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Understanding Heparin-Induced Thrombocytopenia (HIT): Historical and Clinical Perspectives

Understanding Heparin-Induced Thrombocytopenia (HIT): Historical and Clinical Perspectives. Heparin-Induced Thrombocytopenia. Heparin is a widely used anticoagulant drug for the treatment and prevention of thromboembolic disorders

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Understanding Heparin-Induced Thrombocytopenia (HIT): Historical and Clinical Perspectives

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  1. Understanding Heparin-Induced Thrombocytopenia (HIT): Historical and Clinical Perspectives

  2. Heparin-Induced Thrombocytopenia • Heparin is a widely used anticoagulant drug for the treatment and prevention of thromboembolic disorders • Heparin may cause immune thrombocytopenia (a reduction in platelet count), or HIT • HIT can cause life- or limb-threatening thromboses

  3. Clinical Conditions/Causes of Thrombocytopenia • Increased platelet destruction • Non-immune • Septicemia/Inflammation • Disseminated intravascular coagulation • Thrombotic thrombocytopenic purpura • Immune • Autoimmune: idiopathic or secondary immune thrombocytopenia • Alloimmune: post-transfusion purpura • Drug-induced: prothrombic (heparin), prohemorrhagic (quinine, quinidine, gold, sulfa antibiotics, rifampin, vancomycin, NSAIDs, many others)

  4. Clinical Conditions/Causes of Thrombocytopenia (cont.) • Decreased platelet production • Alcohol, cytotoxic drugs • Aplastic anemia • Leukemia, myelodysplasia • Metastatic invasion of marrow • Certain infections • Hypersplenism • Hemodilution (infusion of blood products, colloids, or crystalloids)

  5. Terminology Relating to HIT • Heparin-induced thrombocytopenia (HIT) • Also known as HIT type II, white clot syndrome, and heparin-associated thrombocytopenia (HAT) • Denotes demonstrable role of heparin in “inducing” thrombocytopenia (ie, heparin-dependent antibodies are detectable) • Non-immune heparin-associated thrombocytopenia (non-immune HAT) • Also known as HIT type I, HAT • Denotes absence of heparin-dependent antibodies and the potential role for other factors in causing thrombocytopenia

  6. Frequency of HIT • Related to heparin source • Bovine lung: 1.9% to 30.8%* • Porcine intestine: 1.3% to 8%* • Full-dose IV heparin: 0% to 30%* • Prospective studies (P) and review of literature (R) for HIT • (R) Warkentin and Kelton, 1994: 3.4% • (P) Warkentin et al, 1995: 2.7% (unfractionated; <1% LMW) • (R) Schmitt, 1993; Schulman, 1997: 1.1% to 2.9% *Some high rates are from studies that included patients with non-immune HAT.

  7. Incidence of HIT and HIT Thrombosis: Prospective Studies of IV Therapeutic-Dose Heparin No. of Early ( 4 days) Late ( 5 days)   Patients Thrombosis thrombo- thrombo- Arterial Venous cytopenia cytopenia Ansell, 1980 43 1 4 0 0 Ansell, 1985 104 5 5 0 0 Bailey, 1986 43 0 1 1 0 Ramirez- Lassepas, 1984*; 211 2 9 2 1 Cipolle, 1983* Gallus, 1980 143 4 5 0 1 Green, 1984, 1986 89 0 2 1 1 Holm, 1980 90 0 1 0 0 Kakkasseril, 1985 142 -- 9 2 2 Monreal, 1989 89 -- 2 0 1 Nelson, 1978 37 6 3 0 0 Powers, 1979* 120 2 2 1 1 Powers, 1984 131 2 3 0 0 Rao, 1989 94 3 3 0 0 Total 1,336 24 (1.8%) 46 (3.4%) 7 7 From Warkentin TE, Kelton JG. In: Bounameaux H, ed. Low-Molecular-Weight Heparins in Prophylaxis and Therapy of Thromboembolic Diseases.Fundamental and Clinical Cardiology. New York: Marcel Dekker, Inc; 1994:75–127. * Some information obtained by personal communication.

  8. Differences Between HIT and Non-Immune HAT Non-Immune HAT HIT Usually 5–14 days (may be Onset Within 4 days sooner) Platelet count Typically 100,000–150,000/ L Typically 20,000–150,000/ L    median nadir ~ 50,000/  L in most series; rarely <20,000/ L  sometimes falls >30%, but  remains >150,000/ L  Complications Thromboembolic lesions None 5%–30% 1% at 1 week; 3% at 2 weeks Incidence Recovery 1–3 days 5–7 days Benign, tiny platelet IgG-mediated strong platelet Cause aggregates activation

  9. Thromboembolic Disorders Associated With HIT: Consequences • Venous thrombosis: DVT; venous limb gangrene; pulmonary embolism; cerebral sinus thrombosis • Arterial thrombosis: Limb gangrene; cerebrovascular accident; MI; miscellaneous end-organ thromboses • Other complications: Adrenal hemorrhagic infarction; heparin-induced skin lesions (at injection sites); acute systemic reactions (post IV heparin bolus); disseminated intravascular coagulation

  10. Skin Necrosis Used with permission from Warkentin TE. Br J Haematol. 1996;92:494–497.

  11. Acute Systemic Reactions Caused by IV Heparin Bolus • The following can occur in patients sensitized to heparin within 5–30 minutes: • Fever, chills • Tachycardia, hypertension • Flushing, headache • Chest pain, dyspnea • Nausea, vomiting, large-volume diarrhea • Sudden “anaphylactoid” death • Transient global amnesia

  12. CH2OSO3 MolecularStructure of Heparin Member of heterogeneous family of glycosaminoglycans; MW=3,000–30,000 daltons CH2OH O O OH OH OH OH HO O O NHAc COO NHSO3 OH COO O OH O OH COO OH OH HO OSO3 HO HO OH OH (1) (2) (3) (4) (5) Adapted with permission from Physicians’ Desk Reference. Montvale, NJ: Medical Economics, 1998:3044.

  13. Action of Heparin • Primary action • Binds to antithrombin (cofactor) • After binding, increases antithrombin’s inhibition of thrombin (factor IIa) and factors IXa, Xa, XIa, XIIa, and kallikrein • Limited anticoagulant action • Prevents additional thrombus accretion • Unable to dissolve an existing thrombus directly

  14. Pathophysiology of HIT and Thrombosis Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

  15. Pathophysiology of HIT and Thrombosis (cont.) Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

  16. Pathophysiology of HIT and Thrombosis (cont.) Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

  17. Pathophysiology of HIT and Thrombosis (cont.) Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

  18. Fourteen-Year Study of HIT • Study design: Retrospective cohort study • Population: 127 patients with serologically confirmed HIT in one medical community • Group I (n=65): HIT diagnosed after appearance of new thrombosis • Group II (n=62): Initial diagnosis of isolated HIT (ie, no new thrombosis at time of diagnosis) • Reason for hospitalizations • Surgical: approximately 2/3 (mostly orthopedic) • Medical: approximately 1/3 (DVT or PE) Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

  19. Fourteen-Year Study of HIT:Group II Results After Heparin Discontinuation 100 90 80 70 60 50 40 30 20 10 0 52.8% Cumulative Thrombotic Event Rate (%) 10 12 14 16 18 20 22 24 26 28 30 0 2 4 6 8 Days After Isolated HIT Recognized Adapted with permission from Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

  20. Fourteen-Year Study of HIT: Summary • Relatively conservative, conventional management of patients with isolated HIT (ie, discontinuation of heparin with or without substitution with warfarin) • Conservative treatment approaches can result in unacceptably high rates (~50%) of subsequent thrombosis • Additional clinical studies needed to show whether more aggressive treatments using alternative anticoagulants would be useful for this patient population Warkentin TE, Kelton JG. Am J Med. 1996;101:502–507.

  21. Diagnosis of HIT • Normal platelet count before commencement of heparin therapy • Onset of thrombocytopenia typically 5–14 days after initiation of heparin therapy but can occur earlier • Exclusion of other causes of thrombocytopenia (eg, sepsis) • Occurrence of thromboembolic complications during heparin therapy

  22. Diagnosis Based on Time of Onset 15 First Exposureto Heparin Subsequent Exposureto Heparin 10 Thrombocytopenia Number of Patients 5 Thrombocytopenia 0 Thrombosis Thrombosis 2 4 6 8 10 12 14 16 18 20 2 4 6 8 10 Day of Treatment Day of Treatment Adapted with permission from King DJ, Kelton JG. Ann Intern Med. 1984;100:536–540.

  23. Diagnosis: Platelet Aggregation Assay • Measures platelet aggregation of IgG in serum or plasma of a HIT patient treated with heparin • Donor platelets can be washed or suspended in citrated plasma • Advantages • Easily performed in most laboratories • Specificity greater than 90% • Disadvantages • Low sensitivity: 35%–81%; sensitivity higher using washed platelets • Reactivity varies among donor platelets

  24. Diagnosis: Serotonin Release Assay • Measures the release of serotonin from aggregated platelets in serum of patient with HIT; relies on platelet aggregation in the presence of heparin • Advantages • High specificity and sensitivity • Validated in blinded assessment of a clinical trial • Disadvantages • Technically demanding and time-consuming • Requires the use of radioactive materials • Not widely available

  25. Relationship Between Release of 14C-Serotonin and Final Concentration of Heparin in HIT Patients 100 80 60 40 20 0 1 2 3 4 % 14C-Serotonin Release 0.001 0.01 0.1 1 10 100 1000 0 Heparin Concentration (µ/mL) Adapted with permission from Sheridan D, Carter C, Kelton JG. Blood. 1986;67:27–30.

  26. Diagnosis: Heparin/PF4 ELISA Relative Sensitivity in 12 Patients with HIT Positive Reactions, n Assay Undiluted 1:10 1:100 1:200 1:500 Serotonin 12 12 2 Not Not Release Tested Tested ELISA 12 12 12 12 9 Adapted with permission from Visentin GP, Aster RH. Curr Opin Hematol. 1995;2:351–357.

  27. Prevention of HIT • Obtain medical history regarding previous sensitization to heparin; earlier monitoring may be required if patient previously received heparin • Limit heparin duration whenever possible to <5 days • Avoid heparin flushes • Use warfarin early to minimize the length of heparin administration in patients requiring longer-term anticoagulation, except when HIT is diagnosed • Routinely initiate oral anticoagulation at start of heparin therapy in patients who need longer-term oral anticoagulation • Use LMWH if possible

  28. Prevention of Thrombotic Complications of HIT • When HIT is recognized, promptly discontinue use of heparin • Avoid warfarin unless there is adequate anticoagulant control with a drug such as danaparoid sodium or recombinant hirudin • Monitor platelet count throughout hospitalization • Use alternative antithrombotic therapy, such as danaparoid sodium or recombinant hirudin, for patients with HIT and thrombosis

  29. Incidence of Complications and Mortality of HIT No. of Age (year Complications Mortality n n Year Patients range or SD) (%) (%) M F 1983 62 34 28 19-93 38 (61.0) 14 (23.0) 1986 169 97 72 2-94 38 (22.5) 20 (12.0) 1996* 127 60 67 67.0 +/- 11.4 99 (78.0) 26 (20.5) † 1996 62 33 29 66.7 +/- 12.3 32 (51.6) 13 (21.0) *Includes patients initially presenting with thrombosis †Subgroup of the 127 patients presenting with thrombosis From Laster J, Cikrit D, Walker N, Silver D. Surgery. 1987;102:763-770 and Warkentin TE, Kelton JG. Am J Med. 1996;101;502–507.

  30. Treatment of Non-Immune HAT • Heparin should be continued if still indicated • Patients with non-immune HAT are asymptomatic; platelet counts should return to normal during continuation of heparin therapy • No additional risk of thrombosis Note: It may sometimes be difficult to distinguish between immune HIT and non-immune HAT on clinical grounds alone

  31. Treatment of Suspected HIT • Discontinue all heparin immediately, including • Heparin flushes • Heparin-coated pulmonary catheters • Heparinized dialysate and any other medications or devices containing heparin • Confirm diagnosis of HIT with the appropriate laboratory test • Consider alternative anticoagulation • Monitor carefully for thrombosis • Monitor platelet counts until recovery • Avoid prophylactic platelet transfusions

  32. Conventional Strategies for HIT: Variable Success • Cessation of heparin alone • Warfarin • LMWH • Danaparoid sodium • Ancrod • Prostacyclin analogues

  33. Treatment of HIT Complicated by DVT: Risk for Warfarin-Induced Venous Limb Gangrene • Vitamin K antagonists such as warfarin may also be used for continuing anticoagulant therapy • Mechanism of action: Inhibits vitamin K dependent coagulant factors • Disadvantages • Requires 5 days to achieve full therapeutic effect • Warfarin has been associated with venous limb gangrene when used alone (especially at high doses) or with ancrod during acute HIT, particularly in patients with DVT Note: Venous limb gangrene arises from a disturbance in procoagulant/anticoagulant hemostatic balance (HIT-associated increase in thrombin generation/warfarin-associated depletion of the natural anticoagulant protein C)

  34. Venous Limb Gangrene Used with permission from Warkentin TE, Elavathil LJ, Hayward CPM, Johnston MA, Russett JI, Kelton JG. Ann Intern Med. 1997;127:804–812.

  35. Low-Molecular-Weight Heparins • Advantages • Binding to plasma proteins and endothelial cells not as strong compared with unfractionated heparin • Reduced binding associated with greater bioavailability and more predictable dose response than unfractionated heparin • Disadvantages • High in vitro cross-reactivity rates with heparin-dependent antibody (approaching 100% using sensitive assays) • Potential cause of HIT, but less often than unfractionated heparin • Significant risk of recurrent or progressive thrombocytopenia and/or thrombosis

  36. Danaparoid Sodium - a LMW Heparinoid • Mixture of anticoagulant glucosaminoglycans with a low degree of sulfation (50% fewer sulfate groups than heparin) • Favorable results in ~90% of patients • Half-life of anti-factor Xa activity is ~25 hours; a potential disadvantage for patients who may need surgical procedures • Cross-reactivity with heparin-dependent antibody in vitro is 10% to 20% • Defined as increased platelet activation over background in presence of patient serum and danaparoid • Uncertain clinical significance of in vitro cross-reactivity

  37. Typical Course of a Patient with HIT Treated with Danaparoid Sodium Heparin 500 Heparin Dalteparin Danaparoid Danaparoid 300 Platelets 109/L 200 = Artificial respiration = Dialysis = Thromboembolus 100 10 12 14 17 22 5 Days Adapted with permission from Greinacher A, Drost W, Michels I, et al. Ann Haematol. 1992;64:40–42.

  38. 9 9 x10 x10 /L (d) Clinical Report of HIT Patients Treated with Ancrod Delay for Nadir Platelet Indication for Platelet Count Increase >150 Age Anticoagulant Bleeding /L (yr) Therapy Episode Recurrence 76 DVT 425 N/A No No History of HIT 74 DVT/PE 68 5 No Yes* † 57 DVT/PE 74 10 No Yes 54 Axillary DVT 47 4 No No 65 DVT 26 7 No No 64 DVT 38 6 No No 76 PE 59 4 No No 66 DVT 67 2 No No ‡ 70 DVT 20 6 Yes No 48 DVT 266 N/A No No History of HIT 80 DVT/PE 52 7 No No DVT, deep venous thrombosis; PE, pulmonary embolism; N/A not applicable. *Extension of DVT, 10 days after stopping ancrod while receiving adequate warfarin (INR between 2 and 3). †Terminal carcinoma, phlegmasia cerulea dolens 10 days after stopping ancrod therapy. ‡Increase in thigh volume and 16 g/L decrease in hemoglobin concentration. Adapted with permission from Demers C, Ginsberg JS, Brill-Edwards P, et al. Blood. 1991;78:2194–2197.

  39. Prostacyclin Analogues • Act as natural vasodilators • Inhibit platelet aggregation • Advantages • Platelet activation blocked in patients with HIT • Short half-life (15–30 minutes) permits ease of control • Disadvantage • Adverse reactions, such as hypotension, may limit usefulness

  40. Alternative Treatments of HIT • IV immunoglobulin preparations of the IgG class: success reported in a few cases • Platelet transfusions: usually unnecessary (low bleeding risk in HIT); may increase risk of new thromboembolic lesions • Plasmapheresis: anecdotal experience only Note: Consider alternative treatments only as adjuncts to a major alternative anticoagulant agent such as danaparoid sodium or recombinant hirudin

  41. Factor XIII XIIIa cross-linked fibrin Fibrinogen fibrin Action of Thrombin Factor V Va Factor VIII VIIIa Releases from endothelium: NO PGI2 t-PA von Willebrand ADP Prothrombin thrombin Thrombin Activation of platelets Adapted with permission from Fuster V, Verstraete M. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Company; 1997:1809–1842.

  42. Development of Lepirudin (rDNA) for Injection (Refludan) Lepirudin (recombinant hirudin) approved for anticoagulation in patients 1998 ==== with heparin-induced thrombocytopenia (HIT) and thromboembolic disease ==== in order to prevent further thromboembolic complications ==== ==== ==== Lepirudin phase I-II trials (safety, PK)1990–1993 ==== Potential indications==== ==== ==== Clin-Pharm investigations of lepirudin1987–1989 ==== ==== ==== Lepirudin developed1986–1987 ==== ==== ==== Amino acid sequence determined 1984–1985 ==== ==== LTYTDCTESGQNLCLCEGSNVCGQGNKCILGSDGEKNQCVTGEGTPKPQSHNDGDFEEIPEEYLQ==== Hirudin primary structure determined 1976 ==== ==== ==== Hirudin defined as thrombin inhibitor 1955–1957 ==== ==== ==== Use of hirudin from H. medicinalis 1903–1904 ==== ==== ==== Anticoagulant activity of medicinal leech identified 1884 ====

  43. Coagulation System Clot formation: Fibrinogen  Fibrin F XIII  F XIIIa Amplification: F V F Va F VIII F VIIIa Platelets Aggregation Release reaction TxA2-synthesis Fibroblasts Proliferation Tumor cells Neurons Leukocytes Neurite growth regulation Adhesion Metastasis Cell growth Chemotaxis Cytokine production Heart Macrophages Positive inotrope Chemotaxis Hirudin Inhibition Endothelial Cells Antithrombin Synthesis andrelease: Prostacyclin EDRF, t-PA Endothelin Tissue factor Activation: Protein C PC a Thrombomodulin Thrombin HIRUDIN Smooth Muscle Contraction Mitogenesis Adapted with permission from Markwardt F. Thromb Res. 1994;74:1–23.

  44. Structure of Lepirudin 65 63 COO– 10 Tyr 60 30 Cys Cys 14 6 Cys Cys Leu 1 28 16 NH3+ 22 Cys 20 50 Cys 47 Val 39 Lys 40

  45. Properties of Unfractionated Heparin, LMWH, and Hirudin Unfractionated Heparin LMWH Hirudin Inhibits thrombin and factor Xa equally, less for IXa, XIa, and XIIa Some extent, mainly factor Xa Specific and potent Thrombin inhibition Antithrombin-dependent Yes No Yes Yes, also by several plasma proteins, PF4, and endothelium Neutralized by heparinase Yes, weak endothelium binding No Inactivates clot-bound thrombin and factor VII Yes (clot-bound thrombin) No No No, except prevents thrombin-induced aggregation Affects platelet Yes Yes function Adapted with permission from Fuster V, Verstraete M. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Co.; 1997:1809-1842.

  46. Properties of Unfractionated Heparin, LMWH, and Hirudin (cont.) Unfractionated Heparin LMWH Hirudin Can cause immune Yes Yes No thrombocytopenia Bioavailability after 30% >90% ~85% SC injection Dose effect response Poor Fair Fair Possible in ~ 40% Yes (HIT) Yes (HIT) Immunogenicity of patients Transient increase Transient increase of liver enzymes of liver enzymes No Liver toxicity common possible Increases vascular Yes No No permeability Adapted with permission from Fuster V, Verstraete M. In: Braunwald E, ed. Heart Disease: A Textbook of Cardiovascular Medicine. Philadelphia: WB Saunders Co.; 1997:1809-1842.

  47. Clinical Trials of Lepirudin: HAT-1 and HAT-2 Studies on HIT • Design: Prospective, historically controlled trials • Primary objective: Demonstrate that treatment of HIT with lepirudin increases platelet counts or maintains normal baseline values while providing effective anticoagulation (prolongation of aPTT to 1.5 to 3 times baseline value) • Secondary objective: Evaluate incidences of new arterial or venous thromboembolic complications, major bleeding complications, surgical interventions/limb amputations, and deaths

  48. Baseline Characteristics of Patients Presenting with Thromboembolic Complications in HAT-1 and HAT-2 Historical Control Lepirudin HAT-1 HAT-2 ( =91) n ( =54) ( =59) n n Males 27.8% 44.1% 35.2% Females 72.2% 55.9% 64.8% Age < 65 years 63.0% 67.8% 44.0% Age > 65 years 37.0% 32.2% 56.0%

  49. Lepirudin Treatment Regimens for HAT-1 and HAT-2 • Treatment regimen A1 • HIT patients with arterial or venous thromboembolism without thrombolytic therapy • initial IV bolus = 0.4 mg/kg BW* • continuous IV infusion = 0.15 mg/kg BW/h, 2–10 days† • Treatment regimen A2 • HIT patients with arterial or venous thromboembolism with concomitant thrombolytic therapy • initial IV bolus = 0.2 mg/kg BW* • continuous IV infusion = 0.1 mg/kg BW/h, 2–10 days† BW, body weight *Not to exceed body weight of 110 kg †Typically 2–10 days duration; longer if clinically warranted

  50. Lepirudin Treatment Regimens for HAT-1 and HAT-2 (cont.) • Treatment regimen B • Prophylaxis of arterial or venous thromboembolism • continuous IV infusion = 0.1 mg/kg BW/h*, 2–10 days† • Treatment regimen C • Anticoagulation during cardiopulmonary bypass • priming of HLM = 0.2 mg/kg BW* • initial IV bolus = 0.25 mg/kg BW* • additional boluses = 5 mg (to maintain ECT > 40 s) BW, body weight; ECT, ecarin clotting time *Not to exceed body weight of 110 kg †Typically 2–10 days duration; longer if clinically warranted

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