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Hamostaseologie 1999; 19(01): 1-12
DOI: 10.1055/s-0038-1660372
Übersichtsarbeiten/Review Articles
Schattauer GmbH

Heparin-induzierte Thrombozytopenie – Pathogenese und Behandlung

A. Greinacher
1   Institut für Immunologie und Transfusionsmedizin, Ernst-Moritz-Arndt-Universität Greifswald
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Publication History

Publication Date:
27 June 2018 (online)

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Zusammenfassung

Heparin bindet aufgrund seiner negativen Ladung an Thrombozytenproteine. Hierdurch werden Thrombozyten leicht aktiviert. Dies kann bei Krankheiten, bei denen per se die Thrombozyten aktiviert sind, z.B. periphere arterielle Verschlußkrankheiten, zum Abfall der Thrombozyten führen. Diese nicht-immunologischen Wechselwirkungen von Heparin und Thrombozyten sind klinisch von untergeordneter Bedeutung. Viel wichtiger, da in einigen Fällen mit lebensbedrohlichen neuen thromboembolischen Komplikationen verbunden, ist die immunologische Heparin-induzierte Thrombozytopenie (HIT). Betroffene Patienten bilden Antikörper, die an Komplexe aus Thrombozytenproteinen und Heparin binden. Diese Immunkomplexe aktivieren Thrombozyten und Endothelzellen. Dies führt zu einer massiven Verstärkung der Thrombinbildung mit der Konsequenz der Gerinnungsaktivierung. Daher müssen betroffene Patienten weiter antikoaguliert werden. Hierfür stehen vor allem zwei Medikamente zur Verfügung: Rekombinantes Hirudin (Lepirudin, Refludan®) und Danaparoid-Natrium (Orgaran®). Hirudin ist ein direkter Thrombininhibitor, Danaparoid-Natrium zeigt vor allem Anti-Faktor-Xa-Aktivität. Die wichtigsten Therapieoptionen bei ङ IT-Patienten werden in dem Artikel diskutiert.

Schlüsselwörter

Heparin - Heparin-induzierte Thrombozytopenie - Hirudin - Thrombozyten - Danapa-roid-Natrium - Therapie
 

  • Literatur

  • 1 Chong BH, Fawaz I, Chesterman CN, Berndt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. British Journal of Haematology 1989; 73: 235-40.
    CrossrefPubMedGoogle Scholar
  • 2 Chong BH, Ismail F. The mechanism of heparin-induced platelet aggregation. European Journal of Haematology 1989; 43: 245-51.
    PubMedGoogle Scholar
  • 3 Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: Towards Consensus. Thromb Haemost 1998; 79: 1-7.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Hörne 3rd MDK. The effect of secreted heparin-binding proteins on heparin binding to platelets. Thrombosis Research 1993; 70: 91-8.
    CrossrefPubMedGoogle Scholar
  • 5 Greinacher A, Michels I, Liebenhoff U, Presek P, Mueller-Eckhardt C. Heparin-as-sociated thrombocytopenia: immune complexes are attached to the platelet membrane by the negative charge of highly sulfated oligosaccharides. British Journal of Haematology 1993; 84: 711-6.
    CrossrefPubMedGoogle Scholar
  • 6 Home 3rd MDK, Hutchinson KJ. Simultaneous binding of heparin and platelet factor-4 to platelets: further insights into the mechanism of heparin-induced thrombocytopenia. American Journal of Hematology 1998; 85: 24-30.
    PubMedGoogle Scholar
  • 7 Salzman EW, Rosenberg RD, Smith MH, Lindon JN. Effect of heparin and heparin fractions on platelet aggregation. Journal of Clinical Investigation 1980; 65: 64-73.
    CrossrefPubMedGoogle Scholar
  • 8 Brace LD, Fareed J. Heparin-induced platelet aggregation. II. Dose/response relationships for two low molecular weight heparin fractions (CY 216 and CY 222). Thrombosis Research 1990; 59: 1-14.
    CrossrefPubMedGoogle Scholar
  • 9 Mikhailidis DP, Barradas MA, Jeremy JY. et al. Heparin-induced platelet aggregation in anorexia nervosa and in severe peripheral vascular disease. European Journal of Clinical Investigation 1985; 15: 313-9.
    CrossrefPubMedGoogle Scholar
  • 10 Burgess JK, Chong BH. The platelet proag-gregating and potentiating effects of unfractionated heparin, low molecular weight heparin and heparinoid in intensive care patients and healthy controls. European Journal of Haematology 1997; 58: 279-85.
    PubMedGoogle Scholar
  • 11 Reininger CB, Greinacher A, Graf J. et al. Platelets of patients with peripheral arterial disease are hypersensitive to heparin. Thrombosis Research 1996; 81: 641-9.
    CrossrefPubMedGoogle Scholar
  • 12 Warkentin TE, Levine MN, Hirsh J. et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. New England Journal of Medicine 1995; 332: 1330-5.
    CrossrefPubMedGoogle Scholar
  • 13 Greinacher A. Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Seminars Thrombosis and Haemostasis 1995; 21: 106-16.
    PubMedGoogle Scholar
  • 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). Thrombosis and Haemostasis 1992; 68: 95-6.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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. Thrombosis and Haemostasis 1995; 73: 21-8.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 16 Greinacher A, Pötzsch B, Amiral J. et al. Heparin-associated thrombocytopenia. Isolation of the antibody and characterization of a multimolecular PF4-heparin complex as the major antigen. Thrombosis and Hemostasis 1994; 71: 247-51.
    PubMedGoogle Scholar
  • 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. Journal of Clinical Investigation 1994; 93: 81-8.
    CrossrefPubMedGoogle Scholar
  • 18 Horsewood P, Warkentin TE, Hayward CP, Kelton JG. The epitope specificity of heparin-induced thrombocytopenia. British Journal of Haematology 1996; 95: 161-7.
    CrossrefPubMedGoogle Scholar
  • 19 Suh JS, Aster RH, Visentin GP. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis recognize different epitopes on heparimplatelet factor 4. Blood 1998; 91: 916-22.
    CrossrefPubMedGoogle Scholar
  • 20 Home 3rd MDK, Alkins BRSO. Platelet binding of IgG from patients with heparin-induced thrombocytopenia. Journal of Laboratory and Clinical Medicine 1996; 127: 435-42.
    CrossrefPubMedGoogle Scholar
  • 21 Fondu P. Heparin-associated thrombocytopenia: an update. Acta Clin Belg 1995; 50: 343-57.
    CrossrefPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Turpie AGG. New therapeutic opportunities for heparins: What does low molecular weight heparin offer?. Journal of Thrombosis and Thrombolysis 1996; 3: 145-9.
    PubMedGoogle Scholar
  • 25 Suzuki S, Koide ML, Sakamoto S, Yamamoto S, Matsuo M, Fujil E, Matsuo T. Early onset of immunological heparin-induced thrombocytopenia in acute myocardial infarction. Blood Coagulation and Fibrinolysis 1997; 8: 13-5.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 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: Marcel Dekker Inc; 1994: 75-127.
    Google Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 29 Kelton JG, Sheridan D, Santos A. et al. Heparin-induced thrombocytopenia. Blood 1988; 72: 925-30.
    PubMedGoogle Scholar
  • 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: 641-45.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 31 Chong BH, Murray B, Berndt MC. et al. Plasma P-selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83: 1535-41.
    PubMedGoogle Scholar
  • 32 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. New England Journal of Medicine 1987; 316: 581-9.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 34 Visentin GP, Malik M, Cyganiak KA, Aster RH. Patients treated with unfraction-ated 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 36 Kappers-Klunne MC, Boon DMIS, Hop WCJ. et al. Heparin-indliced thrombocytopenia and thrombosis: a prospective analysis of the incidence in patients with heart and cerebrovascular diseases. British Journal of Haematology 1997; 96: 442-6.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 38 Sun JS, Mohammad IM, Aster RH, Visentin GP. Characterization of the humoral immune response in heparin-induced thrombocytopenia. American Journal of Hematology 1997; 54: 196-201.
    CrossrefPubMedGoogle Scholar
  • 39 Clark MR, Clarkson SB, Ory PA, Stollman N, Goldstein IM. Molecular basis for a polymorphism involving Fc receptor II on human monocytes. Journal of Immunology 1989; 143: 1731.
    PubMedGoogle Scholar
  • 40 Warmerdam PAM, van de Winkel JGJ, Gosselin EJ, Capel PJA. Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). Journal of Experimental Medicine 1990; 172: 19.
    CrossrefPubMedGoogle Scholar
  • 41 Burgess JK, Lindeman R, Chesterman CN, Chong BH. Single amino acid mutation of Fc7 receptor is associated with the development of heparin-induced thrombocytopenia. British Journal of Haematology 1995; 91: 761-6.
    CrossrefPubMedGoogle Scholar
  • 42 Bachelot-Loza C, Saffroy R, Lasne D. et al. Role of Fc7RIIa-Arg/His-131 polymorphism in HIT diagnosis. Thromb Haemost 1997; Supplement: P2305.
    PubMedGoogle Scholar
  • 43 Dénomme GA, Warkentin TE, Horsewood P. et al. Activation of platelets by sera containing IgGl heparin-dependent antibodies: An explanation for the predominance of the Fc7RIIa »low responder« (his131) gene in patients with heparin-induced thrombocytopenia. Journal of Laboratory Clinical Medicine 1997; 130: 278-84.
    CrossrefPubMedGoogle Scholar
  • 44 Arepally G, McKenzie SE, Jiang XM. et al. FeyRIlA 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.
    PubMedGoogle Scholar
  • 45 Brandt JT, Isenhart CE, Osborne JM. et al. On the role of platelet Fc^RIIa phenotype in heparin-induced thrombocytopenia. Thrombosis and Haemostasis 1995; 74: 1564-72.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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 FcyRIIa-R-H131 polymorphism. Blood 1998; 92: 1526-31.
    CrossrefPubMedGoogle Scholar
  • 47 Vandenbroucke JP, Köster 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 49 Bokarewa MI, Bremme K, Blombäck M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. British Journal of Haematology 1996; 92: 473-8.
    CrossrefPubMedGoogle Scholar
  • 50 Gardyn J, Sorkyn P, Kluger Y. et al. Heparin-induced thrombocytopenia and fatal thrombosis in a patient with activated protein C resistance. American Journal of Hematology 1995; 50: 292-5.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 52 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.
    CrossrefPubMedGoogle Scholar
  • 53 Ganzer D, Gutezeit A, Mayer G, Greinacher A, Eichler P. Thromboemboliepro-phylaxe als Auslöser thromboembolischer Komplikationen: Eine Untersuchung zur Inzidenz Heparin-induzierten Thrombozytopenie (HIT) Typ II. Zeitschrift für Orthopädie 1997; 135: 543-9.
    PubMedGoogle Scholar
  • 54 Hach-Wunderle V, Kainer K, Salzmann G, Müller-Berghaus G. Heparin-related thrombosis despite normal platelet counts in vascular surgery. American Journal of Surgery 1997; 173: 117-9.
    CrossrefPubMedGoogle Scholar
  • 55 Warkentin TE, Kelton JG. A 14-years study of heparin-induced thrombocytopenia. American Journal of Medicine 1996; 101: 502-7.
    CrossrefPubMedGoogle Scholar
  • 56 Warkentin TE. Heparin-induced skin lesions. British Journal of Haematology 1996; 92: 494-7.
    CrossrefPubMedGoogle Scholar
  • 57 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 58 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30.
    PubMedGoogle Scholar
  • 59 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992; 67: 545-9.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 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.
    PubMedGoogle Scholar
  • 62 Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554-61.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 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.
    CrossrefPubMedGoogle Scholar
  • 64 Skoutakis VA. Danaparoid in the prevention of thromboembolic complications. Ann Pharmacother 1997; 31: 876-87.
    CrossrefPubMedGoogle Scholar
  • 65 deValk HW, Banga JD, Wester JWJ. et al. Comparing subcutaneous danaparoid with intravenous unfractionated heparin for the treatment of venous thromboembolism. A randomized controlled trial. Ann Intern Med 1995; 123: 1-9.
    CrossrefPubMedGoogle Scholar
  • 66 Henny CP, ten Cate R, Surachno S. et al. The effectiveness of a low molecular weight heparinoid in chronic intermittent haemo-dialysis. Thromb Haemost 1985; 54: 460-2.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 67 Ireland H, Lane DA, Flynn A. et al. The anticoagulant effect of heparinoid Org 10172 during haemodialysis: an objective assessment. Thromb Haemost 1986; 55: 271-5.
    PubMedGoogle Scholar
  • 68 Von Bonsdorff M, Stiekema J, Harjanne A, Alapiessa U. A new low molecular weight heparinoid Org 10172 as anticoagulant in hemodialysis. Int J Artif Organs 1990; 13: 103-8.
    CrossrefPubMedGoogle Scholar
  • 69 Ortel TL, Chong BH. New treatment options for heparin-induced thrombocytopenia. Seminars in Hematology 1998; 35: 26-34.
    PubMedGoogle Scholar
  • 70 Magnani HN. Orgaran (danaparoid-sodi-um) use in the syndrome of heparin-induced thrombocytopenia. Proceedings of a workshop held in London, 1996 Nov 1. Platelets 1997; 8: 74-81.
    PubMedGoogle Scholar
  • 71 Magnani HN, Rieckhof B. Heparin-indu-zierte Thrombozytopenie: Tatsächliche Ergebnisse im Vergleich zu theoretischen Überlegungen einer Therapie mit Orgaran®. In: Haas S, Rieckhof B (Ed). Schwerpunktthema: Gegenwärtiger Stand der Diagnose und Therapie der Heparin-induzierten Thrombozytopenie (HIT). Journal für Anästhesie und Intensivbehandlung 1998; 4: 23-8.
    PubMedGoogle Scholar
  • 72 Magnani HN, Beijering RJR, ten Cate JW. et al. Orgaran anticoagulation for cardiopulmonary bypass in patient with heparin-induced thrombocytopenia. In: Pifarre R. (Ed) New anticoagulation for cardiovascular patient. Philadelphia, PA: Hanley & Belfus; 1997: 487-500.
    Google Scholar
  • 73 Danhof M, de Boer A, Magnani HN, Stiekema JC. Pharmacokinetic considerations of Orgaran (Org 10172) therapy. Haemostasis 1992; 22: 73-84.
    PubMedGoogle Scholar
  • 74 Markwardt DF. Hirudin, the promising antithrombotic. Cardiovasculary Drug Review 1992; 10: 211-32.
    PubMedGoogle Scholar
  • 75 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 76 Stringer KA, Lindenfield J. Hirudins, anti-thrombin anticoagulants. Annuals Pharmacotherapy 1992; 26: 1535-40.
    PubMedGoogle Scholar
  • 77 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 Ill-independent inhibitors. Journal of Clinical Investigation 1990; 86: 385-91.
    CrossrefPubMedGoogle Scholar
  • 78 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.
    CrossrefPubMedGoogle Scholar
  • 79 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.
    CrossrefPubMedGoogle Scholar
  • 80 Greinacher A, Völpel H, Janssens U, Hach-Wunderle V, Kemkes-Matthes B, Eichler P, Mueller-Velten HG, Pötzsch B. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with the immunologic type of heparin-induced thrombocytopenia: A prospective study. Circulation. 1998 in press.
    PubMedGoogle Scholar
  • 81 Neuhaus KL, von Essen R, Tebbe U, Jessel A, Heinrichs H, Maurer W, Döring W, Harmjanz D, Kötter V, Kaihammer E, Simon H, Horacek T. Safety observation from the pilot phase of the randomized r-hirudin for improvement of thrombolysis (HIT III) study: a study of the Arbeitsgemeinschaft Leitender kardiologischer Krankenhausärtze (ALKK). Circulation 1994; 90: 1638-42.
    CrossrefPubMedGoogle Scholar
  • 82 Rupprecht HJ, Terres W, Özbek 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.
    PubMedGoogle Scholar
  • 83 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.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 84 Eriksson BI, Wille-Jörgensen P, Kälebo 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. The New England Journal of Medicine 1997; 337: 1329-35.
    CrossrefPubMedGoogle Scholar
  • 85 Vanholder R, Camez A, Veys N, Soria J, Mirshahi MC, Soria C, Ringoir S. Recombinant hirudin. A specific thrombin-inhibit-ing anticoagulant for haemodialysis. Kidney International 1994; 45: 1754-9.
    CrossrefPubMedGoogle Scholar
  • 86 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.
    PubMedGoogle Scholar
  • 87 Schiele F, Vuillemenot A, Kramarz P. et al. Use of recombinant hirudin as antithrombotic treatment in patients with heparin-induced thrombocytopenia. American Journal of Hematology 1995; 50: 20-5.
    CrossrefPubMedGoogle Scholar
  • 88 Greinacher A, Luz M, Janssens U, Berg G, Böck M, Kwasny H, Kemkes-Matthes B, Eichler P, Völpel H, Pötzsch B. Lepirudin (Recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation. 1998 submitted.
    PubMedGoogle Scholar
  • 89 Greinacher A. Lepirudin for the treatment of heparin-induced thrombocytopenia: a prospective study. Blood 1998; 92: #1490 [abstract].
    PubMedGoogle Scholar
  • 90 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 (abstract). Thromb Haemost 1997; Supplement: PS2014.
    PubMedGoogle Scholar
  • 91 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.
    CrossrefPubMedGoogle Scholar
  • 92 Lewis BE, Walenga JM, Pifarré R, Fareed J. Argatroban in the management of patients with heparin-induced thrombocytopenia and heparin-induced thrombocytopenia and thrombosis syndrome. In: Pifarré R. (ed) New anticoagulants for the cardiovascular patient. Philadelphia: Hanley & Belfus Inc; 1997: 223-9.
    Google Scholar
  • 93 Lewis BE, Johnson SA, Grassman ED, Wrona LL. Argatroban as an anticoagulant for coronary procedures in patients with HIT antibody. In: Pifarré R. (ed) New anticoagulants for the cardiovascular patient. Philadelphia: Hanley & Belfus Inc; 1997: 301-8.
    Google Scholar
  • 94 Bell Jr WR. Defibrinogenating enzymes. Drugs 1997; 54 (Suppl. 03) 18-31.
    CrossrefPubMedGoogle Scholar
  • 95 Demers C, Ginsberg JS, Brill-Edwars P. et al. Rapid anticoagulation using ancrod for heparin-induced thrombocytopenia. Blood 1991; 78: 2194-7.
    PubMedGoogle Scholar
  • 96 Warkentin TE. Limitations of conventional treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (Suppl. 04) 17-25.
    PubMedGoogle Scholar
  • 97 Warkentin TE. Heparin-induced thrombocytopenia. Pathogenesis, frequency, avoidance and management. Drug safety 1997; 17: 325-41.
    CrossrefPubMedGoogle Scholar
  • 98 Gupta AK, Kovacs MJ, Sauder DN. Heparin-induced thrombocytopenia. Ann Phar-macother 1998; 32: 55-9.
    CrossrefPubMedGoogle Scholar
  • 99 Fiessinger JN, Aiach M, Roncato M. et al. Critical ischemia during heparin-induced thrombocytopenia. Treatment by intra-ar-terial streptokinase. Thrombosis Research 1984; 33: 235.
    CrossrefPubMedGoogle Scholar
  • 100 Cohen JI, Cooper MR, Greenberg CS. Streptokinase therapy of pulmonary emboli with heparin-associated thrombocytopenia. Archive Internal Medicine 1985; 145: 1725-6.
    PubMedGoogle Scholar
  • 101 Olbrich K, Wiersbitzky M, Wacke W, Eichler P, Zinke H, Schwock M, Möx 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.
    CrossrefPubMedGoogle Scholar
  • 102 Bouvier JL, Lefebre P, Villain P. et al. Treatment of serious heparin-induced thrombocytopenia by plasma exchange: report on 4 cases. Thrombosis Research 1988; 51: 335-6.
    CrossrefPubMedGoogle Scholar
  • 103 Frame JN, Mulvey KP, Phares JC. et al. Correction of severe heparin-associated thrombocytopenia with intravenous i muno-globulin. Annals Internal Medicine 1989; 111: 946-7.
    CrossrefPubMedGoogle Scholar
  • 104 Nurden AT, Larochc-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.
    PubMedGoogle Scholar
  • 105 Addonizio VP, Fisher CA, Kappa JR. et al. Prevention of heparin-induced thrombocytopenia during open heart surgery with iloprost (ZK36374). Surgery 1987; 102: 796-807.
    PubMedGoogle Scholar
  • 106 Kappa JR, Fisher CA, Todd B. et al. Intraoperative management of patients with heparin-induced thrombocytopenia. Ann Thorac Surg 1990; 49: 714-23.
    CrossrefPubMedGoogle Scholar
  • 107 DiSesa VJ, Huval W, Lclcuk S. et al. Disadvantages of prostacyclin infusion during cardiopulmonary bypass: A double-blind study of 50 patients having coronary revascularization. Ann Thorac Surg 1984; 38: 514-9.
    CrossrefPubMedGoogle Scholar
  • 108 Contreras M. The appropriate use of platelets: an update from the Edinburgh Consensus Conference. Br J Haematol 1998; 101: 10-2.
    CrossrefPubMedGoogle Scholar