Heparin-Induced Thrombocytopenia - HIT
“It don’t come easy”
John R. Bartholomew, MD, FACC Section Head Vascular Medicine Departments of Cardiovascular Medicine and Hematology/Oncology Cleveland Clinic
Heparin The standard of care for the management of venous and arterial disorders for 75 years!
Arterial Embolism Occurring During Systemic Heparin Therapy Case #
Indication for UFH
Day Rx
LWCT
Complications
1
Thrombophlebitis
15√
65
Femoral Embolus
2
Thrombophlebitis
10
23
Femoral/Popliteal Embolus
3
Femoral Endarterectomy
11
27
Femoral/Popliteal Embolus
4
Femoral Endarterectomy
11
58
Femoral Embolus
5
Thrombophlebitis
13
66
Acute MI, Cerebral Embolus
6
Pulmonary Infarct
11
31
Popliteal, Iliac Embolus
7
Femoral Artery Thrombosis
12
79
Femoral, Iliac Embolus
8
Femoral Artery Embolism
7√
53
Cerebral and renal Embolus
9
Popliteal Artery Thrombus
9
43
Renal, Mesenteric Embolus
10
Bilateral femoral artery occlusion
10
4
Cerebral and mesenteric embolus
3 of 10 had a cerebral embolus Weismann and Tobin. Arch Surg.1958;76:219-227
6 of 10 died
Heparin-induced Thrombocytopenia • A common iatrogenic “adverse reaction” to UFH •
•
or LMWH Affects: - 1% to 5% of patients exposed to UFH - <1% of patients exposed to LMWH - case reports with Fondaparinux exposure Antibody formation in as many as 8% (LMWH) to 40% (UFH)
J Vasc Surg 2003; 38: 1316-1322
Is HIT Important?
8th Edition Evidence-Based Clinical Practice Guidelines American College of Chest Physicians Heparin-Induced Thrombocytopenia: Treatment and Prevention of pages 340S-380S
Definition of HIT • An otherwise unexplained platelet count fall
• •
- develops 5 -14 days after UFH/LMWH exposure - thrombocytopenia defined as < 150,000 mm 3 - or a 30 to 50% drop in platelets from baseline With or without thrombosis (arterial or venous) Platelet recovery once UFH or LMWH stopped
Temporal Patterns of HIT Typical-onset HIT (within 5 to 14 days) 2/3 of all HIT cases Hours to days
Rapid-onset HIT (with a recent heparin exposure)
Delayed-onset HIT (average of 9 days after heparin stopped) 0
1
2
3
4
5
6
Heparin exposure
7
8
9 10 11 12 13 14 15 21 Days
40
Rapid-Onset HIT
243 HIT Patients
• 30% developed thrombocytopenia under 4 days (median time 10.5 hours)
• All patients received heparin w/in past 100 days (most w/in 30 days)
• Represents 25 to 30% of all HIT cases
NEJM 2001 344:1286-1292 Warkentin et al. NEJM. 2001;344:1286-1292.
Delayed-Onset HIT Recent UFH exposure uncomplicated
• Patient discharged home off UFH • Readmitted - 9 to 40 days later - new thrombosis ± thrombocytopenia
• High titers of platelet-activating antibodies
• Represents 3%-5% of all HIT cases
Who Develops HIT? Factor
Influence
Type of Heparin
Bovine lung > porcine intestinal UFH UFH > LMWH
Patient Population
Post surgery > medical > obstetrical (orthopedic, cardiovascular highest risk)
Duration of treatment Sex
>1 week of UFH or LMWH more likely
Definition of thrombocytopenia
Proportional platelet count fall (>50%) is more sensitive than absolute count of <150,000 mm3
Female > male
Following exposure to UFH or LMWH during treatment for arterial or venous disorders, prophylaxis of VTE, surgical or interventional procedures, Warkentin. Br J Haematol. 2003;121:535-555. during dialysis, in TPN solutions, heparin flushes, heparin-coated catheters
Complications of HIT Venous Thrombosis
Deep vein thrombosis Pulmonary embolism Cerebral vein thrombosis Adrenal vein thrombosis
Arterial Thrombosis Acute limb ischemia Thrombotic stroke Myocardial infarction Aortic thrombus Renal artery thrombosis Vascular graft occlusion
Venous Thrombosis
PE in 25% of HIT Patients
4 of 5 thrombotic events are venous!
Arterial Thrombosis
Acute limb ischemia more likely than MI or Stroke
Unusual Complications of HIT
• • • • •
Skin lesions at heparin injection sites Adrenal hemorrhagic infarction Disseminated intravascular coagulation Acute systemic reactions following IV bolus Warfarin-associated venous limb gangrene and/or Warfarin-associated skin necrosis
Skin necrosis at injection site
DIC
.
Adrenal hemorrhagic infarction
Venous limb gangrene
Pathophysiology Platelet
alpha granule
PF-4/heparin PFIgG complex PF--4 binds to surface of PF Complexes of heparin (GAG) IgG binds to the PFPF-4/ platelet following activation and PFPF-4 molecules form heparin complex
microparticles
Fc stimulation leads to the generation of procoagulant--rich microparticles procoagulant Courtesy of Dr John G. Kelton, McMaster University
Fc receptor
IgG/PF--4/heparin complex activates IgG/PF via the Fc receptor
Pathophysiology activated endothelium
Antibody binding to PF4 on endothelium leading to activation/injury
activated plts
heparan suflate tissue factor
Enhanced monocyte expression and release of tissue factor with antibody binding
microparticles Fc stimulation leads to the generation of procoagulant-rich microparticles
Courtesy of Dr John G. Kelton, McMaster University
How do we diagnose HIT?
HIT is a clinicopathologic syndrome
Estimating Pretest Probability of HIT: Four T â&#x20AC;&#x2122;s Points: 0,1, 2 for each of 4 categories: Maximum possible score = 8
2
1
0
Thrombocytopenia
>50% fall or platelet nadir: 20,000 -100,000
30-50% fall or platelet nadir: 10,000 -19,000
Fall <30% or platelet nadir: <10,000
Timing of platelet count fall or other sequelae
Clear onset between 510 days; or less than 1 day if heparin exposure w/in past 100 days
Consistent with immunization but not clear, or onset of thrombocytopenia after day 10
Platelet count falls too early (without recent heparin exposure)
Thrombosis or other sequelae (skin lesions)
New thrombosis; skin necrosis; post heparin bolus acute systemic reaction
Progressive or recurrent thrombosis: erythematous skin lesions; suspected thrombosis not yet proven
None
oTher causes of thrombocytopenia not evident
No other cause for platelet count fall is evident
Possible other cause is evident
Definite other cause is present
Br J Haem 2003 121: 535-55 Pretest probability score: 6-8 = high, 4-5 = intermediate, 0-3 = low
Laboratory Testing for HIT Activation Activation assays assays
Antigen Antigen assays assays
(Functional (Functional antibodies) antibodies)
(all (all antibodies) antibodies)
Serotonin Serotonin Release Release Assay Assay
Enzyme -Linked Enzyme-Linked Immunoassay Immunoassay (ELISA) (ELISA)for for Heparin -PF4 Heparin-PF4
Platelet Platelet Aggregation Aggregation Assay Assay
Less sensitive, more specific
More sensitive, less specific
HIT- What is the Risk of Thrombosis? Hypercoagulable State HIT
Odds Ratio
Antithrombin
24.1
Protein C
14.4
Protein S
10.9
Factor V Leiden
6.6
Antiphospholipid syndrome
5.4
Can J Cardiol 1995;11 (Suppl C):29C-34C
36.9
Heparin-Induced Thrombocytopenia: Clinical Consequences if Unrecognized and/or Untreated New Thromboses (Arterial or Venous) Amputation
30-50% 10-20%
Death
20-30%
Warkentin, Greinacher. Heparin-Induced Thrombocytopenia. 4th ed. 2007
Optimizing Treatment of HIT Interrupt the immune response
- DISCONTINUE heparin or LMWH immediately - DO NOT wait for laboratory confirmation
Inhibit thrombin generation - INITIATE an alternative anticoagulant - treat active thrombosis - prevent new thrombosis
Minimize complications
- limb amputation, DVT/PE or death
Direct Thrombin Inhibitors Composition
Argatroban: L-arginine derivative
Lepirudin: recombinant hirudin
Half-life in healthy subjects
40 - 50 minutes
1.3 hours
Elimination
Hepatic
Renal
Proteolytic + 20% Renal
Monitoring
aPTT
aPTT
aPTT
Method of administration
IV
IV, SC
IV
Cross- reactivity with HIT antibodies
NO
NO
NO
*Only FDA approved for HIT in patients undergoing PCI
Bivalirudin* semi synthetic hirulog 25 minutes
Guidelines for Oral Anticoagulants: HIT • Avoid warfarin until platelet count has recovered • • •
(preferably to > 150,000mm3) Minimum 5 day overlap with DTI (or alternative non-heparin anticoagulant) Begin low doses of warfarin (5 mg maximum) Do not stop DTI until INR is = 2 for at least 2 consecutive days (minimum 5 day overlap)
Chest 2008; 133: 340S-380S (8th ACCP Guidelines) Srinivasan et al. Arch Intern Med 2004; 164: 66-70
Venous Limb Gangrene and Skin Necrosis in HIT
Treatment Principles of HIT TWO DO’S
THREE DON’TS
DO stop Heparin or DON’T give Warfarin LMWH immediately! until the platelet count recovers DO give vitamin K if Warfarin has already been started when DON’T place an IVC HIT is first recognized filter unless absolutely necessary DO start an alternative nonheparin anticoagulant
CHEST 2008; 126:340S -380S
DON’T give platelet transfusions unless bleeding develops
TWO DIAGNOSTICS DO test for HIT antibodies
DO investigate for lower limb DVT with ultrasound
How is the Neurology patient affected?
Arterial Embolism Occurring During Systemic Heparin Therapy Case #
Indication for UFH
Day Rx
LWCT
Complications
1
Thrombophlebitis
15â&#x2C6;&#x161;
65
Femoral Embolus
2
Thrombophlebitis
10
23
Femoral/Popliteal Embolus
3
Femoral Endarterectomy
11
27
Femoral/Popliteal Embolus
4
Femoral Endarterectomy
11
58
Femoral Embolus
5
Thrombophlebitis
13
66
Acute MI, Cerebral Embolus
6
Pulmonary Infarct
11
31
Popliteal, Iliac Embolus
7
Femoral Artery Thrombosis
12
79
Femoral, Iliac Embolus
8
Femoral Artery Embolism
7â&#x2C6;&#x161;
53
Cerebral and renal Embolus
9
Popliteal Artery Thrombus
9
43
Renal, Mesenteric Embolus
10
Bilateral femoral artery occlusion
10
4
Cerebral and mesenteric embolus
3 of 10 had a cerebral embolus Weismann and Tobin. Arch Surg.1958;76:219-227
Neurologic Complications of HIT • Cerebral ischemia • Cerebral venous sinus thrombosis • Transient amnestic confusional states • Recurrent stroke • Recurrent TIA’s • Spinal ischemia
Heparin-induced thrombocytopenia in patients with cerebrovascular ischemic disease
• Prospective study of 137 patients treated with •
heparin for cerebral infarction, RIND, TIA 21 (15.3%) = 40% decline in their platelet count – 5 suffered extension of cerebral infarction – 3 of 5 died
• Recommended that a platelet count be •
performed before UFH therapy and at least every 3rd day in patients with acute ischemic strokes. Heparin should be discontinued if the platelet count drops by 30 to 35% of pretreament values
Neurology 1984; 34: 736-740
Heparin-Induced Thrombocytopenia and Thrombosis in Ischemic Stroke • 2527 carotid endarterectomies • 19 occlusions occurred in 18 patients • 6 of 18 had a “heparin-induced coagulation disorder” • “Although heparin is a useful anticoagulant, it may precipitate occlusion of vessels after an endarterectomy procedure” Mayo Clin Proc 1988; 63: 353-361
Heparin-Induced Thrombocytopenia • 29 individuals with stroke due to heparin • • • •
therapy Onset between 0.5 -14 days Platelet count was between 7,000 – 84,000 7 deaths Infarcts observed in carotid and basilar territories and 3 cases of superior sagittal sinus
Stroke 1989:20:1449-1459
Neurologic complications in immune -mediated heparin-induced thrombocytopenia
• Retrospective study of 120 patients with HIT • 11/120 (9.2%) had neurological complications - 7 ischemic cerebrovascular events - 3 cerebral vein thrombosis - 1 transient confusional state • Mortality was greater in patients with neurologic complications from HIT (55%) than non neurologic patients (11%) • Predicted 1 in 1,000 patients receiving UFH will have neurologic complications due to HIT Neurology 2000; 54: 1240-1245
Heparin-induced thrombocytopenia in neurologic disease treated with heparin • Prospective study of 200 neurologic patients receiving UFH • 5 (2.5%) fulfilled criteria for HIT • 4/5 (2%) had HIT-associated thromboses • Prevalence heparin antibodies (41/200) (20.5%) • Increased awareness of HIT is mandatory • In cases of HIT-associated neurologic complications - neurologists will always consider other etiologic conditions before they think of HIT
Neurology 2004: 62:657-659
Heparin-Induced Thrombocytopenia: A Serious Complication of Heparin Therapy for Acute Stroke
• 392 of 1,078 consecutive patients with acute • • • • •
ischemic stroke receiving IV UFH 10 (0.5%) developed/suspected HIT) 3 patients developed further thrombosis 2 patients died Clinical severity and outcomes were unfavorable when compared to other acute patients Monitoring for HIT should be part of the medical management of stroke to avoid further complications
Cerebrovascular Disease 2008; 26: 641-649
Stroke in patients with HIT and the effect of argatroban therapy
• 960 patients with HIT (largest population of HIT
• • • •
patients evaluated for acute stroke) - 767 treated with argatroban - 193 historical controls 30 (3.1%) HIT patients had stroke - 20 (2.6%) argatroban group - 10 (5.2%) control group 9 strokes present at entry 24 new strokes occurred during follow-up 4 patients had more than one stroke
Critical Care Medicine 2004; 32:976-980
Stroke in patients with HIT and the effect of argatroban therapy
• Stroke common in HIT- 3.1% of HIT patients overall and a significant predictor of death • More often in females • Argatroban therapy vs. historical control significantly reduced the likelihood of new stroke and stroke-associated mortality
Critical Care Medicine 2004; 32:976-980
HIT Myths and Misconceptions 1
HIT is rare, I do not have to worry about it
2
This can’t be HIT (the platelets are too low)
3
This can’t be HIT (the platelets are too high)
4
This can’t be HIT (its too early following exposure)
5
This can’t be HIT (its too late)
6
This can’t be HIT the patient is no longer on heparin
7
I can wait for the lab tests to start treatment
8
I can just stop heparin
9
I can switch to LMWH
10
I can just start warfarin
11
I can just transfuse platelets
Arch Intern Med 2004; 1961-1964
“HIT - it don’t come easy”