Thromb Haemost 1999; 82(S 01): 148-156
DOI: 10.1055/s-0037-1615574
Commentaries
Schattauer GmbH

Heparin-induced Thrombocytopenia – Pathogenesis and Treatment

A. Greinacher
1   From the Institute for Immunology and Transfusion Medicine, Ernst-Moritz-Arndt-University, Greifswald, Germany
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Publikationsverlauf

Publikationsdatum:
14. Dezember 2017 (online)

Summary

Heparin-induced thrombocytopenia (HIT) is now recognized as the most frequent immune-mediated adverse drug reaction. During the last decade, fundamental aspects of the pathogenesis of HIT have been resolved. The understanding of some the mechanisms underlying the development of new, paradox thromboembolic complications in HIT led to the concept that thrombin generation plays a key-role in clinically manifest HIT. Consequently new therapeutic concepts imply the use of drugs with either indirect of direct anti-thrombin activity such as donaparoid-sodium and the recombinant hirudin lepirudin. During the last years results of first prospective studies assessing various treatment regimens in HIT became available. Although data of randomized trials are still missing some treatment recommendations can already be drawn from these studies. This review summarizes key aspects of the pathogenesis of HIT and provides an overview of current treatment strategies.

 
  • References

  • 1 Horne 3rd MDK. The effect of secreted heparin-binding proteins on heparin binding to platelets. Thromb Res 1993; 70: 91-8.
  • 2 Greinacher A, Michels I, Liebenhoff U, Presek P, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: immune complexes are attached to the platelet membrane by the negative charge of highly sulfated oligo-saccharides. Br J Haematol 1993; 84: 711-6.
  • 3 Horne 3rd MDK, Hutchinson KJ. Simultaneous binding of heparin and platelet factor-4 to platelets: further insights into the mechanism of heparin-induced thrombocytopenia. Am J Hematol 1998; 85: 24-30.
  • 4 Salzman EW, Rosenberg RD, Smith MH, Lindon JN. Effect of heparin and heparin fractions on platelet aggregation. J Clin Invest 1980; 65: 64-73.
  • 5 Brace LD, Fareed J. Heparin-induced platelet aggregation. II. Dose/ response relationships for two low molecular weight heparin fractions (CY 216 and CY 222). Thromb Res 1990; 59: 1-14.
  • 6 Mikhailidis DP, Barradas MA, Jeremy JY. et al. Heparin-induced platelet aggregation in anorexia nervosa and in severe peripheral vascular disease. Eur J Clin Invest 1985; 15: 313-9.
  • 7 Burgess JK, Chong BH. The platelet proaggregating and potentiating effects of unfractionated heparin, low molecular weight heparin and heparinoid in intensive care patients and healthy controls. Eur J Haematol 1997; 58: 279-85.
  • 8 Reininger CB, Greinacher A, Graf J. et al. Platelets of patients with peripheral arterial disease are hypersensitive to heparin. Thromb Res 1996; 81: 641-9.
  • 9 Chong BH, Fawaz I, Chesterman CN, Berndt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989; 73: 235-40.
  • 10 Chong BH, Ismail F. The mechanism of heparin-induced platelet aggregation. Eur J Haematol 1989; 43: 245-51.
  • 11 Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: Towards Consensus. Thromb Haemost 1998; 79: 1-7.
  • 12 Warkentin TE, Levine MN, Hirsh J. et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. New Engl J Med 1995; 332: 1330-5.
  • 13 Greinacher A. Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Seminars Thromb Haemost 1995; 21: 106-16.
  • 14 Amiral J, Bridey F, Dreyfus M. et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia (letter). Thromb Haemost 1992; 68: 95-6.
  • 15 Amiral J, Bridey F, Wolf M. et al. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia: a study of 44 cases. Thromb Haemost 1995; 73: 21-8.
  • 16 Greinacher A, Potzsch B, Amiral J. et al. Heparin-associated thrombocytopenia: isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thromb Hemost 1994; 71: 247-51.
  • 17 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 Invest 1994; 93: 81-8.
  • 18 Horsewood P, Warkentin TE, Hayward CP, Kelton JG. The epitope specificity of heparin-induced thrombocytopenia. Br J Haematol 1996; 95: 161-7.
  • 19 Suh JS, Aster RH, Visentin GP. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis recognize different epitopes on heparin:platelet factor 4. Blood 1998; 91: 916-22.
  • 20 Horne 3rd MDK, Alkins BRSO. Platelet binding of IgG from patients with heparin-induced thrombocytopenia. Journal of Laboratory and Clinical Medicine 1996; 127: 435-42.
  • 21 Fondu P. Heparin-associated thrombocytopenia: an update. Acta Clin Belg 1995; 50: 343-57.
  • 22 Greinacher A, Alban S, Dummel V. et al. Characterization of the structural requirements for a carbohydrate based anticoagulant with a reduced risk of inducing the immunological type of heparin-associated thrombocytopenia. Thromb Haemost 1995; 74: 886-92.
  • 23 O'Brien JR, Etherington MD, Pashley MA. The heparin-mobilisable pool of platelet factor 4: a comparison of intravenous and subcutaneous heparin and Kabi heparin fragment 2165. Thromb Haemost 1985; 54: 735-8.
  • 24 Turpie AGG. New therapeutic opportunities for heparins: What does low molecular weight heparin offer?. Journal of Thrombosis and Thrombolysis 1996; 3: 145-9.
  • 25 Suzuki S, Koide M, Sakamoto S, Yamamoto S, Matsuo M, Fujii E, Matsuo T. Early onset of immunological heparin-induced thrombocytopenia in acute myocardial infarction. Blood Coagulation and Fibrinolysis 1997; 8: 13-5.
  • 26 Amiral J, Marfaing-Koka A, Wolf M. et al. Presence of autoantibodies to interleukin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia. Blood 1996; 88: 410-6.
  • 27 Warkentin TE, Kelton JG. Interaction of heparin with platelets, including heparin-induced thrombocytopenia. In: Bounameaux H (ed). Low-Molecular-Weight Heparins in Prophylaxis and Therapy of Thromboembolic Diseases. New York, Basel: Marcel Dekker Inc 1994; 75-127.
  • 28 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. Transfusion Medicine Review 1996; 10: 249-58.
  • 29 Kelton JG, Sheridan D, Santos A. et al. Heparin-induced thrombocytopenia. Blood 1988; 72: 925-30.
  • 30 Greinacher A, Liebenhoff U, Kiefel V. et al. Heparin-associated thrombocytopenia: the effects of various intravenous IgG preparations on antibody mediated platelet activation - a possible new indication for high dose i.v. IgG. Thromb Haemost 1994; 71: 641-5.
  • 31 Chong BH, Murray B, Berndt MC. et al. Plasma P-selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83: 1535-41.
  • 32 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. New Engl J Med 1987; 316: 581-9.
  • 33 Warkentin TE, Hayward CPM, Boshkov LK. et 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. Blood 1994; 84: 3691-9.
  • 34 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. Journal of Laboratory Clinical Medicine 1996; 128: 376-83.
  • 35 Bauer TL, Arepally G, Konkle BA. et al. Prevalence of heparin-associated antibodies without thrombosis in patients undergoing cardiopulmonary bypass surgery. Circulation 1997; 95: 1242-6.
  • 36 Kappers-Klunne MC, Boon DMS, Hop WCJ. et al. Heparin-induced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases. Br J Haematol 1997; 96: 442-6.
  • 37 Greinacher A, Zinn S, Wizeman U, Birk B. Heparin-induced antibodies as a risk factor for thromboembolism and haemorrhage in patients undergoing chronic haemodialysis. Lancet. 1996 348. 764.
  • 38 Suh JS, Mohammad IM, Aster RH, Visentin GP. Characterization of the humoral immune response in heparin-induced thrombocytopenia. Am J Hematol 1997; 54: 196-201.
  • 39 Clark MR, Clarkson SB, Ory PA, Stollman N, Goldstein IM. Molecular basis for a polymorphism involving Fc receptor II on human monocytes. J Immunol. 1989 143. 1731.
  • 40 Warmerdam PAM, van de Winkel JGJ, Gosselin EJ, Capel PJA. Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). J Exp Med. 1990 172. 19.
  • 41 Burgess JK, Lindeman R, Chesterman CN, Chong BH. Single amino acid mutation of Fcγ receptor is associated with the development of heparin-induced thrombocytopenia. Br J Haematol 1995; 91: 761-6.
  • 42 Bachelot-Loza C, Saffroy R, Lasne D. et al. Importance of FcγRIIa-Arg/His-131 polymorphism in heparin-induced thrombocytopenia diagnosis. Thromb Haemost 1998; 79: 523-8.
  • 43 Denomme GA, Warkentin TE, Horsewood P. et al. Activation of platelets by sera containing IgG1 heparin-dependent antibodies: An explanation for the predominance of the FcγIIa “low responder” (his131) gene in patients with heparin-induced thrombocytopenia. Journal of Laboratory Clinical Medicine 1997; 130: 278-84.
  • 44 Arepally G, McKenzie SE, Jiang XM. et al. Fc^RIIA H/R 131 polymorphism, subclass-specific IgG anti-heparin/platelet factor 4 antibodies and clinical course in patients with heparin-induced thrombocytopenia and thrombosis. Blood 1997; 89: 370-5.
  • 45 Brandt JT, Isenhart CE, Osborne JM. et al. On the role of platelet Fc^RIIa phenotype in heparin-induced thrombocytopenia. Thromb Haemost 1995; 74: 1564-72.
  • 46 Carlsson LE, Santoso S, Baurichter G, Kroll H, Papenberg S, Eichler P, Westerdaal NAC, Kiefel V, van de, Winkel JGJ, Greinacher A. Heparin-induced thrombocytopenia: New insights into the impact of the FcγRIIa-R-H131 polymorphism. Blood 1998; 92: 1526-31.
  • 47 Vandenbroucke JP, Koster T, Briet E. et al. Increased risk of venous thrombosis in oral contraceptive users who are carriers of factor V Leiden mutation. Lancet 1994; 344: 1453-7.
  • 48 Koeleman BPC, Reitsma PH, Allaart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
  • 49 Bokarewa MI, Bremme K, Blomback M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996; 92: 473-8.
  • 50 Gardyn J, Sorkyn P, Kluger Y. et al. Heparin-induced thrombocytopenia and fatal thrombosis in a patient with activated protein C resistance. Am J Hematol 1995; 50: 292-5.
  • 51 Papenberg S, Carlsson LE, Eichler P. et al. Heterozygosity for factor V leiden is not the major for thromboembolic complications in patients with heparin-induced thrombocytopenia (abstract). Annals of Hematology. 1998 76. A59.
  • 52 Lee DH, Warkentin TE, Denomme GA, Lagrotteria DD, Kelton J. Factor V Leiden and thrombotic complications in heparin-induced thrombocytopenia. Thromb Haemost 1998; 79: 50-3.
  • 53 Polgar J, Eichler P, Greinacher A, Clemetson KJ. Adenosine diphosphate (ADP) and ADP receptor play a major role in platelet activation/aggregation induced by sera from heparin-induced thrombocytopenia patients. Blood 1998; 91: 549-54.
  • 54 Ganzer D, Gutezeit A, Mayer G, Greinacher A, Eichler P. Thromboembo-lieprophylaxe als Ausloser thromboembolischer Komplikationen: Eine Untersuchung zur Inzidenz Heparin-induzierten Thrombozytopenie (HIT) Typ II. Zeitschrift fur Orthopadie 1997; 135: 543-9.
  • 55 Hach-Wunderle V, Kainer K, Salzmann G, Muller-Berghaus G. Heparin-related thrombosis despite normal platelet counts in vascular surgery. Am J Surg 1997; 173: 117-9.
  • 56 Warkentin TE, Kelton JG. A 14-years study of heparin-induced thrombocytopenia. Am J Med 1996; 101: 502-7.
  • 57 Warkentin TE. Heparin-induced skin lesions. Br J Haematol 1996; 92: 494-7.
  • 58 Greinacher A, Michels I, Kiefel V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 1991; 66: 734-6.
  • 59 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30.
  • 60 Greinacher A, Amiral J, Dummel V. et al. 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. Transfusion 1994; 34: 381-5.
  • 61 Chong BH, Ismail F, Cade J. et al. Heparin-induced thrombocytopenia: Studies with a new low molecular weight heparinoid, Org 10172. Blood 1989; 73: 1592-6.
  • 62 Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554-61.
  • 63 Wilde MI, Markham A. Danaparoid: A review of its pharmacology and clinical use in the management of Heparin-induced thrombocytopenia. Drugs 1997; 54: 903-24.
  • 64 Meuleman DG. Orgaran (Org 10172): Its pharmacological profile in experimental models. Haemostasis 1992; 22: 58-65.
  • 65 Danhof M, de Boer A, Magnani HN, Stiekema JC. Pharmacokinetic considerations of Orgaran (Org 10172) therapy. Haemostasis 1992; 22: 73-84.
  • 66 Ortel TL, Chong BH. New treatment options for heparin-induced thrombocytopenia. Seminars in Hematology 1998; 35: 26-34.
  • 67 Magnani HN. Orgaran (danaparoid-sodium) use in the syndrome of heparin-induced thrombocytopenia. Proceedings of a workshop held in London, 1996 Nov 1. Platelets 1997; 8: 74-81.
  • 68 Newman PM, Swanson RL, Chong BH. Heparin-induced thrombocytopenia: IgG binding to PF4-heparin complexes in the fluid phase and cross-reactivity with low molecular weight heparin and heparinoid. Thromb Haemost 1998; 80: 292-7.
  • 69 Warkentin TE. Danaparoid (Orgaran®) for the treatment of heparin-indu-ced thrombocytopenia (HIT) and thrombosis: effects on in vivo thrombin and cross-linked fibrin generation, and evaluation of the clinical significance of in vitro cross-reactivity (XR) of danaparoid for HIT-IgG (abstract). Blood. 1996 88. (Suppl 1) 626a.
  • 70 Markwardt DF. Hirudin: the promising antithrombotic. Cardiovasculary Drug Review 1992; 10: 211-32.
  • 71 Parent F, Bridey F, Dreyfus M, Musset D, Grimon G, Duroux P, Meyer D, Simonneau G. Treatment of severe thromboembolism with intravenous hirudin (HBW 023): a open pilot study. Thromb Haemost 1993; 70: 386-8.
  • 72 Stringer KA, Lindenfield J. Hirudins: antithrombin anticoagulants. Annuals Pharmacotherapy 1992; 26: 1535-40.
  • 73 Weitz JI, Huboda M, Massel D, Marganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III butis susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
  • 74 Weitz JI, Leslie B, Hudoba M. thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation 1998; 97: 544-52.
  • 75 Meyer BJ, Badimon JJ, Chesebro JH, Fallon JT, Fuster V, Badimon L. Dissolution of mural thrombus by specific thrombin inhibition with r-hirudin: comparison with heparin and aspirin. Circulation 1998; 97: 681-5.
  • 76 Greinacher A, Volpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P, Mueller-Velten HG, Potzsch B. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with the immunologic type of heparin-induced thrombocytopenia: A prospective study. Circulation 1999; 99: 73-80.
  • 77 Neuhaus KL, von Essen R, Tebbe U, Jessel A, Heinrichs H, Maurer W, Doring W, Harmjanz D, Kotter V, Kalhammer E, Simon H, Horacek T. Safety observation form the pilot phase of the randomized r-hirudin for improvement of thrombolysis (HIT III) study: a study of the Arbeitsge-meinschaft Leitender kardiologischer Krankenhausartze (ALKK). Circulation 1994; 90: 1638-42.
  • 78 Rupprecht HJ, Terres W, Ozbek C, Luz M, Jessel A, Hafner G, vom Dahl J, Kromer EP, Prellwitz W, Meyer J. Recombinant hirudin (HBW 023) prevents troponin release after coronary angioplasty in patients with unstable angina. Journal of American Coll Cardiology 1995; 26: 1637-42.
  • 79 Schiele F, Lindgaerde F, Eriksson H, Bassand J-P, Wallmark A, Hansson P-O, Grollier G, Sjo M, Moia M, Camez A, Smyth V, Walker M. for the International Multicentre Hirudin Study Group Subcutaneous recombinant hirudin (HBW 023) versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: a multicentre prospective dose-ranging randomized trial. Thromb Haemost 1997; 77: 834-8.
  • 80 Eriksson BI, Wille-Jorgensen P, Kalebo P, Mouret P, Rosencher N, Bosch P, Baur M, Ekman S, Bach D, Lindbratt S, Close P. A comparison of recombinant hirudin with a low-molecular weight heparin to prevent thromboembolic complications after total hip replacement. New Engl J Med 1997; 337: 1329-35.
  • 81 Vanholder R, Camez A, Veys N, Soria J, Mirshahi MC, Soria C, Ringoir S. Recombinant hirudin. A specific thrombin-inhibiting anticoagulant for haemodialysis. Kidney International 1994; 45: 1754-9.
  • 82 Novak G, Buch E, Brauns I, Czerwinski R. Anticoagulation with r-hirudin in regular haemodialysis with heparin-induced thrombocytopenia (HIT II). The first long term application of r-hirudin in a haemodialysis patient. Wiener Klinische Wochenschrift 1997; 109: 354-8.
  • 83 Schiele F, Vuillemenot A, Kramarz P. et al. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. Am J Hematol 1995; 50: 20-5.
  • 84 Greinacher A, Janssens U, Berg G, Bock M, Kwasny H, Kemkes-Matthes B, Eichler P, Volpel H, Potzsch B, Luz M. Lepirudin (Recombinant Hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 1999; 100: 587-93.
  • 85 Eichler P, Olbrich K, Potzsch B, Greinacher A. Anti-hirudin antibodies in patients treated with recombinant hirudin for more than five days, a prospective study (abstract). Thromb Haemost. 1997 (Supplement) PS 2014.
  • 86 Lewis BE, Johnson SA, Grassman ED, Wrona LL. Argatroban as an anticoagulant for coronary procedures in patients with HIT antibody. In: Pifarre R. ed. New anticoagulants for the cardiovascular patient. Philadelphia: Hanley & Belfus Inc; 1997. a pp. 301-8.
  • 87 Lewis BE, Walenga JM, Pifarre R, Fareed J. Argatroban in the management of patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome. In: Pifarre R. ed. New anticoagulants for the cardiovascular patient. Philadelphia: Hanley & Belfus Inc; 1997. b pp. 223-9.
  • 88 Demers C, Ginsberg JS, Brill-Edwars P. et al. Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia. Blood 1991; 78: 2194-7.
  • 89 Warkentin TE. Limitations of conventional treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (Suppl.4) 17-25.
  • 90 Warkentin TE, Elavathil LJ, Hayward CPM. et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Annals Internal Medicine 1997; 127: 804-12.
  • 91 Gupta AK, Kovacs MJ, Sauder DN. Heparin-induced thrombocytopenia. Ann Pharmacother 1998; 32: 55-9.
  • 92 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992; 67: 545-9.
  • 93 Fiessinger JN, Aiach M, Roncato M. et al. Critical ischemia during heparin-induced thrombocytopenia. Treatment by intra-arterial streptokinase. Thromb Res. 1984 33. 235.
  • 94 Cohen JI, Cooper MR, Greenberg CS. Streptokinase therapy of pulmonary emboli with heparin-associated thrombocytopenia. Archive Internal Medicine 1985; 145: 1725-6.
  • 95 Olbrich K, Wiersbitzky M, Wacke W, Eichler P, Zinke H, Schwock M, Mox B, Kraatz G, Motz W, Greinacher A. Atypical heparin-induced thrombocytopenia complicated by intracardiac thrombus, effectively treated with ultra-low-dose rt-PA lysis and recombinant hirudin (Lepirudin). Blood Coagulation and Fibrinolysis 1998; 9: 273-7.
  • 96 Bouvier JL, Lefebre P, Villain P. et al. Treatment of serious heparin-induced thrombocytopenia by plasma exchange: report on 4 cases. Thromb Res 1988; 51: 335-6.
  • 97 Frame JN, Mulvey KP, Phares JC. et al. Correction of severe heparin-associated thrombocytopenia with intravenous imunoglobulin. Annals Internal Medicine 1989; 111: 946-7.
  • 98 Nurden AT, Laroche-Traineau J, Jallu V. et al. Heparin-induced thrombocytopenia: observations on the nature of the antibody activities and on the use of gammaglobulin concentrates in a patient with thrombotic complications (abstract). Thromb Haemost. 1991 65. 796.
  • 99 Gruel Y, Lermusiaux P, Lang M, Darnige L, Rupin A, Delahousse B. et al. Usefulness of antiplatelet drugs in the management of heparin-associated thrombocytopenia and thrombosis. Ann Vasvc Surg 1991; 5: 552-5.
  • 100 Almeida JI, Coats R, Liem TK, Silver D. Reduced morbidity and mortality rates of the heparin-induced thrombocytopenia syndrome. J Vsc Surg 1998; 27: 309-16.
  • 101 Pedicord DL, Thomas BE, Mousa SA, Dicker IB. Glycoprotein IIb/IIIa receptor antagonists inhibit the development of platelet procoagulant activity. Thromb Res 1998; 90: 247-58.
  • 102 Keularts IMLW, Beguin S, de Zwaan C, Hemker HC. Treatment with a GPIIb/III antagonist inhibits thrombin generation in platelet rich plasma from patients. Thromb Haemost 1998; 80: 370-1.
  • 103 Herault JP, Lale 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 Coagulation and Fibrinolysis 1997; 8: 206-7.
  • 104 Herault JP, Peyrou V, Savi P, Bernat A, Herbert JM. Effect of SR 121566A, a potent GP IIb-IIIa antagonist on platelet-mediated thrombin generation in vitro and in vivo. Thromb Haemost 1998; 79: 383-8.
  • 105 Herbert JM, Savi P, Jeske WP, Walenga JM. Effect of SR 121566A, a potent GP IIb-IIIa antagonist, on the HIT serum/ heparin-induced platelet mediated activation of human endothelial cells. Thromb Haemost 1998; 80: 326-31.
  • 106 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 Haemost 1998; 80: 989-93.
  • 107 Tsao PW, Forsythe MS, Mousa SA. Dissociation between the antiaggregatory and anti-secretory effects of platelet integrin αIIbβ2 (GPIIb/IIIa) antagonists, c7E3 and DMP728. Thromb Res 1997; 89 (2) 137-46.
  • 108 Contreras M. The appropriate use of platelets: an update from the Edinburgh Consensus Conference. Br J Haematol 1998; 101 (Suppl. 1) 10-2.