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

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

6. 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

7. 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

8. 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

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

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

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

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

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

14. HIT - a vicious cycle of platelet activation and coagulationPF4/Heparin/HIT-IgG Platelet Activation Coagulation Release PF4 Monocyte Activation Coagulation Endothelial Cell Injury Thrombosis Embolism Morbidity&Death Platelet Activation Release PF4 /HIT-IgG PF4

15. Iceberg model of HIT Thrombocytopenia Positive washed platelet activation assay Positive PF4 antigen assay Thrombosis HIT syndrome Numbers of Patients Warkentin TE. Br J Haematol 2003,121:535

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

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

18. 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 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

19. Clinical Consequences of HIT

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

22. 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 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

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

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

26. 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 Diagnosis

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

29. 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 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

30. 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 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

31. 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.

32. Thrombocytopenia in a patient on UFH/LMWH High or intermediate clinical suspicion of HIT Discontinue heparin or LMWH; initiate alternative anticoagulant therapy Results of immunoassay Low clinical suspicion of HIT Heparin or LMWH therapy may be continued N Eng J Med 2006;355:809-17

33. Immunoassay Pos /High Suspicious HIT Confirmed Pos /Intermediate Suspicious Functional AssayPositiveHIT LikelyNegativeHIT Indeterminate Neg /High Suspicious HIT Indeterminate Neg/Intermediate Suspicious Other DX Restart Heparin N Eng J Med 2006;355:809-17

35. Objectives of Treatment for HIT

36. 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 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

37. Management of HIT Do not start 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 Do not start 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

39. Transitioning to warfarin Warfarin should not be initiated until platelet count is ≥ 150 x 10 9 /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. Warfarin should not be initiated until platelet count is ≥ 150 x 10 9 /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

40. 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. 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

43. 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. summery

44. 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.

45. 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:

46. (1)an otherwise unexplained platelet count (2)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.

47. 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 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