Heparin-induced thrombocytopenia (HIT) is an under-recognized, limb- and life-threatening complication of pharmacologic heparin administration. Antibody formation against heparin complexed to platelet factor 4 (PF4) is central to the pathogenesis of HIT. Heparin: PF4 antibodies promote platelet activation and aggregation as well as excess thrombin generation which may lead to clinical thrombosis. HIT should be suspected in patients who develop thrombocytopenia with or without associated arterial or venous thrombosis while on heparin. HIT is a clinical diagnosis. Specialized HIT assays should be interpreted with care. The cornerstone of HIT management is the discontinuation of all forms of heparin exposure and the institution of anticoagulation with an alternative agent. The direct thrombin inhibitors lepirudin and argatroban are currently available and approved for use in patients with HIT.
Greinacher A.Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Semin Thromb Hemost1995; 21: 106-116.
5.
Visentin GP, Ford SE, Scott JP, Aster RH.Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexed with heparin or bound to endothelial cells. J Clin Invest1994; 93:81-88.
6.
Amiral J, Wolf M, Fischer A, Boyer-Neumann C, Vissac A, Meyer D.Pathogenicity of IgA and/or IgM antibodies to heparin-PF4 complexes in patients with heparin-induced thrombocytopenia. Br J Haematol1996; 92: 954-959.
7.
Greinacher A, Pötzsch B, Amiral J, Dummel V, Eichner A, Mueller-Eckhardt C.Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Haemost1994; 71: 247-251.
8.
Newman PM, Chong BH.Heparin-induced thrombocytopenia: new evidence for the dynamic binding of purified anti-PF4-heparin antibodies to platelets and the resultant platelet activation. Blood2000; 96: 182-187.
9.
Warkentin TE, Hayward CP, Boshkov LKet al.Sera from patients with heparin-induced thrombocytopenia generate platelet-derived microparticles with procoagulant activity: an explanation for the thrombotic complications of heparin-induced thrombocytopenia. Blood1994; 84: 3691-3699.
10.
Hughes M, Hayward CPM, Warkentin TEet al.Morphological analysis of microparticle generation in heparin-induced thrombocytopenia. Blood2000; 96: 188-194.
11.
Kwaan HC, Sakurai S.Endothelial cell hyperplasia contributes to thrombosis in heparin-induced thrombocytopenia. Semin Thromb Hemost1999; 25 (suppl 1): 23-27.
12.
King DJ, Kelton JG.Heparin-associated thrombocytopenia. Ann Intern Med1984; 100: 535-540.
Schmitt BP, Adelman B.Heparin-associated thrombocytopenia: a critical review and pooled analysis. Am J Med Sci1993; 305: 208-215.
15.
Warkentin TE, Kelton JG.A 14-year study of heparin-induced thrombocytopenia. Am J Med1996; 101: 502-507.
16.
Bell WR, Royall RM.Heparin-associated thrombocytopenia: a comparison of three heparin preparations. N Engl J Med1980; 303: 902-907.
17.
Amiral J, Peynaud-Debayle E, Wolf M, Bridey F, Vissac AM, Meyer D.Generation of antibodies to heparin-PF4 complexes without thrombocytopenia in patients treated with unfractionated or low-molecular-weight heparin. Am J Hematol1996; 52:90-95.
18.
Visentin GP, Malik M, Cyganiak KA, Aster RH.Patients treated with unfractionated heparin during open heart surgery are at high risk to form antibodies reactive with heparin: platelet factor 4 complexes. J Lab Clin Med1996; 128: 376-383.
19.
Trossaert M, Gaillard A, Commin PL, Amiral J, Vissac AM, Fressinaud E.High incidence of anti-heparin/platelet factor 4 antibodies after cardiopulmonary bypass surgery. Br J Haematol1998; 101: 653-655.
20.
Pouplard C, May MA, Iochmann Set al.Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin: clinical implication for heparin-induced thrombocytopenia. Circulation1999; 99: 2530-2536.
21.
Lindhoff-Last E, Eichler P, Stein Met al.A prospective study on the incidence and clinical relevance of heparin-induced antibodies in patients after vascular surgery. Thromb Res2000; 97: 387-393.
22.
Klement D, Rammos S, v Kries R, Kirschke W, Kniemeyer HW, Greinacher A.Heparin as a cause of thrombus progression. Heparin-associated thrombocytopenia is an important differential diagnosis in paediatric patients even with normal platelet counts. Eur J Pediatr1996; 155:11-14.
23.
Saxon BR, Black MD, Edgell D, Noel D, Leaker MT.Pediatric heparin-induced thrombocytopenia: management with danaparoid (Orgaran). Ann Thorac Surg1999; 68: 1076-1078.
24.
Bell WR.Heparin-associated thrombocytopenia and thrombosis. J Lab Clin Med1988; 111: 600-605.
25.
Hunter JB, Lonsdale RJ, Wenham PW, Frostick SP.Heparin-induced thrombosis: an important complication of heparin prophylaxis for thromboembolic disease in surgery. BMJ1993; 307:53-55.
Ansell J, Deykin D.Heparin-induced thrombocytopenia and recurrent thromboembolism. Am J Hematol1980; 8: 325-332.
29.
Warkentin TE, Soutar RL, Panju A, Ginsberg JS.Acute systemic reactions to intravenous bolus heparin therapy: characterization and relationship to heparin-induced thrombocytopenia. Blood1992; 80(suppl 1): 160a-160a [Abstract].
30.
Hach-Wunderle V, Kainer K, Salzmann G, Muller-Berghaus G, Pötzsch B.Heparin-related thrombosis despite normal platelet counts in vascular surgery. Am J Surg1997; 173: 117-119.
31.
Calaitges JG, Liem TK, Spadone D, Nichols WK, Silver D.The role of heparin-associated antiplatelet antibodies in the outcome of arterial reconstruction. J Vasc Surg1999; 29: 779-785.
32.
Chong BH, Eisbacher M.Pathophysiology and laboratory testing of heparin-induced thrombocytopenia. Semin Hematol1998; 35 (4 suppl 5): 3-8.
33.
Pouplard C, Amiral J, Borg JY, Laporte-Simitsidis S, Delahousse B, Gruel Y.Decision analysis for use of platelet aggregation test, carbon 14-serotonin release assay, and heparin-platelet factor 4 enzyme-linked immunosorbent assay for diagnosis of heparin-induced thrombocytopenia. Am J Clin Pathol1999; 111: 700-706.
34.
Wallis DE, Workman DL, Lewis BE, Steen L, Pifarre R, Moran JF.Failure of early heparin cessation as treatment for heparin-induced thrombocytopenia. Am J Med1999; 106: 629-635.
35.
Schiele F, Lindgaerde F, Eriksson Het al.Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep venous thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. Thromb Haemost1997; 77: 834-838.
36.
Markwardt F.The development of hirudin as an antithrombotic drug. Thromb Res1994; 74:1-23.
37.
Schiele F, Vuillemenot A, Kramarz Pet al.Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. Am J Hematol1995; 50:20-25.
Greinacher A, Völpel H, Janssens Uet al.Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with heparin-induced thrombocytopenia: a prospective study. Circulation1999; 99:73-80.
40.
Pötzsch B, Madlener K, Seelig C, Riess CF, Greinacher A, Muller-Berghaus G.Monitoring of r-hirudin anticoagulation during cardio-pulmonary bypass: assessment of the whole blood ecarin clotting time. Thromb Haemost1997; 77: 920-925.
41.
Topoulos AP, Bartholomew JR, Mee R, Kirhuk M, Deitcher SR.Refludan™ (lepirudan) in pediatrics: safe use for heparin-induced thrombocytopenia (HIT) and extracorporeal membrane oxygenation (ECMO). Thromb Haemost1999; Suppl 394: Abstract 1250.
42.
Frank RD, Farber H, Stefanidis I, Lanzmich R, Kierdorf HP.Hirudin elimination by hemofiltration: a comparative in vitro study of different membranes. Kidney Int1999; 58 (suppl 72): S41-S45.
43.
Refludan (lepirudan [rDNA] for injection) package insert. Kansas City, MO: Hoechst Marion Roussel, October 1998.
44.
Eichler P, Olbrich K, Pötzsch B, Greinacher A.Anti-hirudin antibodies in patients treated with recombinant hirudin for more than five days, a prospective study. Thromb Haemost1997; Supplement: 493-493 [Abstract PS 2014].
45.
Hursting MJ, Alford KL, Becker JCet al.Novastan®(brand of argatroban): a small-molecule, direct thrombin inhibitor. Semin Thromb Hemost1997; 23: 503-516.
46.
Lewis BE, Wallis DE, Matthai W, for the ARG-911 Study Investigators. Argatroban provides effective and safe anticoagulation in patients with heparin-induced thrombocytopenia: a prospective, historical controlled study. J Am Coll Cardiol2000; 35 (suppl A): 266A-266A [Abstract 832-2].
47.
Lewis BE.Argatroban use in patients with heparin-induced thrombocytopenia during percutaneous coronary intervention. Chest2000; 118 (suppl): 261S-261S.
Magnani HN.Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost1993; 70: 554-561.
50.
Tardy-Poncet B, Tardy B, Reynaud Jet al.Efficacy and safety of danaparoid sodium (ORG 10172) in critically ill patients with heparin-associated thrombocytopenia. Chest1999; 115: 1616-1620.
51.
Greinacher A, Amiral J, Dummel V, Vissac A, Kiefel V, Mueller-Eckhardt C.Laboratory diagnosis of heparin-associated thrombocytopenia and comparison of platelet aggregation test, heparin-induced platelet activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion1994; 34: 381-385.
52.
Tardy B, Tardy-Poncet B, Viallon A, Piot M, Mazet E.Fatal danaparoid-sodium induced thrombocytopenia and arterial thromboses. Thromb Haemost1998; 80: 530-530.
53.
Greinacher A, Drost W, Michels Iet al.Heparin-associated thrombocytopenia: successful therapy with the heparinoid Org 10172 in a patient showing cross-reaction to LMW heparins. Ann Hematol1992; 64:40-42.
54.
Horellou MH, Conrad J, Lecrubier Cet al.Persistent heparin-induced thrombocytopenia despite therapy with low molecular weight heparin. Thromb Haemost1984; 51: 134-134.
55.
Gouault-Heilmann M, Huet Y, Adnot Set al.Low molecular weight heparin fractions as an alternative therapy in heparin-induced thrombocytopenia. Haemostasis1987; 17: 134-140.
56.
Leroy J, Leclerc MH, Delahousse Bet al.Treatment of heparin-associated thrombocytopenia and thrombosis with low-molecular weight heparin (CY216). Semin Thromb Hemost1985; 11: 326-329.
57.
Warkentin TE, Russett JI, Johnston M, Kelton JG.Warfarin treatment of deep vein thrombosis complicating heparin-induced thrombocytopenia (HIT) is a risk factor for initiation of venous limb gangrene: report of nine patients implicating the interacting procoagulant effects of two anticoagulant agents. Thromb Haemost1995; 73: 1110-1110 [Abstract 804].
58.
Warkentin TE.Heparin-induced thrombocytopenia: IgG-mediated platelet activation, platelet microparticle generation, and altered procoagulant/anticoagulant balance in the pathogenesis of thrombosis and venous limb gangrene complicating heparin-induced thrombocytopenia. Transfus Med Rev1996; 10: 249-258.
59.
Addonizio VP Jr, Fisher CA, Kappa JR, Ellison N.Prevention of heparin-induced thrombocytopenia during open heart surgery with iloprost (ZK36374). Surgery1987; 102: 796-807.
60.
Mak KH, Kottke-Marchant K, Brooks LM, Topol EJ.In vitro efficacy of platelet glycoprotein IIb/IIIa antagonist in blocking platelet function in plasma of patients with heparin-induced thrombocytopenia. Thromb Haemost1998; 80: 989-993.
61.
Hérault JP, Lalé A, Savi P, Pflieger AM, Herbert JM.In vitro inhibition of heparin-induced platelet aggregation in plasma from patients with HIT by SR121566, a newly developed GP IIb/IIIa antagonist. Blood Coagul Fibrinolysis1997; 8: 206-207.
62.
Walenga JM, Jeske WP, Wallis DEet al.Clinical experience with combined treatment of thrombin inhibitors and GPIIb/IIIa inhibitors in patients with HIT. Semin Thromb Hemost1999; 25 (suppl 1): 77-81.
63.
Robinson JA, Lewis BE.Plasmapheresis in the management of heparin-induced thrombocytopenia. Semin Hematol1999; 36 (1 Suppl 1): 29-32.
64.
Warkentin TE, Kelton JG.Timing of heparin-induced thrombocytopenia (HIT) in relation to previous heparin use: absence of an anamnestic immune response, and implications for repeated heparin use in patients with a history of HIT. Blood1998; 92 (suppl 1): 182a-182a [Abstract].
65.
Pötzsch B, Klövekorn WP, Madlener K.Use of heparin during cardio-pulmonary bypass in patients with a history of heparin-induced thrombocytopenia. N Engl J Med2000; 343: 515-515.
