombocytopenia associated with HIV or hepatitis C virus, treatment of either infection leads to an amelioration in the platelet count in most cases, whereas refractory thrombocytopenia may be treated with infusion of IVIG or anti-D (HIV and hepatitis C virus), splenectomy (HIV), or interferon-alpha or eltrombopag (hepatitis C virus, including eradication). Treatment with corticosteroids is not recommended in hepatitis C virus infection.
``When to Refer Chronic thrombocytopenia will develop in most adult patients with newly diagnosed ITP; therefore, all patients with ITP should be referred to a subspecialist for evaluation at the time of diagnosis.
``When to Admit Patients with major hemorrhage or very severe thrombocytopenia associated with bleeding should be admitted and monitored in-hospital until the platelet count has risen to > 20,000–30,000/mcL and hemodynamic stability has been achieved.
`
Afdhal N et al. Thrombocytopenia associated with chronic liver disease. J Hepatol. 2008 Jun;48(6):1000–7. [PMID: 18433919] Bussel JB et al. Eltrombopag. Cancer Treat Res. 2011;157: 289–303. [PMID: 21052963] Kuter DJ et al. Romiplostim or standard of care in patients with immune thrombocytopenia. N Engl J Med. 2010 Nov 11;363 (20):1889–99. [PMID: 21067381] Provan D et al. International consensus report on the investigation and management of primary immune thrombocytopenia. Blood. 2010 Jan 14;115(2):168–86. [PMID: 19846889] Semple JW et al. Recent progress in understanding the pathogenesis of immune thrombocytopenia. Curr Opin Hematol. 2010 Nov;17(6):590–5. [PMID: 20739879]
2. Thrombotic Microangiopathy
``
Essentials of diagnosis
Microangiopathic hemolytic anemia and thrombocytopenia, in the absence of another plausible explanation, are sufficient for the diagnosis of TMA. `` Fever, neurologic abnormalities, and renal insufficiency may occur concurrently but are not required for diagnosis. `` Renal insufficiency occurs in hemolytic-uremic syndrome. ``
``General Considerations The thrombotic microangiopathies (TMAs) include thrombotic thrombocytopenic purpura (TTP) and the hemolyticuremic syndrome (HUS). These disorders are characterized by thrombocytopenia, due to the incorporation of platelets into thrombi in the microvasculature, and microangiopathic hemolytic anemia, which results from shearing of erythrocytes in the microcirculation. In idiopathic TTP, autoantibodies against the ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 repeat, member 13) molecule, also known as the von Willebrand factor cleaving protease (vWFCP), leads to accumulation of ultra-large von Willebrand factor (vWF) multimers that bridge platelets and facilitate excessive platelet aggregation, leading to TTP. In some cases of pregnancy-associated TMA, an antibody to vWFCP is present. In contrast, the activity of the vWFCP in congenital TTP is decreased due to a mutation in the gene encoding the molecule. Atypical HUS, an additional thrombotic microangiopathy, is a chronic disorder that typically leads to renal failure. Mutations in complement genes (such as factor H, a complement regulator) account for the uncontrolled activation of complement that characterizes the condition. Damage to endothelial cells—such as the damage that occurs in endemic HUS due to presence of toxins from Escherichia coli (especially type O157:H7 or O145) or in the setting of cancer, hematopoietic stem cell transplantation, or HIV infection—may also lead to TMA. Certain drugs (eg, cyclosporine, quinine, ticlopidine, clopidogrel, mitomycin C, and bleomycin) have been associated with the development of TMA, possibly by promoting injury to endothelial cells, although inhibitory antibodies to ADAMTS-13 also have been demonstrated in some cases.
``Clinical Findings A. Symptoms and Signs Microangiopathic hemolytic anemia and thrombocytopenia are presenting signs in all patients with TTP and most patients with HUS; in a subset of patients with HUS, the platelet count remains in the normal range. Only approximately 25% of patients with TMA manifest all components of the so-called pentad of findings (microangiopathic hemolytic anemia, thrombocytopenia,
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Table 14–4. Clinical features of thrombotic microangiopathy. Parameter
Thrombotic Thrombocytopenic Purpura
Hemolytic-Uremic Syndrome
Microangiopathic hemolytic anemia
All patients
All patients
Thrombocytopenia
All patients
Most patients (may be mild/absent in a subset of patients)
Fever
75% of patients
Usually absent
Renal insufficiency
Mild/absent in some patients
All patients
Neurologic defects
Most patients
Present in less than half
Epidemiologic
Most cases in adults
Most cases in children
Historical
Idiopathic (minority of cases: antecedent viral illness or familial)
Antecedent hemorrhagic enteritis in most patients
Laboratory findings
Decreased activity of ADAMTS-13
Positive stool culture for Escherichia coli O157:H7; ADAMTS-13 activity usually normal
ADAMTS-13, a disintegrin and metalloproteinase with a thrombospondin type 1 repeat, member 13 (von Willebrand factor cleaving protease).
fever, renal insufficiency, and neurologic system abnormalities) (Table 14–4). Most patients (especially children) with HUS have a recent or current diarrheal illness. Neurologic manifestations, including headache, somnolence, delirium, seizures, paresis, and coma, may result from deposition of microthrombi in the cerebral vasculature. Atypical HUS typically presents in childhood.
B. Laboratory Findings Laboratory features of TMA include those associated with microangiopathic hemolytic anemia (anemia, elevated lactate dehydrogenase [LD], elevated indirect bilirubin, decreased haptoglobin, reticulocytosis, negative direct antiglobulin test, and schistocytes on the blood smear); thrombocytopenia; elevated creatinine; positive stool culture for E coli O157:H7 or stool assays for Shiga-toxin producing E coli to detect non-O157:H7 such as E coli O145 (HUS only); reductions in vWFCP activity (idiopathic TTP); and mutations of genes encoding complement proteins (atypical HUS; specialized laboratory assessment). Notably, routine coagulation studies are within the normal range in most patients with TMA.
``Treatment Immediate administration of plasma exchange is essential in most cases due to the mortality rate of > 95% without treatment. With the exception of children or adults with endemic diarrhea-associated HUS, who generally recover with supportive care only, plasma exchange must be initiated as soon as the diagnosis of TMA is suspected. Plasma exchange usually is administered once daily until the platelet count and LD have returned to normal for at least 2 days, after which the frequency of treatments may be tapered slowly while the platelet count and LD are monitored for relapse. In cases of insufficient response to once-daily plasma exchange, twice-daily treatments should be given. Fresh frozen plasma (FFP) may be administered if immediate access to plasma exchange is not available or in cases of familial TMA. Platelet transfusions are contraindicated in the
treatment of TMAs due to reports of worsening thrombotic microangiopathy, possibly due to propagation of plateletrich microthrombi. In cases of documented life-threatening bleeding, however, platelet transfusions may be given slowly and after plasma exchange is underway. Red blood cell transfusions may be administered in cases of clinically significant anemia. Hemodialysis should be considered for patients with significant renal impairment. In cases of relapse following initial treatment, plasma exchange should be reinstituted. If ineffective, or in cases of primary refractoriness, second-line treatments may be considered including rituximab, corticosteroids, IVIG, vincristine, cyclophosphamide, and splenectomy. Cases of atypical HUS may respond to plasma infusion initially, and serial infusions of the anti-complement C5 antibody eculizumab have produced sustained remissions in some patients. If irreversible renal impairment has occurred, hemodialysis or renal transplantation may be necessary.
``When to Refer Consultation by a hematologist or transfusion medicine specialist familiar with plasma exchange is required at the time of presentation. Patients with refractory or relapsing TMA require ongoing care by a subspecialist.
``When to Admit All patients with newly suspected or diagnosed TMA should be hospitalized initially. Alvarez-Larrán A et al. Newly diagnosed versus relapsed idiopathic thrombotic thrombocytopenic purpura: a comparison of presenting clinical characteristics and response to treatment. Ann Hematol. 2009 Oct;88(10):973–8. [PMID: 19205654] Caramazza D et al. Relapsing or refractory idiopathic thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: the role of rituximab. Transfusion. 2010 Dec;50(12): 2753–60. [PMID: 20576013]
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Nürnberger et al. Eculizumab for atypical hemolytic-uremic syndrome. N Engl J Med. 2009 Jan 29;360(5):542–4. [PMID: 19179328] Stella CL et al. The diagnostic dilemma of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome in the obstetric triage and emergency department: lessons from 4 tertiary hospitals. Am J Obstet Gynecol. 2009 Apr;200(4):381.e1–6. [PMID: 19110215] Tschumi S et al. Eculizumab in atypical hemolytic uremic syndrome: long-term clinical course and histological findings. Pediatr Nephrol. 2011 Nov;26(11):2085–8. [PMID: 21877169]
3. Heparin-Induced Thrombocytopenia
``
Essentials of diagnosis
Thrombocytopenia within 5–10 days of exposure to heparin. `` Decline in baseline platelet count of 50% or greater. `` Thrombosis occurs in 50% of cases; bleeding is uncommon. ``
``Treatment Treatment should be initiated as soon as the diagnosis of HIT is suspected, before results of laboratory testing is available. Management of HIT (Table 14–5) involves the immediate discontinuation of all forms of heparin. If thrombosis has not already been detected, duplex Doppler ultrasound of the lower extremities should be performed to rule out subclinical deep venous thrombosis. Despite thrombocytopenia, platelet transfusions are rarely necessary. Due to the substantial frequency of thrombosis among HIT patients, an alternative anticoagulant, typically a direct thrombin inhibitor (DTI) such as argatroban or lepirudin should be administered immediately. The DTI should be continued until the platelet count has recovered to at least 100,000/mcL, at which point treatment with a vitamin K antagonist (warfarin) may be initiated. The DTI should be continued until therapeutic anticoagulation with the vitamin K antagonist has been achieved (international normalized ratio [INR] of 2.0–3.0) due to the warfarin effect; the infusion
Table 14–5. Management of suspected or proven HIT.
``General Considerations
I. Discontinue all forms of heparin. Send PF4-heparin ELISA (if indicated).
Heparin-induced thrombocytopenia (HIT) is an acquired disorder that affects approximately 3% of patients who are exposed to unfractionated heparin and 0.6% of patients who are exposed to low-molecular-weight heparin (LMWH). The condition results from formation of IgG antibodies to heparin-platelet factor 4 (PF4) complexes; the antibodies then bind platelets, which activates them. Platelet activation leads to both thrombocytopenia and a pro-thrombotic state.
II. Begin treatment with direct thrombin inhibitor. Agent
Indication
Argatroban
Prophylaxis or treatment of HIT
Continuous intravenous infusion of 0.5–1.2 mcg/kg/min, titrate to aPTT = 1.5 to 3 × the baseline value.1 Max infusion rate ≤ 10 mcg/kg/min.
Lepirudin
Treatment of HITT
Bolus of 0.4 mg/kg2 slowly intravenously followed by continuous intravenous infusion of 0.15 mg/kg/h. Titrate to aPTT = 1.5 – 2.5 × baseline value.
Bivalirudin
Percutaneous coronary intervention3
Bolus of 0.75 mg/kg intravenously followed by initial continuous intravenous infusion of 1.75 mg/ kg/h. Manufacturer indicates monitoring should be by ACT.
``Clinical Findings A. Symptoms and Signs Patients are usually asymptomatic, and due to the prothrombotic nature of HIT, bleeding usually does not occur. Thrombosis (at any venous or arterial site), however, may be detected in up to 50% of patients, up to 30 days post-diagnosis.
III. Perform Doppler ultrasound of lower extremities to rule out subclinical thrombosis (if indicated).
B. Laboratory Findings A presumptive diagnosis of HIT is made when new-onset thrombocytopenia is detected in a patient (frequently a hospitalized patient) within 5–10 days of exposure to heparin; other presentations (eg, rapid-onset HIT) are less common. A decline of ≥ 50% or more from the baseline platelet count is typical. Clinical prediction systems such as the 4T score may assist in assessment of pretest probability. Confirmation of the diagnosis can be obtained through a positive PF4-heparin antibody enzyme-linked immunosorbent assay (ELISA) or functional assay (such as serotonin release assay), or both. The magnitude of a positive ELISA result correlates with the clinical probability of HIT.
Dosing
IV. Follow platelet counts daily until recovery occurs. V. W hen platelet count has recovered, transition anticoagulation to warfarin; treat for 30 days (HIT) or 3–6 months (HITT). VI. Document heparin allergy in medical record (confirmed cases). Hepatic insufficiency: initial infusion rate = 0.5 mcg/kg/min. Renal insufficiency: initial bolus = 0.2 mg/kg. 3 Not approved for HIT/HITT. ACT, activated clotting time; aPTT, activated partial thromboplastin time; ELISA, enzyme-linked immunosorbent assay; HIT, heparininduced thrombocytopenia; HITT, heparin-induced thrombocytopenia and thrombosis; PF4, platelet factor 4. 1 2
Disorders of Hemostasis, Thrombosis of argatroban must be temporarily discontinued for 2 hours before the INR is obtained so that it reflects the anticoagulant effect of warfarin alone. Warfarin is contraindicated as initial treatment of HIT because of its potential to transiently worsen hypercoagulability. In all patients with HIT, warfarin subsequently should be continued for at least 30 days, due to a persistent risk of thrombosis even after the platelet count has recovered, whereas in patients in whom thrombosis has been documented, anticoagulation with warfarin should continue for 3–6 months. Subsequent exposure to heparin should be avoided in all patients with a prior history of HIT, if possible. If its use is regarded as necessary for a procedure, it should not be given until PF4-heparin antibodies are no longer detectable by ELISA (usually as of 100 days following an episode of HIT), and exposure should be limited to the shortest time period possible.
``When to Refer Due to the tremendous thrombotic potential of the disorder and the complexity of use of the DTI, all patients with HIT should be evaluated by a hematologist.
``When to Admit Most patients with HIT are hospitalized at the time of detection of thrombocytopenia. Any outpatient in whom HIT is suspected should be admitted because the DTIs must be administered by continuous intravenous infusion.
`
Cuker A. Heparin-induced thrombocytopenia: present and future. J Thromb Thrombolysis. 2011 Apr;31(3):353–66. [PMID: 21327506] Otis SA et al. Heparin-induced thrombocytopenia: current status and diagnostic challenges. Am J Hematol. 2010 Sep;85(9):700–6. [PMID: 20665476] Shantsila E et al. Heparin-induced thrombocytopenia. A contemporary clinical approach to diagnosis and management. Chest. 2009 Jun;135(6):1651–64. [PMID: 19497901] Warkentin TE. Agents for the treatment of heparin-induced thrombocytopenia. Hematol Oncol Clin North Am. 2010 Aug;24(4):755–75. [PMID: 20659659]
4. Disseminated Intravascular Coagulation
``
Essentials of diagnosis
A frequent cause of thrombocytopenia in hospitalized patients. `` Prolonged activated partial thromboplastin time and prothrombin time. `` Thrombocytopenia and decreased fibrinogen levels. ``
``General Considerations Disseminated intravascular coagulation (DIC) results from uncontrolled local or systemic activation of coagulation, which leads to depletion of coagulation factors and
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fibrinogen and to thrombocytopenia as platelets are activated and consumed. The numerous disorders that are associated with DIC include sepsis (in which coagulation is activated by presence of lipopolysaccharide) as well as cancer, trauma, burns, or pregnancy-associated morbidity (in which tissue factor is released). Aortic aneurysm and cavernous hemangiomas may promote DIC by leading to vascular stasis, and snake bites may result in DIC due to the introduction of exogenous toxins.
``Clinical Findings A. Symptoms and Signs Bleeding in DIC usually occurs at multiple sites, such as intravenous catheters or incisions, and may be widespread (purpura fulminans). Malignancy-related DIC may manifest principally as thrombosis (Trousseau syndrome).
B. Laboratory Findings Frequently, there are acute and progressive prolongations in coagulation studies or thrombocytopenia is found in a patient who is being treated for a separate disorder. In early DIC, the platelet count and fibrinogen levels may remain within the normal range, albeit reduced from baseline levels. There is progressive thrombocytopenia (rarely severe), prolongation of the activated partial thromboplastin time (aPTT) and prothrombin time (PT), and low levels of fibrinogen. D-dimer levels typically are elevated due to the activation of coagulation and diffuse cross-linking of fibrin. Schistocytes on the blood smear, due to shearing of red cells through the microvasculature, are present in 10–20% of patients. Laboratory abnormalities in the HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), a severe form of DIC with a particularly high mortality rate that occurs in peripartum women, include elevated liver transaminases and (many cases) renal dysfunction due to gross hemoglobinuria and pigment nephropathy. Malignancy-related DIC may feature normal platelet counts and coagulation studies.
``Treatment The underlying causative disorder must be treated (eg, antimicrobials, chemotherapy, surgery, or delivery of conceptus [see below]). If clinically significant bleeding is present, hemostasis must be achieved (Table 14–6). Blood products should be administered only if clinically significant hemorrhage has occurred or is thought likely to occur without intervention (Table 14–6). The goal of platelet therapy for most cases is > 20,000/mcL or > 50,000/mcL for serious bleeding, such as intracranial bleeding. FFP should be given only to patients with a prolonged aPTT and PT and significant bleeding; 4 units typically are administered at a time, and the posttransfusion platelet count should be documented. Cryoprecipitate may be given for bleeding and fibrinogen levels < 80–100 mg/dL. The PT, aPTT, fibrinogen, and platelet count should be monitored at least every 6 hours in acutely ill patients with DIC.
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Table 14–6. Management of DIC. I. Assess for underlying cause of DIC and treat.
``When to Admit Most patients with DIC are hospitalized when DIC is detected.
II. Establish baseline platelet count, PT, aPTT, D-dimer, fibrinogen. III. Transfuse blood products only if ongoing bleeding or high risk of bleeding:
Platelets: goal > 20,000/mcL (most patients) or > 50,000/mcL (severe bleeding, eg, intracranial hemorrhage) Cryoprecipitate: goal fibrinogen level > 80–100 mg/dL Fresh frozen plasma: goal PT and aPTT < 1.5 × normal Packed red blood cells: goal hemoglobin > 8 g/dL or improvement in symptomatic anemia
IV. F ollow platelets, aPTT/PT, fibrinogen every 4–6 hours or as clinically indicated. V. I f persistent bleeding, consider use of heparin1 (initial infusion, 5–10 units/kg/h); do not administer bolus. VI. Follow laboratory parameters every 4–6 hours until DIC resolved and underlying condition successfully treated 1 Contraindicated if platelets cannot be maintained at > 50,000/mcL, in cases of gastrointestinal or central nervous system bleeding, in conditions that may require surgical management, or placental abruption. aPTT, activated partial thromboplastin time; DIC, disseminated intravascular coagulation; PT, prothrombin time.
In some cases of refractory bleeding despite replacement of blood products, administration of low doses of heparin can be considered; it may help interfere with thrombin generation, which then could lead to a lessened consumption of coagulation proteins and platelets. An infusion of 6–10 units/kg/h (no bolus) may be used. Heparin, however, is contraindicated if the platelet count cannot be maintained at ≥ 50,000/mcL and in cases of central nervous system/gastrointestinal bleeding, placental abruption, and any other condition that is likely to require imminent surgery. Fibrinolysis inhibitors may be considered in some patients with refractory DIC. The treatment of HELLP syndrome must include evacuation of the uterus (eg, delivery of a term or near-term infant or removal of retained placental or fetal fragments). Patients with Trousseau syndrome require treatment of the underlying malignancy or administration of unfractionated heparin or subcutaneous therapeutic-dose LMWH as treatment of thrombosis, since warfarin typically is ineffective at secondary prevention of thromboembolism in the disorder. Immediate initiation of chemotherapy (usually within 24 hours of diagnosis) is required for patients with acute promyelocytic leukemia (APL)–associated DIC, along with administration of blood products as clinically indicated.
``When to Refer Patients with diffuse bleeding that is unresponsive to administration of blood products should be evaluated by a hematologist.
`
Franchini M et al. Disseminated intravascular coagulation in hematologic malignancies. Semin Thromb Hemost. 2010 Jun;36(4):388–403. [PMID: 20614391] Levi M et al. Disseminated intravascular coagulation in infectious disease. Semin Thromb Hemost. 2010 Jun;36(4):367–77. [PMID: 20614389] Levi M et al. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Haematol. 2009 Apr;145(1):24–33. [PMID: 19222477] Lippi G et al. Disseminated intravascular coagulation in trauma injuries. Semin Thromb Hemost. 2010 Jun;36(4):378–87. [PMID: 20614390] Martí-Carvajal AJ et al. Treatment for disseminated intravascular coagulation in patients with acute and chronic leukemia. Cochrane Database Syst Rev. 2011 Jun 15;(6):CD008562. [PMID: 21678379]
OTHER CONDITIONS CAUSING THROMBOCYTOPENIA 1. Drug-Induced Thrombocytopenia The mechanisms underlying drug-induced thrombocytopenia are thought in most cases to be immune, although exceptions exist (such as chemotherapy). Table 14–7 lists medications associated with thrombocytopenia. The typical presentation of drug-induced thrombocytopenia is severe thrombocytopenia and mucocutaneous bleeding 7–14 days after exposure to a new drug, although a range of presentations is possible. Discontinuation of the offending agent leads to resolution of thrombocytopenia within 7–10 days in most cases, but patients with severe thrombocytopenia should be given platelet transfusions with (immune cases only) or without IVIG.
2. Posttransfusion Purpura Posttransfusion purpura (PTP) is a rare disorder that features sudden-onset thrombocytopenia in an individual who recently has received transfusion of red cells, platelets, or plasma within 1 week prior to detection of thrombocytopenia. Antibodies against the human platelet antigen PlA1 are detected in most individuals with PTP. Patients with PTP almost universally are either multiparous women or persons who have received transfusions previously. Severe thrombocytopenia and bleeding is typical. Initial treatment consists of administration of IVIG (1 g/kg/d for 2 days) which should be administered as soon as the diagnosis is suspected. Platelets are not indicated unless severe bleeding is present, but if they are to be administered, HLA-matched platelets are preferred. A second course or IVIG, plasma exchange, corticosteroids, or splenectomy may be used in case of refractoriness. PlA1-negative or washed blood products are preferred for subsequent transfusions.
Disorders of Hemostasis, Thrombosis
Table 14–7. Medications causing drug-associated thrombocytopenia. Class
Examples
Chemotherapy
Most agents
Antiplatelet agents
Anagrelide Abciximab Eptifibatide Tirofiban Ticlopidine
Antimicrobial agents
Penicillins Isoniazid Rifampin Sulfa drugs Vancomycin Adefovir Indinavir Ritonavir Fluconazole Linezolid
Cardiovascular agents
Digoxin Amiodarone Captopril Hydrochlorothiazide Procainamide Atorvastatin Simvastatin
Gastrointestinal agents
Cimetidine Ranitidine Famotidine
Neuropsychiatric agents
Haloperidol Carbamazepine Methyldopa Phenytoin
Analgesic agents
Acetaminophen Ibuprofen Sulindac Diclofenac Naproxen
Anticoagulant agents
Heparin Low-molecular-weight heparin
Immunomodulator agents
Interferon-alpha Gold Rituximab
Immunosuppressant agents
Mycophenolate mofetil Tacrolimus
Other agents
Iodinated contrast dye Immunizations
3. von Willebrand Disease Type 2B von Willebrand disease (vWD) type 2B leads to chronic, characteristically mild to moderate thrombocytopenia via an abnormal vWF molecule that binds platelets with increased affinity, resulting in aggregation and clearance.
4. Platelet Sequestration At any given time, one-third of the platelet mass is sequestered in the spleen. Splenomegaly, due to a variety of
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Table 14–8. Selected causes of splenomegaly. Lymphoproliferative/myeloproliferative disease Lymphoma Chronic lymphocytic leukemia Chronic myeloid leukemia Polycythemia vera Essential thrombocythemia Vascular congestion Congestive heart failure Cirrhosis Hematologic defects Hereditary spherocytosis Paroxysmal nocturnal hemoglobinuria Thalassemia Autoimmunity Collagen vascular disease Felty syndrome, Systemic Lupus Erythematosus Autoimmune lymphoproliferative disorder Infection Infectious hepatitis Cytomegalovirus, Epstein Barr Virus Malaria Babesiosis Inborn errors of metabolism Gaucher disease Niemann-Pick disease
conditions (Table 14–8), may lead to thrombocytopenia of variable severity. Whenever possible, treatment of the underlying disorder should be pursued, but splenectomy, splenic embolization, or splenic irradiation may be considered in selected cases.
5. Pregnancy Gestational thrombocytopenia results from progressive expansion of the blood volume that typically occurs during pregnancy, leading to hemodilution. Cytopenias result, although production of blood cells is normal or increased. Platelet counts <100,000/mcL, however, are observed in <10% of pregnant women in the third trimester; decreases to < 70,000/mcL should prompt consideration of pregnancyrelated ITP (see above) as well as preeclampsia or a pregnancy-related thrombotic microangiopathy.
6. Infection or Sepsis Both immune- and platelet production–mediated defects are possible, and there may be significant overlap with concomitant DIC (see above). In either case, the platelet count typically improves with effective antimicrobial treatment or after the infection has resolved. In some critically ill patients, a defect in immunomodulation may lead to bone marrow macrophages (histiocytes) engulfing cellular components of the marrow in a process also called hemophagocytosis. The phenomenon typically resolves with resolution of the infection, but with certain infections (Epstein Barr virus) immunosuppression may be required. Hemophagocytosis also may arise in the setting of malignancy, in which case the disorder is usually unresponsive to treatment with immunosuppression.
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7. Pseudothrombocytopenia
B. Laboratory Findings
Pseudothrombocytopenia results from EDTA anticoagulantinduced platelet clumping; the phenomenon typically disappears when blood is collected in a tube containing citrate anticoagulant.
In Bernard-Soulier syndrome, there are abnormally large platelets (approaching the size of red cells), moderate thrombocytopenia, and a prolonged bleeding time. Platelet aggregation studies show a marked defect in response to ristocetin, whereas aggregation in response to other agonists is normal; the addition of normal platelets corrects the abnormal aggregation. The diagnosis can be confirmed by platelet flow cytometry. In Glanzmann thrombasthenia, platelet aggregation studies show marked impairment of aggregation in response to stimulation with typical agonists. Storage pool disease describes defects in the number or content of platelet alpha or dense granules or both. The gray platelet syndrome comprises abnormalities of platelet alpha granules, thrombocytopenia, and marrow fibrosis. The blood smear shows agranular platelets, and the diagnosis is confirmed with electron microscopy. Albinism-associated storage pool disease involves defective dense granules in disorders of oculocutaneous albinism, such as the Hermansky-Pudlak and Chediak-Higashi syndromes. Electron microscopy confirms the diagnosis. Non–albinism-associated storage pool disease results from quantitative or qualitative defects in dense granules and is seen in Ehlers-Danlos and Wiskott-Aldrich syndromes, among others. The Quebec platelet disorder comprises mild thrombocytopenia, an abnormal platelet factor V molecule, and a prolonged bleeding time. Patients typically experience moderate bleeding. Interestingly, platelet transfusion does not ameliorate the bleeding. Patients have a prolonged bleeding time. Platelet aggregation studies characteristically show platelet dissociation following an initial aggregatory response, and electron microscopy confirms the diagnosis.
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Bockenstedt PL. Thrombocytopenia in pregnancy. Hematol Oncol Clin North Am. 2011 Apr;25(2):293–310. [PMID: 21444031] Perdomo J et al. Quinine-induced thrombocytopenia: drugdependent GPIb/IX antibodies inhibit megakaryocyte and proplatelet production in vitro. Blood. 2011 Jun 2;117(22): 5975–86. [PMID: 21487107]
QUALITATIVE PLATELET DISORDERS Congenital Disorders of PLATELET FUNCTION
``
EssentialS of diagnosis
Usually diagnosed in childhood. Family history usually is positive. `` May be diagnosed in adulthood when there is excessive bleeding. `` ``
``General Considerations Heritable qualitative platelet disorders are far less common than acquired disorders of platelet function (see below) and lead to variably severe bleeding, often beginning in childhood. Occasionally, however, disorders of platelet function may go undetected until later in life when excessive bleeding occurs following a sufficient hemostatic insult. Thus, the true incidence of hereditary qualitative platelet disorders is unknown. Bernard-Soulier syndrome (BSS) is a rare, autosomal recessive bleeding disorder that is due to reduced or abnormal platelet membrane expression of glycoprotein Ib/IX (vWF receptor). Glanzmann thrombasthenia results from a qualitative or quantitative abnormality in glycoprotein IIb/IIIa receptors on the platelet membrane, which are required to bind fibrinogen and vWF, both of which bridge platelets during aggregation. Inheritance is autosomal recessive. Under normal circumstances, activated platelets release the contents of platelet granules to reinforce the aggregatory response. Storage pool disease is caused by defects in release of alpha or dense (delta) platelet granules, or both (alpha-delta storage pool disease).
``Clinical Findings A. Symptoms and Signs In patients with Glanzmann thrombasthenia, the onset of bleeding is usually in infancy or childhood. The degree of deficiency in IIb/IIIa may not correlate well with bleeding symptoms. Patients with storage pool disease are affected by variable bleeding, ranging from mild and trauma-related to spontaneous.
``Treatment The mainstay of treatment (including periprocedural prophylaxis) is transfusion of normal platelets, although desmopressin acetate (DDAVP), antifibrinolytic agents, and recombinant human activated factor VII also have been used successfully.
`
Hers I et al. Understanding the therapeutic action of recombinant factor VIIa in platelet disorders. Platelets. 2008 Dec;19(8):571–81. [PMID: 19012175] Kannan M et al. Glanzmann’s thrombasthenia: an overview. Clin Appl Thromb Hemost. 2009 Mar–Apr;15(2):152–65. [PMID: 18930954] Nurden P et al. Congenital disorders associated with platelet dysfunctions. Thromb Haemost. 2008 Feb;99(2):253–63. [PMID: 18278172]
Acquired Disorders OF PLATELET FUNCTION Platelet dysfunction is more commonly acquired than inherited; the widespread use of platelet-active medications accounts for most of the cases of qualitative defects (Table 14–9). In these cases, platelet inhibition typically declines within 5–10 days following discontinuation of the drug, and transfusion of platelets may be required if clinically significant bleeding is present.
Disorders of Hemostasis, Thrombosis
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Table 14–9. Causes of acquired platelet dysfunction. Cause
Mechanism(s)
Treatment of Bleeding
Drug-induced Salicylates (eg, aspirin)
Irreversible inhibition of platelet cyclooxygenase
Discontinuation of drug; platelet transfusion
NSAIDs (eg, ibuprofen)
Reversible inhibition of cyclooxygenase
Glycoprotein IIb/IIIa inhibitors (eg, abciximab, tirofiban, eptifibatide
↓ Binding of fibrinogen to PM IIb/IIIa receptor
Thienopyridines (eg, clopidogrel, ticlopidine)
↓ ADP binding to PM receptor
Dipyridamole
↓ Intracellular cAMP metabolism
SSRIs (eg, paroxetine, fluoxetine)
↓ Serotonin in dense-granules
Omega-3 fatty acids (eg, DHA, EHA)
Disruption of PM phospholipid
Antibiotics, (eg, high-dose penicillin, nafcillin, ticarcillin, cephalothin, moxalactam)
Not fully elucidated; PM binding may interfere with receptor-ligand interactions
Alcohol
↓ TXA2 release
Uremia
↑ Nitric oxide; ↓ release of granules
DDAVP, high-dose estrogens; platelet transfusion, dialysis
Myeloproliferative disorder/myelodysplastic syndrome
Abnormal PM receptors, signal transduction, and/or granule release
Platelet transfusion; myelosuppressive treatment (myeloproliferative disorder)
Cardiac bypass
Platelet activation in bypass circuit
Platelet transfusion
ADP, adenosine diphosphate; cAMP, cyclic adenosine monophosphate; DDAVP, desmopressin acetate; DHA, docosahexaenoic acid; EHA, eicosahexaenoic acid; NSAIDs, nonsteroidal anti-inflammatory drugs; PM, platelet membrane; SSRIs, selective serotonin release inhibitors; TXA2, thromboxane A2.
Laboratory manifestations of aspirin toxicity include a prolonged epinephrine cartridge closure time in the platelet function analyzer (PFA)-100 system, or a decreased aggregation to low-dose collagen and thrombin (and preserved aggregation in response to high-dose collagen and thrombin) on platelet aggregation studies. cc
DISORDERS OF COAGULATION
Congenital Disorders of coagulation 1. Hemophilia A & B
``
Essentials of diagnosis
Hemophilia A: congenital deficiency of coagulation factor VIII. `` Hemophilia B: congenital deficiency of coagulation factor IX. `` Recurrent hemarthroses and arthropathy. `` Risk of development of inhibitory antibodies to factor VII or factor IX. `` In many older patients, infection with HIV or hepatitis C virus from receipt of contaminated blood products. ``
``General Considerations The frequency of hemophilia A is 1 per 5000 live male births, whereas hemophilia B occurs in approximately 1 in 25,000 live male births. Inheritance is X-linked recessive, leading to affected males and carrier females. There is no race predilection. Testing is indicated for asymptomatic male infants with a hemophilic pedigree, for male infants with a family history of hemophilia who experience excessive bleeding, or for an otherwise asymptomatic adolescent or adult who experiences unexpected excessive bleeding with trauma or invasion. Inhibitors to factor VIII will develop in approximately 25% of patients with hemophilia A, and inhibitors to factor IX will develop in < 5% of patients with hemophilia B.
``Clinical Findings A. Symptoms and Signs Severe hemophilia presents in infant males or in early childhood with spontaneous bleeding into joints, soft tissues, or other locations. Spontaneous bleeding is rare in patients with mild hemophilia, but bleeding may occur with a significant hemostatic challenge (eg, surgery, trauma). Intermediate clinical symptoms are seen in patients with moderate hemophilia. Female carriers of hemophilia are usually asymptomatic. Significant hemophilic arthropathy is usually avoided in patients who have received long-term prophylaxis with factor concentrate starting in childhood, whereas joint
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disease is common in adults who have experienced recurrent hemarthroses. Inhibitor development to factor VIII or factor IX is characterized by bleeding episodes that are resistant to treatment with clotting factor VIII or IX concentrate, and by new or atypical bleeding.
B. Laboratory Findings Hemophilia is diagnosed by demonstration of an isolated reproducibly low factor VIII or factor IX activity level, in the absence of other conditions. If the aPTT is prolonged, it typically corrects upon mixing with normal plasma. A variety of mutations, including inversions, large and small deletions, insertions, missense mutations, and nonsense mutations may be causative. Depending on the level of residual factor VIII or factor IX activity and the sensitivity of the thromboplastin used in the aPTT coagulation reaction, the aPTT may or may not be prolonged (although it typically is markedly prolonged in severe hemophilia). Hemophilia is classified according to the level of factor activity in the plasma. Severe hemophilia is characterized by < 1% factor activity, mild hemophilia features > 5% factor activity, and moderate hemophilia features 1–5% factor activity. Female carriers may become symptomatic if significant lyonization has occurred favoring the defective factor
VIII or factor IX gene, leading to factor VIII or factor IX activity level markedly < 50%. In the presence of an inhibitor to factor VIII or factor IX, there is accelerated clearance of and suboptimal or absent rise in measured activity of infused factor, and the aPTT does not correct on mixing. The Bethesda assay measures the potency of the inhibitor.
``Treatment Plasma-derived or recombinant factor concentrates are the mainstay of treatment. By the age of 4 years, most children with severe hemophilia have begun twice- or thrice-weekly infusions of factor to prevent the recurrent joint bleeding that otherwise would characterize the disorder and lead to severe musculoskeletal morbidity. Adults are frequently treated with factor concentrate as needed for bleeding episodes or prior to high-risk activities (Table 14–10). Patients with mild hemophilia A may respond to as-needed intravenous or intranasal treatment with DDAVP. Antifibrinolytic agents may be useful in cases of mucosal bleeding and are commonly used adjunctively, such as following dental procedures. Clinical trials of longer-acting FVIII and FIX molecules are underway. Delivery of normal factor VIII or factor IX genes via viral vectors continues to be explored in gene therapy trials. It may be possible to overcome low-titer inhibitors (< 5 Bethesda units [BU]) by giving larger doses of factor,
Table 14–10. Treatment of selected inherited bleeding disorders. Disorder Hemophilia A
Subtype
Treatment for Minor Bleeding
Treatment for Major Bleeding
Comment Treat for 3–10 days for major bleeding or following surgery, keeping factor activity level 50–80% initially. Adjunctive aminocaproic acid may be useful for mucosal bleeding or procedures
Mild
DDAVP1
DDAVP1 or factor VIII concentrate
Moderate or severe
Factor VIII concentrate
Factor VIII concentrate
Hemophilia B
Mild, moderate, or severe
Factor IX concentrate
Factor IX concentrate
von Willebrand disease
Type 1
DDAVP
DDAVP, vWF concentrate
Factor XI deficiency
1
Type 2
DDAVP, vWF concentrate
vWF concentrate
Type 3
vWF concentrate
vWF concentrate
—
FFP or aminocaproic acid
FFP
Adjunctive aminocaproic acid should be used for mucosal bleeding or procedures
1 Mild hemophilia A and type 2A or 2B vWD patients: therapeutic trial must have previously confirmed an adequate response (ie, elevation of factor VIII or vWF activity level into the normal range) and (for type 2B) no exacerbation of thrombocytopenia. DDAVP is not typically effective for type 2M vWD. A vWF-containing factor VIII concentrate is preferred for treatment of type 2N vWD. Notes: DDAVP dose is 0.3 mcg/kg intravenously in 50 mL saline over 20 minutes, or nasal spray 300 mcg for weight > 50 kg or 150 mcg for < 50 kg, every 12–24 hours, maximum of three doses in a 48-hour period. If more than two doses are used in a 12–24 hour period, free water restriction and/or monitoring for hyponatremia is essential. EACA dose is 50 mg/kg orally four times daily for 3–5 d; maximum 24 g/d, useful for mucosal bleeding/dental procedures. Factor VIII concentrate dose is 50 units/kg intravenously initially followed by 25 units/kg every 8 hours followed by lesser doses at longer intervals once hemostasis has been established. Factor IX concentrate dose is 100 units/kg (120 units/kg if using Benefix) intravenously initially followed by 50 units/kg (60 units/kg if using Benefix) every 8 hours followed by lesser doses at longer intervals once hemostasis has been established. vWF-containing factor VIII concentrate dose is 60–80 RCoF units/kg intravenously every 12 hours initially followed by lesser doses at longer intervals once hemostasis has been established. FFP is typically administered in 4-unit boluses and may not need to be re-bolused after the initial administration due to the long half-life of factor XI. DDAVP, desmopressin acetate; FFP, fresh frozen plasma; vWF, von Willebrand factor.
Disorders of Hemostasis, Thrombosis whereas treatment of bleeding in the presence of a high-titer inhibitor (> 5 BU) requires infusion of an activated prothrombin complex concentrate or recombinant activated factor VII. Inhibitor tolerance induction, achieved by giving large doses (50–300 units/kg intravenously of factor VIII daily) for 6–18 months, succeeds in eradicating the inhibitor in 70% of patients with hemophilia A and in 30% of patients with hemophilia B. Patients with hemophilia B who receive inhibitor tolerance induction, however, are at risk for development of nephrotic syndrome and anaphylactic reactions, making eradication of their inhibitors less feasible. Additional immunomodulation may allow for eradication in selected inhibitor tolerance induction– refractory patients. Highly active antiretroviral treatment is almost universally administered to individuals with HIV infection.
``When to Refer All patients with hemophilia should be seen regularly in a comprehensive hemophilia treatment center staffed by a hematologist.
``When to Admit Most bleeding events can be treated as an outpatient. • Some invasive procedures due to the need for serial infusions of clotting factor concentrate. • Patients with hemophilia (with or without inhibitors) who experience bleeding that is unresponsive to outpatient treatment.
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Berntorp E. Importance of rapid bleeding control in haemophilia complicated by inhibitors. Haemophilia. 2011 Jan; 17(1):11–6. [PMID: 20565546] Callaghan MU. What is the evidence for the use of immunomodulatory agents to eradicate inhibitory antibodies in patients with severe hemophilia A who have previously failed to respond to immune tolerance induction? Hematology Am Soc Hematol Educ Program. 2011;2011:405–6. [PMID: 22160065] Chambost H. Assessing risk factors: prevention of inhibitors in haemophilia. Haemophilia. 2010 Mar;16(Suppl 2):10–5. [PMID: 20132333] Fogarty PF. Biological rationale for new drugs in the bleeding disorders pipeline. Hematology Am Soc Hematol Educ Program. 2011;2011:397–404. [PMID: 22160064] Gringeri A et al; ESPRIT Study Group. A randomized clinical trial of prophylaxis in children with hemophilia A (the ESPRIT Study). J Thromb Haemost. 2011 Apr;9(4):700–10. [PMID: 21255253]
2. von Willebrand Disease
``
Essentials of diagnosis
The most common inherited bleeding disorder. von Willebrand factor aggregates platelets and prolongs the half-life of factor VIII.
`` ``
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``General Considerations vWF is an unusually large multimeric glycoprotein that binds to its receptor, platelet glycoprotein Ib, bridging platelets together and tethering them to the subendothelial matrix at the site of vascular injury. vWF also has a binding site for factor VIII, prolonging its half-life in the circulation. Between 75% and 80% of patients with vWD have type 1. It is a quantitative abnormality of the vWF molecule that usually does not feature an identifiable causal mutation in the vWF gene. Type 2 vWD is seen in 15–20% of patients with vWD. In type 2A or 2B vWD, a qualitative defect in the vWF molecule is causative. Type 2N and 2M vWD are due to defects in vWF that decrease binding to factor VIII or to platelets, respectively. Importantly, type 2N vWD clinically resembles hemophilia A, with the exception of a family history that shows affected females. Factor VIII activity levels are markedly decreased, and vWF activity and antigen (Ag) are normal. Type 2M vWD features a normal multimer pattern. Type 3 vWD is rare, and mutational homozygosity or double heterozygosity leads to undetectable levels of vWF and severe bleeding in infancy or childhood.
``Clinical Findings A. Symptoms and Signs Patients with type 1 vWD usually have mild or moderate platelet-type bleeding (especially involving the integument and mucous membranes). Patients with type 2 vWD usually have moderate to severe bleeding that presents in childhood or adolescence.
B. Laboratory Findings In type 1 vWD, the vWF activity (by ristocetin co-factor assay) and Ag are mildly depressed, whereas the vWF multimer pattern is normal (Table 14–11). Laboratory testing of type 2A or 2B vWD typically shows a ratio of vWF Ag:vWF activity of approximately 2:1 and a multimer pattern that lacks the highest molecular weight multimers. Thrombocytopenia is common in type 2B vWD due to a gain-of-function mutation of the vWF molecule, which leads to increased binding to its receptor on platelets, resulting in clearance; a ristocetin-induced platelet aggregation (RIPA) study shows an increase in platelet aggregation in response to low concentrations of ristocetin. Except in the more severe forms of vWD that feature a significantly decreased factor VIII activity, the aPTT and PT in vWD are usually normal.
``Treatment The treatment of vWD is summarized in Table 14–10. DDAVP is useful in the treatment of mild bleeding in most cases of type 1 and some cases of type 2 vWD. DDAVP causes release of vWF and factor VIII from storage sites, leading to increases in vWF and factor VIII twofold to sevenfold that of baseline levels. Cryoprecipitate should not be given due to lack of viral inactivation. Antifibrinolytic agents (eg, aminocaproic acid) may be used adjunctively
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Table 14–11. Laboratory diagnosis of von Willebrand disease. Type
vWF Activity
vWF Antigen
FVIII
RIPA
↓
↓
Nl or ↓
↓
Normal pattern; uniform ↓ intensity of bands
A
↓↓
↓
↓
↓
Large and intermediate multimers decreased or absent
B
↓↓
↓
↓
↑
Large multimers decreased or absent
M
↓
↓
↓
↓
Normal pattern; uniform ↓ intensity of bands Nl
1 2
N 3
Nl
Nl
↓↓
Nl
↓↓↓
↓↓↓
↓↓↓
↓↓↓
Multimer Analysis
Multimers absent
Nl, normal; RIPA, ristocetin-induced platelet aggregation; vWF, von Willebrand factor.
for mucosal bleeding or procedures. Pregnant patients with vWD usually do not require treatment because of the natural physiologic increase in vWF levels (up to threefold that of baseline) that are observed by the time of delivery; however, if excessive bleeding is encountered, vWF-containing factor VIII concentrates may be given.
`
Castaman G et al. von Willebrand’s disease diagnosis and laboratory issues. Haemophilia. 2010 Jul;16(Suppl 5):67–73. [PMID: 20590859] Lipe BC et al. Von Willebrand disease in pregnancy. Hematol Oncol Clin North Am. 2011 Apr;25(2):335–58. [PMID: 21444034] Mannucci PM et al; Italian Association of Hemophilia Centers. Evidence-based recommendations on the treatment of von Willebrand disease in Italy. Blood Transfus. 2009 Apr;7(2):117–26. [PMID: 19503633]
3. Factor XI Deficiency Factor XI deficiency (sometimes referred to as hemophilia C) is inherited in an autosomal recessive manner, leading to heterozygous or homozygous defects. It is most prevalent among individuals of Ashkenazi Jewish descent. Levels of factor XI, while variably reduced, do not correlate well with bleeding symptoms. Mild bleeding is most common, and surgery or trauma may expose or worsen the bleeding tendency. FFP is the mainstay of treatment in locales where the plasma-derived factor XI concentrate is not available. Administration of adjunctive aminocaproic acid is regarded as mandatory for procedures or bleeding episodes involving the mucosa (Table 14–10).
`
Gomez K et al. Factor XI deficiency. Haemophilia. 2008 Nov;14(6):1183–9. [PMID: 18312365] Martín-Salces M et al. Review: Factor XI deficiency: review and management in pregnant women. Clin Appl Thromb Hemost. 2010 Apr;16(2):209–13. [PMID: 19049995]
4. Less Common Heritable Disorders of Coagulation Congenital deficiencies of clotting factors II, V, VII, and X are rare and typically are inherited in an autosomal recessive pattern. A prolongation in the PT (and aPTT for factor
X and factor II deficiency) that corrects upon mixing with normal plasma is typical. The treatment of factor II deficiency is with a prothrombin complex concentrate; factor V deficiency is treated with infusions of FFP or platelets (which contain factor V in alpha granules); factor VII deficiency is treated with recombinant human activated factor VII at 15–30 mcg/kg every 4–6 hours; and infusions of FFP may be used to treat factor X deficiency. Deficiency of factor XIII, a transglutamase that crosslinks fibrin, characteristically leads to delayed bleeding that occurs hours to days after a hemostatic challenge (such as surgery or trauma). The condition is usually lifelong, and spontaneous intracranial hemorrhages as well as recurrent pregnancy loss appear to occur with increased frequency in these patients compared with other congenital deficiencies. Cryoprecipitate or infusion of a plasmaderived factor XIII concentrate (available through a research study; appropriate for patients with A-subunit deficiency only) is the treatment of choice for bleeding or surgical prophylaxis. `2-Antiplasmin deficiency is a rare disorder that leads to accelerated fibrinolysis via insufficient inhibition of plasmin. Heterozygosity for the condition usually produces a mild bleeding tendency, while bleeding symptoms in homozygotes may be severe. The diagnosis is made by a documented antiplasmin level below the reference range; the aPTT and PT are normal. In some cases, treatment of bleeding or surgical prophylaxis is with aminocaproic acid. A congenital deficiency of plasminogen activator I (PAI-1) is extremely rare and can lead to mild to moderate bleeding; testing for the disorder can be difficult due to the extremely low extension of the normal reference range for PAI-1. Congenital afibrinogenemia is exceedingly rare and produces mild to severe bleeding; the frequency of firsttrimester miscarriage is increased among women with the disorder. The PT is more typically prolonged than the aPTT, and a functional fibrinogen assay shows reduced activity. Treatment is with a fibrinogen concentrate (RiaSTAP) (preferred and now FDA approved), cryoprecipitate, or FFP and is aimed at increasing the plasma fibrinogen concentration to at least > 80 mg/dL. Congenital deficiencies of factor XII, prekallikrein, high molecular-weight kininogen may lead to a prolonged aPTT that corrects with extended incubation but do not lead to bleeding.
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Bereczky Z et al. Factor XIII and venous thromboembolism. Semin Thromb Hemost. 2011 Apr;37(3):305–14. [PMID: 21455864] Peyvandi F et al. Rare bleeding disorders. Semin Thromb Hemost. 2009 Jun;35(4):345–7. [PMID: 19598062]
Acquired Disorders of coagulation 1. Acquired Antibodies to Factor VIII Spontaneous antibodies to factor VIII occasionally occur in adults without a prior history of hemophilia; the elderly and patients with lymphoproliferative malignancy or connective tissue disease, who are postpartum, or postsurgical are at highest risk. The clinical presentation typically includes extensive soft-tissue ecchymoses, hematomas, and mucosal bleeding, as opposed to hemarthrosis in congenital hemophilia A. The aPTT is typically prolonged and does not correct upon mixing; factor VIII activity is found to be low and a Bethesda assay reveals the titer of the inhibitor. Inhibitors of low titer (< 5 BU) may often be overcome by infusion of high doses of factor VIII concentrates, whereas high-titer inhibitors (>5 BU) must be treated with serial infusions of activated prothrombin complex concentrates or recombinant human activated factor VII. Along with establishment of hemostasis by one of these measures, immunosuppressive treatment with corticosteroids and oral cyclophosphamide should be instituted; treatment with IVIG, rituximab, or plasmapheresis can be considered in refractory cases.
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Bitting RL et al. The prognosis and treatment of acquired hemophilia: a systematic review and meta-analysis. Blood Coagul Fibrinolysis. 2009 Oct;20(7):517–23. [PMID: 19644360] Huth-Kühne A et al. International recommendations on the diagnosis and treatment of patients with acquired hemophilia A. Haematologica. 2009 Apr;94(4):566–75. [PMID: 19336751]
2. Acquired Antibodies to Factor II Patients with antiphospholipid antibodies occasionally manifest specificity to coagulation factor II (prothrombin), leading typically to a severe hypoprothrombinemia and bleeding. Mixing studies may or may not reveal presence of an inhibitor, as the antibody typically binds a non-enzymatically active portion of the molecule that leads to accelerated clearance, but characteristically the PT is prolonged and levels of factor II are low. FFP should be administered for treatment of bleeding. Treatment is immunosuppressive.
3. Acquired Antibodies to Factor V Products containing bovine factor V (such as topical thrombin or fibrin glue, frequently used in surgical procedures) can lead to formation of an anti-factor V antibody that has specificity for human factor V. Clinicopathologic manifestations range from a prolonged PT in an otherwise asymptomatic individual to severe bleeding. Mixing studies suggest the presence of an inhibitor, and the factor V activity level is low. In cases of serious or life-threatening
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bleeding, IVIG or platelet transfusions, or both, should be administered, and immunosuppression (as for acquired inhibitors to factor VIII) may be offered.
4. Vitamin K Deficiency Vitamin K deficiency may occur as a result of deficient dietary intake of vitamin K (from green leafy vegetables, soybeans, and other sources), malabsorption, or decreased production by intestinal bacteria (due to treatment with chemotherapy or antibiotics). Vitamin K normally participates in activity of the vitamin K epoxide reductase that assists in posttranslational gamma-carboxylation of the coagulation factors II, VII, IX, and X that is necessary for their activity. Thus, vitamin K deficiency typically features a prolonged PT (in which the activity of the vitamin K–dependent factors is more reflected than in the aPTT) that corrects upon mixing; levels of individual clotting factors II, VII, IX, and X typically are low. Importantly, a concomitantly low factor V activity level is not indicative of isolated vitamin K deficiency, and may indicate an underlying defect in liver synthetic function (see below). For treatment, vitamin K1 (phytonadione) may be administered via intravenous or oral routes; the subcutaneous route is not recommended due to erratic absorption. Oral absorption is typically excellent and at least partial improvement in the PT should be observed within 1 day of administration. Intravenous administration (1 mg/d) results in even faster normalization of a prolonged PT than oral administration (5–10 mg/d); due to descriptions of anaphylaxis, parenteral doses should be administered at lower doses and slowly (eg, over 30 minutes) with concomitant monitoring.
5. Coagulopathy of Liver Disease Impaired hepatic function due to cirrhosis or other causes leads to decreased synthesis of clotting factors, including factors II, VII, V, IX, and fibrinogen, whereas factor VIII levels may be elevated in spite of depressed levels of other coagulation factors. The PT (and with advanced disease, the aPTT) is typically prolonged and corrects on mixing with normal plasma. A normal factor V level, in spite of decreases in the activity of factors II, VII, IX, and X, however, suggests vitamin K deficiency rather than liver disease (see above). Qualitative and quantitative deficiencies of fibrinogen also are prevalent among patients with advanced liver disease, typically leading to a prolonged PT, thrombin time, and reptilase time. The coagulopathy of liver disease usually does not require hemostatic treatment until bleeding complications occur. Infusion of FFP may be considered if active bleeding is present and the aPTT and PT are markedly prolonged; however, the effect is transient and concern for volume overload may limit infusions. Patients with bleeding and a fibrinogen level consistently below 80 mg/dL should receive cryoprecipitate. Liver transplantation, if feasible, results in production of coagulation factors at normal levels. The appropriateness of use of recombinant human activated factor VII in patients with bleeding varices is controversial, although some patient subgroups may experience benefit.
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De Gasperi A et al. Acute liver failure: managing coagulopathy and the bleeding diathesis. Transplant Proc. 2009 May;41(4): 1256–9. [PMID: 19460532] Franchini M et al. Acquired factor V inhibitors: a systematic review. J Thromb Thrombolysis. 2011 May;31(4):449–57. [PMID: 21052780] Pluta A et al. Coagulopathy in liver diseases. Adv Med Sci. 2010 Jun;55(1):16–21. [PMID: 20513645]
6. Warfarin Ingestion See Antithrombotic Therapy section, below.
7. Disseminated Intravascular Coagulation The consumptive coagulopathy of DIC results in decreases in the activity of clotting factors, leading to bleeding in most patients (see above). The aPTT and PT are characteristically prolonged, and platelets and fibrinogen levels are reduced from baseline.
8. Heparin/Fondaparinux Use The thrombin time is dramatically prolonged in the presence of heparin. Patients who are receiving heparin and who have bleeding should be managed by discontinuation of the heparin and (some cases) administration of protamine sulfate; 1 mg of protamine neutralizes approximately 100 units of heparin sulfate, and the maximum dose is 50 mg intravenously. LMWHs typically do not prolong clotting times and are incompletely reversible with protamine. There is no reversal agent for fondaparinux, although some experts have suggested using recombinant human activated factor VIIa for cases of life-threatening bleeding.
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Schulman S et al. Anticoagulants and their reversal. Transfus Med Rev. 2007 Jan;21(1):37–48. [PMID: 17174219]
9. Lupus Anticoagulants Lupus anticoagulants do not cause bleeding; however, because they prolong clotting times by binding proteins associated with phospholipid, which is a necessary component of coagulation reactions, clinicians may be concerned about a risk of bleeding. Lupus anticoagulants were so named because of their increased prevalence among patients with connective tissue disease, although they may occur with increased frequency in individuals with underlying infection, inflammation, or malignancy, and they also can occur in asymptomatic individuals in the general population. A prolongation in the aPTT is observed that does not correct completely on mixing. Specialized testing such as the hexagonal phase phospholipid neutralization assay, the dilute Russell viper venom time, and platelet neutralization assays can confirm the presence of a lupus anticoagulant.
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Pengo V et al; Subcommittee on Lupus Anticoagulant/ Antiphospholipid Antibody of the Scientific and Standardisation Committee of the International Society on Thrombosis and Haemostasis. Update of the guidelines for lupus anticoagulant detection. J Thromb Haemost. 2009 Oct;7(10):1737–40. [PMID: 19624461]
OTHER CAUSes of BLEEDING Occasionally, abnormalities of the vasculature and integument may lead to bleeding despite normal hemostasis; congenital or acquired disorders may be causative. These abnormalities include Ehlers-Danlos syndrome, osteogenesis imperfecta, Osler-Weber-Rendu disease, and Marfan syndrome (heritable defects) and integumentary thinning due to prolonged corticosteroid administration or normal aging, amyloidosis, vasculitis, and scurvy (acquired defects). The bleeding time often is prolonged. If possible, treatment of the underlying condition should be pursued, but if this is not possible or feasible (ie, congenital syndromes), globally hemostatic agents such as DDAVP can be considered for treatment of bleeding.
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Sharathkumar AA et al. Hereditary haemorrhagic telangiectasia. Haemophilia. 2008 Nov;14(6):1269–80. [PMID: 19141168]
cc
ANTITHROMBOTIC THERAPY
The currently available anticoagulants include unfractionated heparin, LMWHs, fondaparinux, dabigatran, rivaroxaban, and vitamin K antagonists. (For a discussion of the injectable DTIs, see section on Heparin-Induced Thrombocytopenia, above.) Unfractionated heparin is a repeating polymer of sulfated glycosaminoglycans that is most commonly derived from porcine intestinal tissue, which is rich in heparin-bearing mast cells. The pharmacokinetics of unfractionated heparin are poorly predictable, and the degree of anticoagulation must be monitored (by aPTT or anti-Xa level) in patients who are receiving the drug in therapeutic doses. Only a fraction of an infused dose of heparin is metabolized by the kidneys, however, making it safe to use in most patients with significant renal impairment. Unfractionated heparin can be effectively neutralized with the positively charged protamine sulfate (1 mg of protamine neutralizes approximately 100 units of heparin sulfate; maximum dose, 50 mg intravenously). Use of unfractionated heparin leads to HIT in approximately 3% of patients, so most individuals require serial platelet count determinations during the initial 10–14 days of exposure and (some patients) periodically thereafter. The LMWHs are produced from chemical depolymerization of unfractionated heparin, resulting in products of lower molecular weight (mean molecular weight, 4500-6500d, depending on the LMWH). Due to less protein and cellular binding, the pharmacokinetics of the LMWHs are much more predictable than those of unfractionated heparin, allowing for fixed weight-based dosing. All LMWHs are principally renally cleared and must be avoided or used with extreme caution in individuals with creatinine clearance < 30 mL/min. A longer half-life permits once- or twice-daily subcutaneous dosing, allowing for greater convenience and outpatient therapy in selected cases. Most patients do not require monitoring, although
Disorders of Hemostasis, Thrombosis monitoring using the anti-Xa activity level is appropriate for morbidly obese (BMI > 35) and selected pregnant patients. About 30% of the molecules in a dose of LMWH are long enough (ie, sufficiently negatively charged) to bind protamine sulfate, allowing for some neutralization of anticoagulant effect. LMWHs are associated with a lower frequency of HIT (approximately 0.6%) than unfractionated heparin. Fondaparinux is a synthetic molecule consisting of the highly active pentasaccharide sequence. Fondaparinux, like the LMWHs, is almost exclusively metabolized by the kidneys, and should be avoided or used with caution in patients with severe renal impairment. Predictable pharmacokinetics allow for weight-based dosing. A particularly long half-life (17–21 hours) allows for once-daily dosing, but the absence of necessary charge characteristics leads to a lack of binding to protamine sulfate; therefore, no effective neutralizing agent exists. Dabigatran etexilate is an oral DTI that is approved for use in the United States for prevention of stroke and systemic embolism in nonvalvular atrial fibrillation. It is a prodrug that is converted to dabigatran with peak effect within 2 hours. Steady state is reached within 3 days. As renal excretion accounts for about 80% of clearance, dose adjustment is required for decreased renal function. It utilizes the p-glycoprotein transport system and so concomitant use of strong inducers, eg, rifampin, should be avoided. Concomitant use of strong P-gp inhibitors (eg, ketoconazole and dronedarone) should be used with caution, and dose reduction should be considered particularly if renal function is compromised. The half-life of the dabigatran etexilate is 12–17 hours. No laboratory monitoring is required. Neither the INR nor the aPTT may be used to reliably monitor drug effect. No antidote is available to reverse its effect although the drug may be removed by dialysis. Rivaroxaban is an oral anti-Xa inhibitor that is approved in the United States for post-hip or post-knee replacement prevention of venous thrombosis and for prevention of nonvalvular atrial fibrillation–associated stroke. Its half-life ranges from 5 hours to 13 hours (longer in the elderly). As it has no antidote, rivaroxabanassociated bleeding may be treated by withholding the drug while the anticoagulant effect dissipates and by administration of activated charcoal (if a dose was taken recently). Vitamin K antagonists such as warfarin inhibit the activity of the vitamin K–dependent carboxylase that is important for the posttranslational modification of coagulation factors II, VII, IX, and X. Although warfarin may be taken orally, leading to a significant advantage over the heparins and heparin derivatives, which must be given parenterally or subcutaneously, inter-individual differences in response to the agent related to nutritional status, comorbid diseases, concomitant medications, and genetic polymorphisms lead to a poorly predictable anticoagulant response. Individuals taking warfarin must undergo periodic monitoring to verify the intensity of the anticoagulant effect. The intensity of anticoagulant effect is reported as the INR, which corrects for differences in
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potency of commercially available thromboplastin used to perform the PT.�1
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Eerenberg ES et al. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebocontrolled, crossover study in healthy subjects. Circulation. 2011 Oct 4;124(14):1573–9. [PMID: 21900088] Ma TK et al. Dabigatran etexilate versus warfarin as the oral anticoagulant of choice? A review of the clinical data. Pharmacol Ther. 2011 Feb;129(2):185–94. [PMID: 20920530] Sattari M et al. Novel oral anticoagulants in development: dabigatran, rivaroxaban, and apixaban. Am J Ther. 2011 Jul;18(4):332–8. [PMID: 20535013]
``Prevention of Venous Thromboembolic Disease The frequency of venous thromboembolic disease (VTE) among hospitalized patients ranges widely; up to 20% of low-risk medical patients and 80% of critical care patients and high-risk surgical patients have been reported to experience this complication, which includes deep venous thrombosis (DVT) and pulmonary embolism (PE). Avoidance of fatal PE, which occurs in up to 5% of high-risk inpatients as a consequence of hospitalization or surgery is a major goal of pharmacologic prophylaxis. Table 14–12 provides a risk stratification for DVT/VTE among hospital inpatients. Standard prophylactic regimens are listed in Table 14–13. Prophylactic strategies should be guided by individual risk stratification, with all moderateand high-risk patients receiving pharmacologic prophylaxis, unless contraindicated. Contraindications to VTE prophylaxis for hospital inpatients at high risk for VTE are listed in Table 14–14. Certain high-risk patients should be considered for extended-duration prophylaxis, including those undergoing total hip replacement, hip fracture repair, cancer surgery, and high-risk medical patients (such as those who are immobile or older than 75 years of age). Despite the wellestablished efficacy and safety of these strategies, thromboprophylaxis continues to be underutilized, particularly in medical patients. Implementation of risk stratification schemas, electronic order sets, availability of new easily administered oral anticoagulants, and physician alerts may increase utilization. A new four-element risk assessment model (cancer, prior VTE, peripherally inserted central catheter [PICC line], or bed rest) may make risk stratification in medical patients easier, increasing use of DVT prophylaxis strategies. If bleeding is present, if the risk of bleeding is high, or if the risk of VTE is high for the inpatient (Table 14–12) and therefore combined prophylactic strategies are needed, some measure of thromboprophylaxis may be provided through use of mechanical devices, including intermittent pneumatic compression devices, venous foot pumps, or graduated compression stockings. The efficacy and safety of graduated compression stockings
1
Importantly, because the INR is not standardized for abnormalities of factor V and fibrinogen, the INR should be used only in reference to anticoagulation in patients who are receiving warfarin.
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Table 14–12. Risk stratification for DVT/VTE among hospital inpatients. High Risk Recent major orthopedic surgery/arthroplasty/or fracture Abdominal/pelvic cancer undergoing surgery Recent spinal cord injury or major trauma within 90 days More than 3 of the intermediate risk factors (see below) Intermediate Risk Not ambulating independently outside of room at least twice daily Active infectious or inflammatory process Active malignancy Major surgery (non-orthopedic) History of VTE Stroke Central venous access or PICC line Inflammatory bowel disease Prior immobilization (> 72 hours) preoperatively Obesity (BMI > 30) Patient age > 50 years Hormone replacement or oral contraceptive therapy Hypercoagulable state Nephrotic syndrome Burns Cellulitis Varicose veins Paresis CHF (systolic dysfunction) COPD exacerbation Low Risk Minor procedure and age < 40 years with no additional risk factors Ambulatory with expected length of stay of < 24 hours or minor surgery BMI, body mass index; CHF, congestive heart failure; COPD, chronic obstructive pulmonary disease; DVT, deep venous thrombosis; PICC, peripherally inserted central catheter; VTE, venous thromboembolic disease (includes DVT and PE). Adapted from Guidelines used at the VA Medical Center, San Francisco, CA.
in nonsurgical patients have recently been challenged. The CLOTS1 trial found no reduction in VTE in stroke patients randomized to receive them; however, a statistically significant increase in rates of skin breakdown, blisters and necrosis was found.
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Bump GM et al. How complete is the evidence for thromboembolism prophylaxis in general medicine patients? A metaanalysis of randomized controlled trials. J Hosp Med. 2009 May;4(5):289–97. [PMID: 19504490] CLOTS Trials Collaboration; Dennis M et al. Effectiveness of thigh-length graduated compression stockings to reduce deep vein thrombosis after stroke (CLOTS trial 1): a multicentre, randomised, controlled trial. Lancet 2009 Jun 6;373(9679): 1958–65. [PMID: 19477503] Geerts WH et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133 (6 Suppl):381S–453S. [PMID: 18574271] Hull RD et al; EXCLAIM (Extended Prophylaxis for Venous ThromboEmbolism in Acutely Ill Medical Patients With Prolonged Immobilization) study. Extended-duration venous thromboembolism prophylaxis in acutely ill medical patients
`
with recently reduced mobility: a randomized trial. Ann Intern Med. 2010 Jul 6;153(1):8–18. [PMID: 20621900] Piazza G et al. Physician alerts to prevent symptomatic venous thromboembolism in hospitalized patients. Circulation. 2009 Apr 28;119(16):2196–201. [PMID: 19364975] Rasmussen MS et al. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 2009 Jan 21;(1):CD004318. [PMID: 19160234] Woller SC et al. Derivation and validation of a simple model to identify venous thromboembolism risk in medical patients. Am J Med. 2011 Oct;124(10):947–54. [PMID: 21962315]
``Treatment of Venous Thromboembolic Disease A. Anticoagulant Therapy Treatment for VTE should be offered to patients with objectively confirmed DVT or PE, or to those in whom the clinical suspicion is high for the disorder yet have not yet undergone diagnostic testing (see Chapter 9). The management of VTE primarily involves administration of anticoagulants, which initially are given parenterally followed by long-term oral therapy; the goal is to prevent recurrence, extension and embolization of thrombosis and to reduce the risk of post-thrombotic syndrome. Suggested anticoagulation regimens are found in Table 14–15.
B. Selecting Appropriate Anticoagulant Therapy Most patients with DVT alone may be treated as outpatients, provided that their risk of bleeding is low, they are candidates for injectable anticoagulants, and they have good follow-up. Table 14–16 outlines the selection criteria for outpatient treatment of DVT. Patients who are hospitalized for DVT should receive initial anticoagulation with heparin or LMWH as outlined in Table 14–15. Among patients with PE, risk stratification should be done at time of diagnosis to direct treatment and triage. Patients with persistent hemodynamic instability (or patients with massive PE) are classified as high risk and have an early PE-related mortality of > 15%. These patients should be admitted to an intensive care unit and receive thrombolysis in addition to anticoagulation. Intermediaterisk patients have a mortality rate of up to 15% and should be admitted to a higher level of inpatient care, with consideration of thrombolysis on a case-by-case basis. Those classified as low risk have a mortality rate < 3% and are candidates for expedited discharge or outpatient therapy. Although both intermediate- and low-risk patients are hemodynamically stable, additional assessment is necessary to differentiate the two. Echocardiography can be used to identify patients with right ventricular dysfunction, which connotes intermediate risk. However, real-time echocardiography involves added cost and is not always immediately available. An LV/RV ratio < 1.0 on chest CT angiogram has been shown to have good negative predictive value for adverse outcome but suffers from interobserver variability. Serum biomarkers such as B-type natriuretic peptide and troponin have been studied and are
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Table 14–13. Pharmacologic prophylaxis of VTE in selected clinical scenarios.1 Anticoagulant Enoxaparin
Dose 40 mg
Frequency Once daily
Clinical Scenario Most medical inpatients and critical care patients Surgical patients (moderate risk for VTE)
Comment — Consider continuing for 4 weeks total duration for cancer surgery and high-risk medical patients
Abdominal/pelvic cancer surgery Twice daily 30 mg
Dalteparin
2500 units 5000 units
Twice daily
Once daily Once daily
Bariatric surgery Orthopedic surgery
Higher doses may be required 2
Give for at least 10 days. For THR, TKA, or HFS, consider continuing up to 1 month after surgery in high-risk patients
Major trauma
Not applicable to patients with isolated lower extremity trauma
Acute spinal cord injury
—
Most medical inpatients
—
Abdominal surgery (moderate risk for VTE)
Give for 5–10 days
Orthopedic surgery
First dose = 2500 units. Give for at least 10 days. For THR, TKA, or HFS, consider continuing up to 1 month after surgery in high-risk patients
2
Abdominal surgery (higher-risk for VTE)
Give for 5–10 days
Medical inpatients
— 2
Fondaparinux
2.5 mg
Once daily
Orthopedic surgery
Rivaroxaban
10 mg
Once daily
Orthopedic surgery-total hip and total knee replacement
Give for 12 days following total knee replacement; give for 35 days following total hip replacement
Unfractionated heparin
5000 units
Three times daily
Higher VTE risk with low bleeding risk
Includes gynecologic surgery for malignancy and urologic surgery, medical patients with multiple risk factors for VTE
5000 units
Twice daily
Hospitalized patients at intermediate risk for VTE
Includes gynecologic surgery (moderate risk)
Patients with epidural catheters
LMWHs usually avoided due to risk of spinal hematoma
Patients with severe renal insufficiency3
LMWHs contraindicated
Orthopedic surgery2
Titrate to goal INR = 2.5. Give for at least 10 days. For high-risk patients undergoing THR, TKA, or HFS, consider continuing up to 1 month after surgery
Warfarin
(variable)
Once daily
Give for at least 10 days. For THR, TKA or HFS, consider continuing up to 1 month after surgery in high-risk patients
1
All regimens administered subcutaneously, except for warfarin. Includes TKA, THR, and HFS. 3 Defined 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. 2
most useful for their negative predictive value, and mainly in combination with other predictors. The PESI (pulmonary embolism severity index) clinical risk score, which does not require additional testing, has been validated and accurately identifies patients at low risk for 30-day PE-related mortality (Table 14–17). A simplified version of this risk score has been proposed and is undergoing further validation.
1. Heparin—Selection of a parenteral anticoagulant should be determined by patient characteristics (kidney function, immediate bleeding risk, weight) and clinical scenario (eg, whether thrombolysis is being considered). LMWHs are as efficacious as unfractionated heparin in the immediate treatment of DVT and PE and are preferred as initial treatment because of predictable pharmacokinetics, which allow for subcutaneous, once- or twice-daily dosing
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Table 14–14. Contraindications to VTE prophylaxis for medical or surgical hospital inpatients at high risk for VTE. Absolute contraindications Acute hemorrhage from wounds or drains or lesions Intracranial hemorrhage within prior 24 hours Heparin-induced thrombocytopenia (HIT) considering using fondaparinux Severe trauma to head or spinal cord or extremities Epidural anesthesia/spinal block within 12 hours of initiation of anticoagulation (concurrent use of an epidural catheter and LMWH thromboprophylaxis should require approval by service who performed the epidural or spinal procedure, eg, anesthesia/ pain service) Currently receiving warfarin or heparin or LMWH or direct thrombin inhibitor for other indications Relative contraindications Coagulopathy (INR > 1.5) Intracranial lesion or neoplasm Severe thrombocytopenia (platelet count < 50,000/mcL) Intracranial hemorrhage within past 6 months Gastrointestinal or genitourinary hemorrhage within past 6 months INR, international normalized ratio; LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease. Adapted from Guidelines used at the VA Medical Center, San Francisco, CA.
with no requirement for monitoring in most patients. Monitoring of the therapeutic effect of LMWH may be indicated in pregnancy, compromised kidney function, and extremes of weight. Accumulation of LMWH and increased rates of bleeding have been observed among patients with severe chronic kidney disease (creatinine clearance < 30 mL/min), leading to a recommendation to use intravenous unfractionated heparin preferentially in these patients. If concomitant thrombolysis is being considered, unfractionated heparin is indicated. In addition, patients with VTE and a perceived higher risk of bleeding (ie, post-surgery) may be better candidates for treatment with unfractionated heparin than LMWH given its shorter half-life and reversibility. Weight-based, fixed-dose daily subcutaneous fondaparinux (a synthetic factor Xa inhibitor) may also be used for the initial treatment of DVT and PE, with no increase in bleeding over that observed with LMWH. Its lack of reversibility, long half-life, and primarily renal clearance limits its use in patients with an increased risk of bleeding or renal failure. 2. Warfarin—Patients with DVT with or without PE require a minimum of 3 months of anticoagulation in order to reduce the risk of recurrence of thrombosis. An oral vitamin K antagonist, such as warfarin, is usually initiated along with the parenteral anticoagulant, although patients with cancer-related thrombosis may benefit from ongoing treatment with LMWH alone. Most patients require 5 mg of warfarin daily for initial treatment, but lower doses (2.5 mg daily) should be considered for patients of Asian descent, the elderly, and those with hyperthyroidism, congestive heart failure, liver disease, recent
major surgery, malnutrition, certain polymorphisms for the CYP2C9 or the VKORC1 genes or who are receiving concurrent medications that increase sensitivity to warfarin (Table 14–18). Conversely, individuals of African descent, those with larger body mass index or hypothyroidism, and those who are receiving medications that increase warfarin metabolism may require higher initial doses (7.5 mg daily). Daily INR results should guide dosing adjustments (Table 14–19). Web-based warfarin dosing calculators that consider these clinical and genetic factors are available to help clinicians choose the appropriate starting dose (eg, see www.warfarindosing.org). Because an average of 5 days is required to achieve a steady-state reduction in the activity of vitamin K–dependent coagulation factors, the parenteral anticoagulant should be continued for at least 5 days and until the INR is > 2.0 on 2 consecutive days. Meticulous follow-up should be arranged for all patients taking warfarin (Table 14–19) because of the bleeding risk that is associated with initiation of therapy. INR monitoring should occur at least twice weekly during initiation. Once stabilized, the INR should be checked at an interval no longer than every 4 weeks and warfarin dosing adjusted in accordance with the guidelines outlined in Table 14–20. Nontherapeutic INRs should be managed according to evidence-based guidelines (Table 14–21). 3. New investigational oral anticoagulants—The vitamin K antagonists have been the only oral anticoagulants available for nearly 7 decades. Now, a number of novel oral anticoagulant agents that promise more predictable dose effect and ease of administration than warfarin are becoming available. Dabigatran, an oral DTI, has been shown to be noninferior to warfarin for treatment of VTE. Although not yet approved by the FDA for this indication, it is currently available for prevention of embolization in nonvalvular atrial fibrillation. Rivaroxaban, an oral direct factor Xa inhibitor, is approved in the United States for DVT prevention and stroke prevention in patients with atrial fibrillation; it has been shown to be as effective as standard therapy for the prevention of recurrent DVT. These new agents have predictable dose effects, minimal drug interactions, rapid onset of action, and no need for laboratory monitoring. Once additional therapies are available for treatment of VTE, agent selection will depend on renal function, concomitant medications, cost, and adherence issues. 4. Duration of anticoagulation therapy—The clinical scenario in which the thrombosis occurred is the strongest predictor of recurrence and, in most cases, guides duration of anticoagulation (Table 14–22). In the first year after discontinuation of anticoagulation therapy, the frequency of recurrence of VTE among individuals whose thrombosis occurred in the setting of a transient, major, reversible risk factor (such as surgery) is approximately 3%, compared with at least 8% for individuals whose thrombosis was unprovoked, and > 20% in patients with cancer. Patients with provoked VTE are generally treated with a minimum of 3 months of anticoagulation, whereas unprovoked VTE should prompt consideration of indefinite anticoagulation. Individual risk stratification may
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Table 14–15. Initial anticoagulation for VTE.1 Clinical Scenario
Anticoagulant Unfractionated heparin
Dose/ Frequency 80 units/kg intravenous bolus then continuous intravenous infusion of 18 units/kg/h
DVT, Lower Extremity
DVT, Upper Extremity
PE
VTE, with Concomitant Severe Renal Impairment2
×
×
×
×
VTE, CancerRelated
Bolus may be omitted if risk of bleeding is perceived to be elevated. Maximum bolus, 10,000 units. Requires aPTT monitoring. Most patients: begin warfarin at time of initiation of heparin aPTT monitoring required with dose adjustment
17,500 units subcutaneously every 12 hours (initial dose)
Enoxaparin3
Comment
330 units/kg subcutaneously × 1 then 250 units/kg subcutaneously every 12 hours
×
1 mg/kg subcutaneously every 12 hours
×
Fixed-dose; no aPTT monitoring required
×
×
Most patients: begin warfarin at time of initiation of LMWH
×
1.5 mg/kg subcutaneously once daily Tinzaparin3
175 units/kg subcutaneously once daily
×
×
×
×
Cancer: administer LMWH for ≥ 3–6 months
Dalteparin3
200 units/kg subcutaneously once daily for first month
×
×
×
×
Cancer: administer LMWH for ≥ 3–6 months; reduce dose to 150 units/kg after first month of treatment
Fondaparinux
5–10 mg subcutaneously once daily (see Comment)
×
×
×
Use 7.5 mg for body weight 50–100 kg; 10 mg for body weight > 100 kg
Note: An “×” denotes appropriate use of the anticoagulant. Obtain 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. 2 Defined as creatinine clearance < 30 mL/min. 3 Body weight < 50 kg: reduce dose and monitor anti-Xa levels. DVT, deep venous thrombosis; PE, pulmonary embolism; VTE, venous thromboembolic disease (includes DVT and PE). 1
help identify patients most likely to suffer recurrent disease and thus most likely to benefit from ongoing anticoagulation therapy. Normal D-dimer levels 1 month after cessation of anticoagulation are associated with lower recurrence risk, although some would argue not low enough to consider staying off therapy. The predictive value of presence of residual vein thrombosis after completion of 3 months of anticoagulation is unclear, with some studies showing much lower recurrence rates in patients without residual thrombosis while other studies show equal recurrence rates regardless of findings on follow-up ultrasound. A risk scoring system using BMI, age, D-dimer and post-phlebitic symptoms has been developed to identify women at lower risk for recurrence after unprovoked VTE. The Vienna Prediction Model, a simple
scoring system based on age, sex, D-dimer, and location of thrombosis, can help estimate an individual's recurrence risk to guide duration of therapy decisions. The following facts are important to consider when determining duration of therapy: (1) men have a greater than twofold higher risk of recurrent VTE compared to women; and (2) recurrent PE is more likely to develop in patients with clinically apparent PE than in those with DVT alone. Work up for laboratory thrombophilia is no longer recommended routinely for determining duration of therapy because clinical presentation is a much stronger predictor of recurrence risk. This work up may be pursued in patients younger than 50 years, with a strong family history, with a clot in unusual locations, or with recurrent thromboses. In addition, a work up for thrombophilia
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Table 14–16. Patient selection for outpatient treatment of DVT.
Table 14–18. Commonly used agents and their potential effect on the INR.
Patients considered appropriate for outpatient treatment No clinical signs or symptoms of PE and pain controlled Motivated and capable of self-administration of injections Confirmed prescription insurance that covers injectable medication or patient can pay out-of-pocket for injectable agents Capable and willing to comply with frequent follow-up Initially, patients may need to be seen daily to weekly Potential contraindications for outpatient treatment DVT involving inferior vena cava, iliac, common femoral, or upper extremity vein (these patients might benefit from vascular intervention) Comorbid conditions Active peptic ulcer disease, GI bleeding in past 14 days, liver synthetic dysfunction Brain metastases, current or recent CNS or spinal cord injury/ surgery in the last 10 days, CVA ≤ 4–6 weeks Familial bleeding diathesis Active bleeding from source other than GI Thrombocytopenia Creatinine clearance < 30 mL/min Patient weighs < 55 kg (male) or < 45 kg (female) Recent surgery, spinal or epidural anesthesia in the past 3 days History of heparin-induced thrombocytopenia Inability to inject medication at home, reliably follow medication schedule, recognize changes in health status, understand or follow directions
Table 14–17. Pulmonary Embolism Severity Index (PESI) Risk factor
Tendency to Increase INR
Tendency to Decrease INR
Phenytoin
Phenytoin
Erythromycin
Rifampin/rifabutin
Metronidazole
Carbamazepine
Ketoconazole
Vitamin K
Trimethoprim-sulfamethoxazole
Phenobarbital
Amiodarone
Sucralfate
Cimetidine
Ginseng
Alcohol
Alcohol
Fluconazole Itraconazole Statins INR, international normalized ratio.
should be considered in women of childbearing age in whom results may influence fertility and pregnancy outcomes and management. The benefit of anticoagulation must be weighed against the bleeding risks posed, and the benefit-risk ratio should be assessed at the initiation of therapy, at 3 months, and then at least annually in any patient receiving prolonged anticoagulant therapy. Bleeding risk scores have been developed to help clinicians in this process.
Points
Age
No. of years of age
Male sex
10
Cancer
30
Heart failure
10
Chronic lung disease
10
Heart rate > 110 bpm
20
Systolic blood pressure < 100 mm Hg
20
Respiratory rate > 30 breaths per minute
20
Temperature < 36°C
20
Change in mental status
60
Oxygen saturation < 90%
20
Severity class
Points
30-day mortality
I
0–65
< 1.6%
II
66–85
< 3.5%
III
86–105
< 7.1%
IV
106–125
4–11.4%
V
> 125
10–24.5%
Adapted, with permission, from Aujesky D et al. Derivation and validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med. 2005 Oct 15;172(8):1041–6. Reprinted with permission of the American Thoracic Society. © American Thoracic Society
Table 14–19. Warfarin adjustment guidelines for patients newly starting therapy. INR Day 1 Day 2
Day 3
Day 4 until therapeutic
1
Action 5 mg (2.5 or 7.5 mg in select populations1)
< 1.5
Continue dose
≥ 1.5
Decrease or hold dose2
≤ 1.2
Increase dose2
> 1.2 and < 1.7
Continue dose
≥ 1.7
Decrease dose2
Daily increase is < 0.2 units
Increase dose2
Daily increase 0.2–0.3 units
Continue dose
Daily increase 0.4–0.6 units
Decrease dose2
Daily increase ≥ 0.7 units
Hold dose
See text In general, dosage adjustments should not exceed 2.5 mg or 50%.
2
Disorders of Hemostasis, Thrombosis
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Table 14–20. Warfarin dosing adjustment guidelines for patients receiving long-term therapy. Weekly Dosing Change Goal = 1.5–2.0 INR
Patient INR
Goal = 2.0–3.0 INR
Goal = 2.5–3.5 INR
< 1.5
↑5–10%
↑5–20%
↑15–20%
1.5–2.0
Therapeutic
↑5–10%
↑5–20%
2.0–2.5
↓ 5–10%
Therapeutic
↑5–10%
2.5–3.0
↓ 5–15%
Therapeutic
Therapeutic
3.0–3.5
(May hold) ↓ 10–20%
↓ 5–10% Or may stay same if just at or above 3.0
Therapeutic
3.5–4.0
HOLD dose ↓ 20–50%
(May hold) ↓ 5–10%
↓ 5–10% Or may stay same if just at or above 3.5
4.0–5.0
HOLD 2–3 days ↓ 20–50%
HOLD 1–2 days ↓ 10–20%
(May hold) ↓ 5–15%
Adapted from Guidelines used at the VA Medical Center, Reno NV.
Aujesky D et al. Outpatient versus inpatient treatment for patients with acute pulmonary embolism: an international, open-label, randomised, non-inferiority trial. Lancet. 2011 Jul 2;378(9785):41–8. [PMID: 21703676] Douketis J et al. Risk of recurrence after venous thromboembolism in men and women: patient level meta-analysis. BMJ. 2011 Feb 24;342:d813. [PMID: 21349898] Eichinger S et al. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna Prediction Model. Circulation. 2010 Apr 13;121(14):1630–6. [PMID: 20351233]
EINSTEIN Investigators; Bauersachs R et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;Dec 23;363(26):2499–510. [PMID: 21128814] Gage BF. Pharmacogenetics-based coumarin therapy. Hematology Am Soc Hematol Educ Program. 2006:467–73. [PMID: 17124101] Jiménez D et al. Simplification of the Pulmonary Embolism Severity Index for prognostication in patients with acute symptomatic pulmonary embolism. Arch Intern Med. 2010;170(15):1383–9. [PMID: 20696966]
Table 14–21. American College of Chest Physicians Evidence-based Clinical Practice Guidelines for the Management of Nontherapeutic INR. Clinical Situation No significant bleed
INR
Recommendations
Above therapeutic range but < 5.0
• Lower dose or omit dose
≥ 5.0 but < 9.0
• Hold next 1–2 doses
• Monitor more frequently and resume at lower dose when INR falls within therapeutic range (if INR only slightly above range, may not be necessary to decrease dose) • Monitor more frequently and resume therapy at lower dose when INR falls within therapeutic range • Patients at high risk for bleeding1: Hold warfarin PLUS give vitamin K1 1–2.5 mg orally, check INR in 24–48 h to ensure response to therapy
≥ 9.0
• Hold warfarin • Vitamin K1 2.5–5 mg orally • Monitor frequently and resume therapy at lower dose when INR within therapeutic range
Serious/life-threatening bleed
• Hold warfarin and give 10 mg vitamin K by slow intravenous infusion supplemented by FFP, PCC, or recombinant factor VIIa
1 Patients at higher risk for bleeding include the elderly; conditions that increase the risk of bleeding include renal failure, hypertension, falls, liver disease, and history of gastrointestinal or genitourinary bleeding. FFP, fresh frozen plasma; INR, international normalized ratio; PCC, prothrombin complex concentrate. Adapted, with permission, from Ansell J et al. Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008 Jun;133(6 Suppl):160S–198S.
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Table 14–22. Duration of treatment of VTE. Scenario
Suggested Duration of Therapy
Comments
Major transient risk factor (eg, immobilization, major surgery, major trauma, major hospitalization)
At least 3 months
VTE prophylaxis upon future exposure to transient risk factors
Minor transient risk factor (eg, exposure to exogenous estrogens/progestins, pregnancy, airline travel lasting more than 6 hours)
At least 3 months
VTE prophylaxis upon future exposure to transient risk factors
Cancer-related VTE
≥ 3–6 months or as long as cancer active, whichever is longer
LMWH recommended for initial treatment (see Table 14–15)
Unprovoked thrombosis
At least 3 months, consider indefinite if bleeding risk allows
May individually risk-stratify for recurrence with follow-up ultrasound, D-dimer, clinical risk score, and clinical presentation
Underlying significant thrombophilia (eg, antiphospholipid antibody syndrome, antithrombin deficiency, protein C deficiency, protein S deficiency, ≥ two concomitant thrombophilic conditions)
Indefinite
To avoid false positives, consider delaying investigation for laboratory thrombophilia until 3 months after event
LMWH, low-molecular-weight heparin; VTE, venous thromboembolic disease.
Kearon C et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians EvidenceBased Clinical Practice Guideline (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S–545S. [PMID: 18574272] Prandoni P et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica. 2007 Feb;92(2):199–205. [PMID: 17296569] Rodger MA et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ. 2008 Aug 26;179(5):417–26. [PMID: 18725614] Ruiz-Gimenez N et al. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost. 2008 Jul;100(1):26–31. [PMID: 18612534] Schulman S et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009 Dec 10;361(24):2342–52. [PMID: 19966341] Siragusa S et al. Residual vein thrombosis to establish duration of anticoagulation after a first episode of deep vein thrombosis: the Duration of Anticoagulation based on Compressive UltraSonography (DACUS) study. Blood. 2008 Aug 1;112(3):511–5. [PMID: 18497320]
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Torbicki A et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur Heart J. 2008 Sep;29(18):2276–315. [PMID: 18757870] Verhovsek M et al. Systematic review: D-dimer to predict recurrent disease after stopping anticoagulant therapy for unprovoked venous thromboembolism. Ann Intern Med. 2008 Oct 7;149(7):481–90. [PMID: 18838728] Weitz J et al. New antithrombotic drugs: American College of Chest Physicians Evidence-Based Clinical Practice Guideline (8th Edition). Chest. 2008 Jun;133(6 Suppl):234S–256S. [PMID: 18574267] Wittkowsky AK. New oral anticoagulants: a practical guide for clinicians. J Thromb Thrombolysis. 2010 Feb;29(2):182–91. [PMID: 19888552]
C. Thrombolytic Therapy Anticoagulation alone is appropriate treatment for most patients with PE; however, those with high-risk, massive PE, defined as PE with persistent hemodynamic instability, have an in-hospital mortality rate that approaches 30% and require immediate thrombolysis in combination with anticoagulation (Table 14–23). A 50% reduced dosing
Table 14–23. Thrombolytic therapies for acute massive pulmonary embolism. Thrombolytic Agent Alteplase
Urokinase
Dose
Frequency
Comment
100 mg
Continuous intravenous infusion over 2 hours
Follow with continuous intravenous infusion of unfractionated heparin
100 mg
Intravenous bolus × 1
Appropriate for acute management of cardiac arrest and suspected pulmonary embolism
4400 international units/kg
Intravenous bolus × 1 followed by 4400 international units/kg continuous intravenous infusion for 12 hours
Unfractionated heparin should be administered concurrently
Disorders of Hemostasis, Thrombosis regimen for tissue plasminogen activator (TPA) has recently been proposed, offering similar efficacy with lower risk of complications. Thrombolytic therapy also has been used in selected patients with intermediate-risk, submassive PE, defined as PE without hemodynamic instability but with evidence of right ventricular compromise. This approach remains controversial, however, given the paucity of data showing a clinically significant benefit of thrombolysis. Limited data suggest that patients with large proximal iliofemoral DVT may also benefit from catheter-directed thrombolysis in addition to treatment with anticoagulation. However, standardized guidelines are lacking, and use of the intervention may be limited by institutional availability and provider experience. Importantly, thrombolytics should be considered only in patients who have a low risk of bleeding, as rates of bleeding are increased in patients who receive these products compared with rates of hemorrhage in those who are treated with anticoagulation alone.
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Dong BR et al. Thrombolytic therapy for pulmonary embolism. Cochrane Database Syst Rev. 2009 Jul 8;(3):CD004437. [PMID: 19588357] Enden T et al; CaVenT study group. Catheter-directed thrombolysis vs. anticoagulant therapy alone in deep vein thrombosis: results of an open randomized, controlled trial reporting on short-term patency. J Thromb Haemost. 2009 Aug;7(8):1268–75. [PMID: 19422443] Kearon C et al. Antithrombotic therapy for venous thromboembolic disease: American College of Chest Physicians EvidenceBased Clinical Practice Guideline (8th Edition). Chest. 2008 Jun;133(6 Suppl):454S–545S. [PMID: 18574272] Todd JL et al. Thrombolytic therapy for acute pulmonary embolism: a critical appraisal. Chest. 2009 May;135(5):1321–9. [PMID: 19420199] Vedantham S. Interventional approaches to acute venous thromboembolism. Semin Respir Crit Care Med. 2008 Feb;29(1):56–65. [PMID: 18302087] Wang C et al; China Venous Thromboembolism (VTE) Study Group. Efficacy and safety of low dose recombinant tissuetype plasminogen activator for the treatment of acute pulmonary thromboembolism: a randomized, multicenter, controlled trial. Chest. 2010 Feb;137(2):254–62. [PMID: 19741062]
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In this study, patients with documented DVT received full intensity, time-limited anticoagulation with or without placement of an IVC filter. Patients with IVC filters had a lower rate of nonfatal PE at 12 days but an increased rate of DVT at 2 years. Most experts agree with placement of an IVC filter in patients with acute proximal DVT who concurrently have an absolute contraindication to anticoagulation. While IVC filters were once commonly used to prevent VTE recurrence in the setting of anticoagulation failure, many experts now recommend switching to an alternative agent or increasing the intensity of the current anticoagulant regimen instead. The remainder of the indications (submassive/ intermediate-risk PE, free-floating iliofemoral DVT, perioperative risk reduction) are controversial. If the contraindication to anticoagulation is temporary (active bleeding with subsequent resolution), placement of a retrievable IVC filter should be considered so that the device can be removed once anticoagulation has been started and has been shown to be tolerated. Rates of IVC filter retrieval are very low, often due to a failure to arrange for its removal. Thus, if a device is placed, timely removal should be arranged at the time of device placement. Complications of IVC filters include local thrombosis, tilting, migration, fracture, and inability to retrieve the device. When considering placement of an IVC filter, it is best to consider both short- and long-term complications, since devices intended for removal may become permanent. To improve patient safety, institutions should develop systems that guide appropriate patient selection for IVC filter placement, tracking, and removal.
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Barral FG. Vena cava filters: why, when, what and how? J Cardiovasc Surg (Torino). 2008 Feb;49(1):35–49. [PMID: 18212686] Minichiello TA. Efforts to optimize patient benefit from inferior vena cava filters. Arch Intern Med. 2011 Nov 28;171(21): 1948–64. [PMID: 22123807] PREPIC Study Group. Eight-year follow-up of patients with permanent vena cava filters in the prevention of pulmonary embolism: the PREPIC (Prévention du Risque d’Embolie Pulmonaire par Interruption Cave) randomized study. Circulation. 2005 Jul 19;112(3):416–22. [PMID: 16009794]
D. Nonpharmacologic Therapy
``When to Refer
1. Graduated compression stockings—In order to reduce the likelihood of the post-thrombotic syndrome, which is characterized by swelling, pain, and skin ulceration, all patients with DVT should wear a graduated compression stocking with 30–40 mm Hg pressure at the ankle on the affected lower extremity for 1–2 years. Stockings should be provided immediately to have the most impact on postthrombotic syndrome; however, they are contraindicated in patients with peripheral vascular disease.
• Presence of large iliofemoral VTE, IVC thrombosis, portal vein thrombosis, or Budd-Chiari syndrome for consideration of catheter-directed thrombolysis. • Massive PE for urgent embolectomy. • History of HIT or prolonged PTT plus renal failure for alternative anticoagulation regimens. • Consideration of IVC filter placement.
`
Kolbach DN et al. Non-pharmacologic measures for prevention of post-thrombotic syndrome. Cochrane Database Syst Rev. 2004;(1):CD004174. [PMID: 14974060]
2. Inferior vena caval (IVC) filters—There is a paucity of data to support the use of IVC filters for the prevention of PE in any clinical scenario. There is only one available randomized, controlled trial of IVC filters for prevention of PE.
``When to Admit • Documented or suspected PE (some patients with lowrisk PE may not require admission). • DVT with poorly controlled pain, high bleeding risk, contraindications to LMWH or fondaparinux. • Large iliofemoral DVT for consideration of thrombolysis. • Acute DVT and absolute contraindication to anticoagulation for IVC filter placement.