Heparin-Induced Thrombocytopenia DR VINOD G V HIT An immunoglobulin-mediated adverse drug reaction characterized by: platelet activation thrombocytopenia thrombotic complications
Incidence Depends on clinical setting Medical or surgical Type of Heparin UFH-more LMWH-less Medical Cardiovascular disease 0.3% Critical care 0.4%
Newly treated with hemodialysis 3.2% Overall (hospital-wide surveillance studies) 1.0% to 1.2% Cardiac surgery UFH postoperatively 1.0% to 2.4% Cardiac transplantation 11% Orthopedic surgery UFH postoperatively 4.8% LMWH postoperatively 0.6%
Iceberg Model Multiple thrombosis (white clot syndrome) 0.01-0.1% Isolated thrombosis 30-80% of below groups Asymptomatic thrombocytopenia 30-50% of below group HIT - IgG seroconversion 0-10%
HIT Syndrome Type I associated with an early (within 4 days) and usually mild decrease in platelet count (rarely <100 x 109/L) typically recovers within 3 days despite continued use of heparin nonimmunologic mechanisms (mild direct platelet activation by heparin) not associated with any major clinical sequelae occurs primarily with high dose iv heparin
HIT Syndrome Type II
substantial fall in platelet count (> 50%) count in the 50,000 - 150,000 /mm range typical onset of 4-14 days occurs with any dose by any route induced by immunologic mechanisms rarely causes bleeding (think of alternative Dx) potential for development of life-threatening thromboembolic complications Risks for HIT Type I
intravenous high-dose heparin Type II varies with dose of heparin unfractionated heparin > LMWH bovine > porcine surgical > medical patients Pathogenesis of HIT Most commonly caused by IgG antibodies (designated HIT-IgG) that
activate platelets through their Fc receptors Cascade of events leading to formation of HIT antibodies and prothrombotic components 10/98 medslides.com 11 Diagnosis of HIT
absence of another clear cause for thrombocytopenia the timing of thrombocytopenia the degree of thrombocytopenia adverse clinical events (thrombocytopenia,thrombosis) positive laboratory tests for HIT antibodies Characteristic features of HIT platelet count typically begin to fall 5-8 days after heparin therapy is started
may develop within the first day with repeat exposure consider other causes if occurs after 2 wks of therapy thrombocytopenia is usually mild to moderate, with platelet counts ranging from 20 to 150 x 109/L Clinical Features Suspicious for HIT a rapid drop in platelets may also be indicative of HIT, particularly if the patients received heparin within the previous 3
months a fall in platelet count of >50% that begins after 5 days of heparin therapy, but with the platelet count > 150 x 109/L, should also raise the suspicion of HIT Unusual Clinical Events Suspicious for HIT mild to moderate thrombocytopenia, often in conjunction with thrombosis adrenal hemorrhagic infarction (caused by adrenal
vein thrombosis) warfarin-induced venous limb gangrene fever, chills, flushing, or transient amnesia beginning 5 to 30 minutes after an IV heparin bolus heparin-induced skin lesions associated with HIT antibodies, even in the absence of thrombocytopania Clinical Syndromes Associated with HIT Venous thromboembolism Arterial thrombosis
Skin lesions at heparin injection site Acute platelet activation syndromes Venous Thromboembolism Deep vein thrombosis
Lower limb involvement Stroke Myocardial infarction Other Venous thrombotic events predominate over arterial events by 4:1 ratio. Usually involving large vessels. Other Clinical Syndromes Skin lesions at heparin injection site Skin necrosis Erythematous plaques
Acute platelet activation syndrome Acute inflammatory reactions (fever, chills, etc.) Transient global amnesia Functional Assays exploits the ability of HIT antibodies to activate normal platelets platelet aggregation assay (PAA) serotonin release assay (SRA)
heparin induced platelet activation (HIPA) Functional Assay Platelet aggregation assay (PAA) performed by many laboratories incubate platelet-rich plasma from normal donors with patient plasma and heparin limited by poor sensitivity and specificity because heparin can activate platelets under these conditions, even in the absence of HIT antibodies
Antibody Assay Antibodies against heparin/PF4 complexes (the major antigen of HIT) are measured by colorimetric absorbance ELISA limited by high cost Common Laboratory Tests for HIT Test Advantages
PAA Disadvantages Rapid and simple Low sensitivity - not suitable for testing multiple samples SRA Sensitivity >90% Washed platelet (technically demanding), needs radiolabeled material 14C HIPA Rapid, sensitivity >90% Washed platelets
ELISA High sensitivity, High cost, lower specificity for detects IgA and IgM clinically significant HIT Management of HIT risk for thrombosis is high in HIT, prevention of thrombosis is the goal of intervention heparin is contraindicated in patients with HIT discontinuation of heparin - all sources of heparin must be eliminated most patients will require treatment with an alternate
anticoagulant for initial clinical problem HIT induced thrombosis Antithrombin Drugs Agents that reduce or inhibit thrombin
lepirudin danaparoid sodium argatroban Bivalirudin Lepirudin A direct thrombin inhibitor recombinant form of the leech anticoagulant hirudin, the most potent direct thrombin inhibitors yet identified
Rapid anticoagulant effect with IV bolus Relatively short half-life (1.3 hours) Relatively contraindicated in renal failure Anticoagulant effect readily monitored with aPTT (target range 1.5-3.0 times normal) Danaparoid
a low-molecular-weight heparinoid mixture of anticoagulant glycosaminoglycans (heparin sulfate, dermatan sulfate, and chondroitin sulfate) with predominant anti-factor Xa activity rapid anticoagulant effect with IV bolus long half-life (~25 hours) for anti-Xa activity in vitro cross-reactivity with the HIT antibody (10% to 40% ) does not predict development of thrombocytopenia or thrombosis
Argatroban a small synthetic non-polypeptide molecule a direct thrombin inhibitor FDA approved June30, 2000 has the same theoretical advantages of lepirudin short half-life (< 1hr)
lack of cross-reactivity for HIT antibodies potent antithrombin activity metabolized predominantly by the liver, may require dose adjustment excreted normally even in severe renal failure Dos and Donts of HIT Management Drug Warfarin
Do Dont Comments x warfarin in the absence of an anticoagulant can precipitate venous limb gangrene Platelet x infusing platelets merely adds fuel to the fire Vena caval filter
x often results in devastating caval, pelvic, and lower leg venous thrombosis LMWH x low molecular weight heparin usually crossreact with unfractionated heparin after HIT or HITTS (HIT thrombosis syndrome) has occurred Ancrod x not readily available; difficult to titrate dose Danaparoid x cross-reacts with UFH in about 10-15% of cases; titrate with unwieldy anti-factor Xa levels
Hirudin x Beware renal insufficiency, antibody formation Plasmapheresis x removes micro-particles formed from platelet activation; not a standard indication Argatroban x FDA approved June 30, 2000
Steps to Prevent HIT porcine heparin preferred over bovine heparin LMWH preferred over unfractionated heapirn oral anticoagulation should be started as early as possible to reduce the duration of heparin exposure monitoring serial platelet counts for developing thrombocytopenia
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