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Heparin induce thrombocytopenia

Heparin induce thrombocytopenia. Presented by the American Society of Hematology, adapted in part from the: American College of Chest Physicians Evidence-Based Clinical Practice Guideline on Antithrombotic and Thrombolytic Therapy (8th Edition). DEFENITION.

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Heparin induce thrombocytopenia

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  1. Heparin induce thrombocytopenia

  2. Presented by the American Society of Hematology, adapted in part from the: American College of Chest Physicians Evidence-Based Clinical Practice Guideline on Antithrombotic and Thrombolytic Therapy (8th Edition).

  3. DEFENITION • Nonimmune heparin-associated thrombocytopenia • Previously called HIT type I • Immune HIT • Previously called HIT type II Shantsila E,Chest 2009,135:6

  4. Epidemiology • Drug Dependent Characteristics • Patient Characteristics ASH State of Art symposium 2009

  5. DRUG DEPENDENT CHARACTERISTICS • Chain length: • UFH> LMWH>Fondaparinux • Source: • Bovine> Porcine • Dose /Duration • Possibly increased(Heparin duration >4 days) ASH State of Art symposium 2009

  6. The frequency of HIT among patients exposed to heparin is highly variable, and is influenced by the heparin preparation (bovine UFH porcine UFH low-molecular-weight heparin [LMWH]), type of heparin-exposed patient population (postsurgery medical pregnancy), duration of heparin exposure patient sex (female male). Thus, whether to perform platelet count monitoring,and the intensity of such monitoring, depends on theseconsiderations, particularly heparin and patient type and the duration of heparin use

  7. PATIENT CHARACTERISTICS • High Risk: 3-5% • Surgical( Postsurgical > medical > obstetric) • Intermediate Risk: 0.8-3% • General medical • Low Risk: <0.1% • Obstetrics, general pediatrics, chronic hemodialysis ASH State of Art symposium 2009

  8. Pathophysiology Platelet alpha granule PF-4/heparin complex IgG PF-4 binds to surface of platelet following activation Complexes of heparin (GAG) and PF-4 molecules form IgG binds to the PF-4/ heparin complex microparticles Fc receptor Fc stimulation leads to the generation of procoagulant-rich microparticles IgG/PF-4/heparin complex activates via the Fc receptor Hirsh et al. Arch Intern Med. 2004;164:361-369. Courtesy of Dr John G. Kelton, McMaster University.

  9. Pathophysiology Platelet alpha granule PF-4/heparin complex IgG PF-4 binds to surface of platelet following activation Complexes of heparin (GAG) and PF-4 molecules form IgG binds to the PF-4/ heparin complex microparticles Fc receptor Fc stimulation leads to the generation of procoagulant-rich microparticles IgG/PF-4/heparin complex activates via the Fc receptor Hirsh et al. Arch Intern Med. 2004;164:361-369. Courtesy of Dr John G. Kelton, McMaster University.

  10. Pathophysiology Platelet alpha granule PF-4/heparin complex IgG PF-4 binds to surface of platelet following activation Complexes of heparin (GAG) and PF-4 molecules form IgG binds to the PF-4/ heparin complex microparticles Fc receptor Fc stimulation leads to the generation of procoagulant-rich microparticles IgG/PF-4/heparin complex activates via the Fc receptor Hirsh et al. Arch Intern Med. 2004;164:361-369. Courtesy of Dr John G. Kelton, McMaster University.

  11. Pathophysiology Platelet alpha granule PF-4/heparin complex IgG PF-4 binds to surface of platelet following activation Complexes of heparin (GAG) and PF-4 molecules form IgG binds to the PF-4/ heparin complex microparticles Fc receptor Fc stimulation leads to the generation of procoagulant-rich microparticles IgG/PF-4/heparin complex activates via the Fc receptor Hirsh et al. Arch Intern Med. 2004;164:361-369. Courtesy of Dr John G. Kelton, McMaster University.

  12. Pathophysiology Platelet alpha granule PF-4/heparin complex IgG PF-4 binds to surface of platelet following activation Complexes of heparin (GAG) and PF-4 molecules form IgG binds to the PF-4/ heparin complex microparticles Fc receptor Fc stimulation leads to the generation of procoagulant-rich microparticles IgG/PF-4/heparin complex activates via the Fc receptor Arch Intern Med. 2004;164:361-369.

  13. PF4/Heparin/HIT-IgG Platelet Activation Thrombosis Release PF4 Embolism Coagulation Morbidity & Death Endothelial Cell Injury Platelet Activation PF4 /HIT-IgG /HIT-IgG Release PF4 Monocyte Activation Platelet Activation Coagulation HIT - a vicious cycle of platelet activation and coagulation

  14. Iceberg model of HIT Thrombosis HIT syndrome Thrombocytopenia Positive washed platelet activation assay PositivePF4 antigen assay Numbers of Patients Warkentin TE. Br J Haematol 2003,121:535

  15. Clinical presentation • Classic Presentation: • 5-10 days after exposure • Isolated thrombocytopenia or with thrombosis • Delayed HIT: • Days to weeks after exposure • Often with thrombocytopenia and thrombosis • Rapid/Acute Onset: • Within 24 hour ASH State of Art symposium 2009

  16. Heparin (re) Exposure Typical HIT Mean Day 9 (5–14 days) Rapid-onset HIT (hours–days) Delayed-onset HIT (14–30 days) Day 1 Day 5 Day 14 Day 30 THROMBOCYTOPENIA (± THROMBOSIS) HIT Temporal Variants

  17. Consequences of HIT • If left untreated, risk of thrombosis persists even after platelet counts have returned to normal • Approximately 5-10% increased risk per day immediately following discontinuation of heparin ASH State of Art symposium 2009

  18. Clinical Consequences of HIT

  19. Features of the history and physical examination that support a diagnosis of HIT

  20. Unusual Clinical Events Suspicious for HIT • 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

  21. Venous Gangrene Warkentin. Ann Intern Med. 1997;127:804-812.

  22. Skin Manifestations of HIT Skin necrosis Warkentin. Br J Haematol. 1996;92:494-497

  23. Diagnosis Diagnostic specificity can be further increased by use of a sensitive washed platelet activation assay; a positive platelet activation assay is much more specific for clinical HIT than a positive platelet factor 4 (PF4)-dependent immunoassay

  24. The 4Ts: A clinical probability scoring model High probability: 6-8 points; intermediate probability: 4-5 points,low probability: ≤3 points.

  25. 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) • Use of washed donor platelets increase sensitivity and specificity to >90% for SRA and HIPA

  26. Serologic Assays • Antibodies against heparin/PF4 complexes antigen of are measured by colorimetric absorbance • PF4/heparin ELISA • Gel-particle assay • High sensitivity , • Lower specificity for clinically significant HIT • Detects IgA and IgM

  27. Functional assays analyzewhether the combination of heparin and the patient’s plasma can inducenormal platelets to aggregate or to secrete serotonin; these assays have veryhigh specificity but relatively low sensitivity. Immunologic assays test thepatient’s plasma for antibodies that bind to the heparin-PF4 complex; theyhave very high sensitivity but lack specificity. Consequently, a negative immunologic assay is useful in excluding this diagnosis, and a positive functional assayis very useful in confirming the diagnosis of HIT.

  28. N Eng J Med 2006;355:809-17

  29. N Eng J Med 2006;355:809-17

  30. Objectives of Treatment for HIT

  31. Management of HIT • Stop heparin (UFH/LMWH), even in patients without thrombosis • Initiate alternative non-heparin anticoagulant because of high risk of symptomatic thrombosis • Test for HIT antibodies • Duplex ultrasonography for lower-limb DVT 2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH

  32. Management of HIT • Do notstart a vitamin K antagonist (VKA) - if started prior to diagnosis it should be reversed by vitamin K • Do not use low-molecular-weight heparin (LMWH) • Do not give platelet transfusions unless needed to manage serious hemorrhage 2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH

  33. Transitioning to warfarin • Warfarin should not be initiated until platelet count is ≥ 150 x 109/L • Initial warfarin dose should be ≤ 5 mg/day. Larger loading doses should be avoided. • • A parenteral non-heparin anticoagulant should be overlapped with warfarin for ≥ 5 days and until INR has reached intended target . 2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH

  34. Duration of anticoagulation • For patients with HITT: • anticoagulate for a defined course (typically 3-6 months • For patients with HIT without thrombosis • the optimal duration of anticoagulation is unknown. Because there is an elevated risk of thrombosis extending at least 30 days after the diagnosis of HIT, anticoagulation for at least one month should be considered. 2009 Clinical Practice Guideline on the Evaluation and Management of Heparin-Induced Thrombocytopenia ASH

  35. summery Heparin-induced thrombocytopenia (HIT) is an adverse drug reaction caused by platelet-activating immunoglobulin G (IgG) antibodies that recognize complexes of platelet factor 4 (PF4) bound to heparin. HIT is highly prothrombotic: at least 50% of affected patients develop thrombosis involving veins, arteries, or even the microcirculation.

  36. Because the diagnosis is based on both clinical and serologic grounds, clinicians should consider HIT a clinicopathologic syndrome. Thus, neither thrombocytopenia or thrombosis without the presence of heparin-dependent antibodies, nor the isolated presenceof antibodies without thrombocytopenia, thrombosis,or other clinical sequelae, meet the criteria for HIT.

  37. Rather, clinicians make a diagnosis of HIT when any of the following events occurs in association with the presence of “HIT antibodies” detected by in vitro assays:

  38. an otherwise unexplained platelet count venous orarterial thrombosis (most often, deep venous thrombosis [DVT] pulmonary embolism limb artery thrombosis, thrombotic stroke, myocardial infarction, adrenal hemorrhagic necrosis (3) skin lesions at heparin injectionsites; (4) acute systemic (anaphylactoid) reactions (eg, fever/chills, tachycardia, hypertension, dyspnea,cardiopulmonary arrest) that occur after IV heparin bolus administration.

  39. Steps to Prevent HIT • Porcine heparin preferred over bovine heparin • LMWH preferred over unfractionated heparin • Oral anticoagulation should be started as early as possible to reduce the duration of heparin exposure • Intravenous adapters should not be flush with heparin • Monitoring serial plate counts for developing thrombocytopenia Serial platelet counts in patients receiving heparin: Check platelets at baseline, 24 hours, and then every other day for first 14 days

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