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Heparin-Induced Thrombocytopenia (HIT)

Heparin-Induced Thrombocytopenia (HIT). Heparin-Induced Thrombocytopenia (HIT). HIT is an immune-mediated adverse effect of heparin that paradoxically increases risk of thrombosis. HIT is a clinico-pathological syndrome. Thrombocytopenia and/or Thrombosis. Clinical. Pathological.

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Heparin-Induced Thrombocytopenia (HIT)

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  1. Heparin-Induced Thrombocytopenia(HIT)

  2. Heparin-Induced Thrombocytopenia(HIT) HIT is an immune-mediated adverse effect of heparin that paradoxically increases risk of thrombosis

  3. HIT is a clinico-pathological syndrome • Thrombocytopenia and/or • Thrombosis Clinical Pathological • Heparin-dependent, platelet-activating IgG antibodies Warkentin TE, Chong BH, Greinacher A. Thromb Haemost 1998;79:1-7. Greinacher et al. Blood 2005;106:2921-2922. Greinacher et al. Thromb Haemost 2005;94:132-135.

  4. Heparin-induced thrombocytopenia (HIT) • Anaphylactoid reaction after i.v. heparin bolus • Skin lesions at s.c. heparin injection sites • Overt (decompensated) disseminated intravascular coagulation (DIC) Less frequent clinical manifestations

  5. Approach to diagnose HIT Yes HIT Possible Thrombocytopenia (> 50% decrease) + Timing 5-14 days after starting heparin + Thrombosis + Unusual thromboembolism; skín lesions; anaphylaxis + OTher cause not apparent + Strongly Suspected Confirmed when positive in context of strong clinical suspicion + Test for HIT antibodies positive (usually strongly positive)

  6. Clinical events associated with HIT • Venous thrombosis (30-70%) • Deep vein thrombosis (DVT) • Pulmonary embolism (PE) • Adrenal necrosis (adrenal vein thrombosis) • Cerebral venous (sinus) thrombosis • Venous limb gangrene (VKA associated) • Arterial thrombosis (“white clots”) (15-30%) • Limb artery thrombosis • Stroke • Myocardial infarction • Skin lesions at heparin injection sites (10%) • Skin necrosis • Erythematous plaques • Acute reactions after i.v. heparin bolus (10%) • Disseminated intravascular coagulation (DIC) (10%)

  7. Drugs associated with HIT • Unfractionated heparin • Prophylactic dose • Therapeutic dose • Flushes • Heparin-coated devices • Low-molecular-weight heparin • Prophylactic dose • Therapeutic dose • Other highly sulfated polysaccharides • Pentosan polysulfate • Hypersulfated chondroitin sulfate • PI-88 (anti-angiogenic drug)

  8. FcgRIIa Heparansulfate Heparin PF4 B-L EC Tissue factor Thrombin Ring of positive charge HIT: a link between immune system and hemostasis PF4 tetramer Li et al, Blood 2002; 99:1230 Thrombosis Warkentin TE, Chong BH, Greinacher A. Heparin induced thrombocytopenia: Towards consensus. Thromb Haemost 1998,79:1-7

  9. Sequence of eventsin the development of HIT • Current or recent exposure to heparin • Immune response against platelet factor 4 (PF4)/heparin complexes • Anti-PF4/heparin IgG antibodies crosslink platelet Fc receptors and trigger platelet activation • Positive feedback for platelet activation (e.g., adenosine diphosphate, thromboxane A2) • Platelet activation results in shedding of procoagulant platelet microparticles Initiation

  10. Sequence of events in the development of HIT • Platelet microparticles promote thrombin generation • Endothelial cell injury and monocyte activation further enhance thrombin generation • PF4 release neutralizes heparin • PF4 release leads to formation of additional PF4/heparin complexes, exposing more antigens, and thus further amplifying platelet activation Development of a hypercoagulable state

  11. 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

  12. Factors influencing frequency of HIT

  13. “Iceberg model” of HIT HIT and associated thrombosis occurs in the subset of patients with platelet-activating anti-PF4/H antibodies Thrombosis HIT syndrome Thrombocytopenia Positive washed platelet activation assay PositivePF4 antigen assay Numbers of Patients Adapted from Warkentin TE. Br J Haematol 2003,121:535

  14. Type of HIT- 60 Median platelet count nadir associated thrombosis 9 55 x 10 /L Nil (N=72) 50 Venous (N=132) Venous & arterial (N=6) 40 Arterial (N=24) Platelet fall <50% 30 Number of Patients 20 10 0 £5 6-10 21-30 31-45 46-70 11-15 16-20 71-100 >400 151-200 101-150 201-300 301-400 Platelet Count Nadir (x 10 9 /L) Platelet count nadir distribution in HIT Adapted from Warkentin TE. Br J Haematol 2003,121:535

  15. Management of HIT – diagnosisThree different clinical presentations Adapted from Warkentin TE. Br J Haematol 2003, 121: 535

  16. Detection of HIT antibodies • Platelet activation assays • Serotonin release assay (SRA; uses “washed” platelets) • Heparin-induced platelet activation (HIPA) assay (uses “washed” platelets) • Platelet aggregation test (PAT; uses citrate-anticoagulated platelet-rich plasma) • Platelet microparticles (flow cytometry) • Antigen assays • PF4/heparin-enzyme immunoassay (EIA) • PF4/polyvinyl sulfonate EIA • Fluid-phase EIA • Particle gel immunoassay

  17. Detection of HIT antibodies Adapted from 7th. ACCP Conference 2004 Chest 126, 311S

  18. Detection of HIT antibodies • High negative predictive value • Negative test usually rules out HIT * • Moderate positive predictive value • Stronger test result = higher chance of HIT • Routine antibody testing is NOT recommended unless: • Thrombocytopenia or >50%  in platelet count • Thrombosis • Heparin-induced skin necrosis • Other sequelae of HIT * Applies to solid-phase EIAs and washed platelet activation assays 7th. ACCP Conference 2004 Chest 126, 311S

  19. Erythematous plaques 1 Deep venous thrombosis 1 Venous gangrene 2 Skin necrosis 1 Clinical signs of HIT 1 Reproduced with permission Blackwell Publishing (Warkentin TE. Br J Haematol 1996 2 Warkentin TE et al. Ann Intern Med 1997

  20. Clinical signs of HIT • Fever, chills, flushing • Respiratory distress • Hypertension, tachycardia, chest pain • Transient global amnesia, headache Acute reactions after intravenous heparin bolus Venous and/or arterial thrombosis • Deep vein thrombosis • Pulmonary embolism • Limb ischemia and infarction • Thrombotic stroke and cerebral (sinus) vein thrombosis • Myocardial infarction • Adrenal necrosis

  21. Differential diagnosis • Hemodilution post-surgery • Severe pulmonary embolism • Sepsis • DIC (multiple causes besides HIT) • Cancer-associated DIC • Antiphospholipid syndrome • Thrombolytic therapy • EDTA-induced pseudothrombocytopenia • GP IIb/IIIa inhibitor-induced thrombocytopenia • Drug-induced thrombocytopenia (other than heparin) • Post-transfusion purpura • Thrombotic thrombocytopenic purpura • Non-immune heparin-associated thrombocytopenia

  22. Platelet count monitoring is recommended in patients at risk of HIT > 0.1%* * 7th. ACCP Conference 2004 Chest, 126: 311S

  23. Diagnosis - pretest probability: the 4 T’s Points:Score 0, 1 or 2 for each of 4 categories: A B C D Adapted from Lo et al. J Thromb Haemost 2006, in press

  24. Diagnosis - pretest probabilityInterpretation of 4 T’s score • Score 0-3: very unlikely to be HIT (<5%) • Score 4 - 5: a minority have HIT (10-30%) • Score 6 – 8: 20 to >80% have HIT, depending on the clinical setting and scorer´s experience: these patients usually require an alternative, non-heparin anticoagulant in therapeutic doses Adapted from Lo et al. J Thromb Haemost 2006, in press

  25. Management of HIT – treatment • 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 When HIT is strongly-suspected:

  26. Management of HIT – treatment • 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 * Recommendation to give vitamin K applies particularly to direct thrombin inhibitors (DTIs), because prolongation of the aPTT by warfarin can lead to underdosing of DTI therapy (in contrast, danaparoid is not monitored by aPTT) When HIT is strongly-suspected: • 7th. ACCP Conference 2004 Chest, 126: 311S-337S • Warkentin TE. J Thromb Haemost 2006; in press.

  27. Management of HIT – treatment • Postpone starting overlapping coumarin until the platelet count has recovered to at least 100 (and preferably) 150 x 109/L • Therapeutic doses of alternative, non-heparin anticoagulants are usually required • If a sensitive test for HIT is negative, heparin therapy may be re-started with regular platelet count monitoring When the diagnosis of HIT is confirmed: * 7th. ACCP Conference 2004 Chest, 126, 311S-337S

  28. Management of HIT – treatment • If the patient requires therapeutic dose anticoagulation for non-HIT reasons, use alternative anticoagulant in therapeutic dose. • If patient does not require therapeutic dose anticoagulation for non-HIT reasons, consider prophylactic-dose alternative anticoagulation, e.g. danaparoid 750 U b.i.d. or t.i.d. until HIT antibody test results are available. When HIT is clinically possible but platelet count decrease is more likely caused by other reasons: Selleng K and Greinacher A: Intensiv up-2-date 2005;1:329-341

  29. 100 90 80 70 60 50 40 30 20 10 0 10 12 14 16 18 20 22 24 26 28 30 2 6 8 0 4 Occurrence of symptomatic thrombosisafter stopping heparin in patients confirmed to have isolated HIT 14-year retrospective study Cumulative thrombotic event-rate (%) N = 62 52.8% Days after isolated HIT recognized Adapted from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

  30. Odds ratios for risk of thrombosis • Prothrombin anomaly 2.0 • Lupus anticoagulant 5.4 • Factor V Leiden 6.6 • Protein S deficiency 10.9 • Dysfibrinogenaemia 11.3 • Protein C deficiency 14.4 • Antithrombin deficiency 24.1 • HIT 20-40 Warkentin TE. Can J Cardiol 1995;11(Suppl. C):29C-34C Warkentin TE. Thromb Res; 2003; 110:73-82

  31. Management of HIT – treatment • Danaparoid – Xa/IIa inhibitor (anti-Xa >> anti-IIa) • Direct thrombin inhibitor (DTI): • Lepirudin • Argatroban • Bivalirudin Suitable alternative non-heparin antithrombotic therapies are: * 7th. ACCP Conference 2004 Chest 126: 311S-337S

  32. HIT – summary & conclusions • HIT is a potentially fatal side effect of heparin that is more common with UFH than LMWH • HIT is a clinico-pathologic syndrome: its diagnosis is based on compatible clinical features and presence of HIT antibodies • Antibodies against PF4/heparin are formed commonly during heparin treatment; HIT occurs in the subset of patients with strong platelet-activating IgG antibodies

  33. HIT – summary & conclusions • Binding of HIT antibodies to PF4/heparin complexes on the platelet surface results in platelet activation, thrombocytopenia and increased risk of arterial thrombosis • Platelet, monocyte, and endothelial cell activation results in a hypercoagulable state, and increased risk of venous thrombosis • HIT-associated thrombosis occurs in some patients 1 – 2 days before platelet counts decrease

  34. HIT – summary & conclusions • Platelet count monitoring is important to diagnose isolated HIT and thus has the potential to prevent thrombosis • Recognizing a relative decrease of platelet count is important since platelets do not always fall below 150 x 109/L • Platelet count monitoring is recommended in most patients receiving UFH and in some patients receiving LMWH.

  35. HIT – summary & conclusions • Heparin should be stopped immediately in all situations where HIT is strongly suspected • Due to the high risk of thrombosis in patients with HIT anticoagulation with a non-heparin anticoagulant should be started even in the absence of overt thrombosis • Danaparoid provides an option for anticoagulation in either prophylactic or therapeutic doses

  36. Heparin-Induced Thrombocytopenia(HIT)

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