Download PDF
Hamostaseologie 1996; 16(01): 41-49
DOI: 10.1055/s-0038-1656637
Übersichtsarbeiten/Review Articles
Schattauer GmbH

Heparinoide als eine Alternative für die parenterale Antikoagulation bei Patienten mit Heparin-induzierter Thrombozytopenie

A. Greinacher
1   Abteilung Transfusionsmedizin, Institut für Immunologie und Transfusions-medizin (Direktorin: Prof. Dr. C. Schütt), Ernst-Moritz-Arndt-Universität Greifswald (Leiter: Prof. Dr. A. Greinacher)
,
S. Alban
2   Institut für Pharmazie, Universität Regensburg (Leiter: Prof. Dr. G. Franz)
› Author Affiliations
Further Information

Publication History

Publication Date:
26 June 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Die Heparin-induzierte Thrombozytopenie (HIT Typ II) ist eine lebensbedrohliche Komplikation der Heparintherapie. Da betroffene Patienten durch diese immunologische, unerwünschte Wirkung der Heparingabe gefährdet sind, neue throm-boembolische Gefäßverschlüsse zu entwickeln, ist bei hinreichendem klinischen Verdacht die sofortige Umstellung auf ein kompatibles Antikoagulans notwendig. Hierfür kommen, neben rekombinantem Hirudin, verschiedene Heparinoide in Betracht. Die Pathophysiologie der HIT Typ II sowie die Struktur und die anti-koagulatorischen Eigenschaften verschiedener Heparinoide werden dargestellt. Der letzte Teil des Artikels faßt den gegenwärtigen Stand der Dosierungsempfehlungen für das Heparinoid Danaparoid (Orgaran®, NV Organon, Niederlande) bei HIT-Typ-Il-Patienten zusammen.

Schlüsselwörter

Heparin - Heparin-induzierte Thrombozytopenie - Thrombozyten - Danaparoid-Natrium - Heparinoide - Heparansulfat - Chondroitinsulfat - Therapie - Antikoagulanzien
 

  • LITERATUR

  • 1 AbuRahma AF, Boland JP, Witsberger T. Diagnostic and therapeutic strategies of white clot syndrome. Am J Surg 1991; 162: 175-9
    CrossrefPubMedGoogle Scholar
  • 2 Amiral J, Bridey F, Dreyfus M. et al. Platelet factor 4 complexed to heparin is the target for antibodies generated in heparin-induced thrombocytopenia. Thromb Haemost 1992; 68: 95-6
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Anderson GP. Insights into heparin-induced thrombocytopenia. Br J Haematol 1992; 80: 504-8
    CrossrefPubMedGoogle Scholar
  • 4 Banga JD, de Valk HW, Wester JWJ. et al. A dose-finding study of subcutaneous hepari-noid Orgaran (Org 10172) twice daily compared to continuous intravenous un-fractionated heparin in the treatment of venous thromboembolism. Thromb Haemost (Abstracts of XlVth ISTH congress NY) 1993; 69 (Abstr. 20) 545
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Barbanti M, Calani F, Milani MR. et al. Therapeutic effect of low molecular weight dermatan sulfate (Desmin 370) in rat venous thrombosis - evidence for an anticoagulant-independent mechanism. Thromb Haemost 1993; 69: 147-51
    Article in Thieme ConnectPubMedGoogle Scholar
  • 6 Barbanti M, Guizzardi S, Calanni F. et al. Antithrombotic and thrombolytic activity of sulodexide in rats. Int J Clin Lab Res 1992; 22: 179-84
    CrossrefPubMedGoogle Scholar
  • 7 Bergqvist D, Lindblad B, Mätzsch T. Glyc-osaminoglycans in prophylaxis against venous thromboembolism. In:. Lane DA, Björk I, Lindahl U. (eds) Heparin and Related Polysaccharides. New York: Plenum Press; 1992: 259-74
    Google Scholar
  • 8 van Besien K, Hoffman R, Golichowski A. Pregnancy associated with lupus anticoagulant and heparin induced thrombocytopenia: management with a low molecular weight heparinoid. Thromb Res 1991; 62: 23-9
    CrossrefPubMedGoogle Scholar
  • 9 Bianchini P, Osima B, Parma B. et al. Lack of correlation between 'in vitro' and 'in vivo' antithrombotic activity of heparin fractions and related compounds. Heparan sulfate as an antithrombotic agent 'in vivo'. Thromb Res 1995; 39: 21-8
    PubMedGoogle Scholar
  • 10 Bleasel JF, Rasko JEJ, Richard KA, Richard G. Acute adrenal insufficiency secondary to heparin-induced thrombocytopenia thrombosis syndrome. Med J Aust 1992; 157: 192-3
    PubMedGoogle Scholar
  • 11 van Boeckel CAA, Petitou M. The unique antithrombin III binding domain of heparin: a lead to new synthetic antithrombotics. An-gew Chem Int Ed Engl 1993; 32: 1671-90
    CrossrefPubMedGoogle Scholar
  • 12 Buchanan MR, Liao P, Smith LJ, Ofosu FA. Prevention of thrombus formation and growth by antithrombin III and heparin cofactor II-dependent thrombin inhibitors: importance of heparin cofactor II. Thromb Res 1994; 74: 463-75
    CrossrefPubMedGoogle Scholar
  • 13 Callas DD, Hoppensteadt DA, Jeske W. et al. Comparative pharmacological profile of a glycosaminoglycan mixture, Sulodexide®, and a chemically modified heparin derivative, Suleparoide®. Semin Thromb Hemost 1993; 19 (Suppl. 01) 49-57
    PubMedGoogle Scholar
  • 14 Cannell PK, Herrmann RP, Marshall L. Heparinoid during cardiopulmonary bypass. Aust NZ J Med 1991; 21 (Suppl. 01) 141
    PubMedGoogle Scholar
  • 15 Chong BH, Berndt MC. Heparin-induced thrombocytopenia. Blut 1989; 58: 53-7
    CrossrefPubMedGoogle Scholar
  • 16 Chong BH, Fawaz I, Chesterman CN, Berndt MC. Heparin-induced thrombocytopenia: mechanism of interaction of the hepa-rin-dependent antibody with platelets. Br J Haematol 1989; 73: 235-40
    CrossrefPubMedGoogle Scholar
  • 17 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
  • 18 Chong BH, Magnani HN. Orgaran in heparin-induced thrombocytopenia. Haemostasis 1992; 22: 85-91
    PubMedGoogle Scholar
  • 19 Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-asso-ciated thrombocytopenia. N Engl J Med 1987; 316: 581-9
    CrossrefPubMedGoogle Scholar
  • 20 Condorelli M, Chiariello M, Dagianti A. et al. IPO-V2: a prospective, multicenter, randomized, comparative clinical investigation of the effects of sulodexide in preventing cardiovasular accidents in the first year after acute myocardial infarction. J Am Coll Cardiol 1994; 23: 27-34
    CrossrefPubMedGoogle Scholar
  • 21 Danhof M, de Boer A, Magnani HN, Stieke-ma JC. Pharmacokinetic considerations of Orgaran (Orgl0172) therapy. Haemostasis 1992; 22: 73-84
    PubMedGoogle Scholar
  • 22 Dawes J. Measurement of the affinities of heparins, naturally occuring GAGs, and other sulfated polymers for antithrombin III and thrombin. Anal Biochem 1988; 174: 177-86
    CrossrefPubMedGoogle Scholar
  • 23 Doherty DC, Ortel TL, De Bruijn N. et al. »Heparin-free« cardiopulmonary bypass: first reported use of heparinoid (Org 10172) to provide anticoagulation for cardiopulmonary bypass. Anesthesiology 1990; 73: 562-5
    CrossrefPubMedGoogle Scholar
  • 24 Dol F, Petitou M, Lormeau JC. et al. Pharmacologic properties of a low molecular weight dermatan sulfate (4kDa): comparison with unfractionated dermatan sulfate (25kDa). J Lab Clin Med 1990; 115: 43-51
    PubMedGoogle Scholar
  • 25 Fareed J, Hoppensteadt D, Jeske W, Walenga JM. An overview of non-heparin glycos-aminoglycans as antithrombotic agents. In: . Poller L. (ed) Recent Advances in Blood Coagulation. London: Churchill Livingstone; 1993: 169-87
    Google Scholar
  • 26 Fischer AM, Dautzenberg MD, Aurousseau MH. et al. Comparison between the effect of pentosan polysulphate, heparin and antithrombin III injections in antithrombin III. Thromb Res 1985; 37: 295-307
    CrossrefPubMedGoogle Scholar
  • 27 Goad HE, Home MK , Gralnick HR. Pentosan-induced thrombocytopenia: support for an immune complex mechanism. Br J Haematol 1994; 88: 803-8
    CrossrefPubMedGoogle Scholar
  • 28 Gordon DL, Libhardt R, Adams HP. Low molecular weight heparins and heparinoids and their use in acute or progressing ischemic stroke. Clin Neuropharmacol 1990; 13: 522-43
    CrossrefPubMedGoogle Scholar
  • 29 Greinacher A. The nonimmunologic type I and the immunologic type II of heparin associated thrombocytopenia are closely linked in their pathogenesis. Semin Thromb He-most 1995; 21: 106-16
    Article in Thieme ConnectPubMedGoogle Scholar
  • 30 Greinacher A, Amiral J, Dummel Vissac A. et al. Laboratory diagnosis of heparin-asso-ciated thrombocytopenia and comparison of platelet aggregation test, heparin-induced activation test, and platelet factor 4/heparin enzyme-linked immunosorbent assay. Transfusion 1994; 34: 381-5
    CrossrefPubMedGoogle Scholar
  • 31 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 immunologic type of heparin associated thrombocytopenia. Thromb Haemost 1995; 74: 886-92
    Article in Thieme ConnectPubMedGoogle Scholar
  • 32 Greinacher A, Drost W, Michels I. et al. Heparin-associated thrombocytopenia: successful therapy with the heparinoid Org 10172 in a patient showing cross-reaction to LMW-heparins. Ann Hematol 1992; 64: 40-2
    CrossrefPubMedGoogle Scholar
  • 33 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
  • 34 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
  • 35 Greinacher A, Michels I, Liebenhoff U. et al. Heparin-associated thrombocytopenia: immune complexes are attached to platelet membrane by the negative charge of highly sulphated oligosaccharides. Br J Haematol 1993; 45 (03) 252-7
    PubMedGoogle Scholar
  • 36 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. Thromb Haemost 1994; 71: 247-51
    PubMedGoogle Scholar
  • 37 Harenberg J, Zimmerman R, Schwarz F, Kubler W. Treatment of heparin-induced thrombocytopenia with thrombosis by new heparinoid. Lancet 1983; i: 986-7
    PubMedGoogle Scholar
  • 38 Herbert JM, Hérault JP, Barzu T. et al. Biochemical and pharmacological properties of SANORG 32701; a potent analogue of the 'natural pentasaccharide'. Thromb Haemost 1995; 73: 1321
    PubMedGoogle Scholar
  • 39 Henny CP, ten Cate H, ten Cate JW. et al. Thrombosis prophylaxis in an AT III deficient pregnant woman: application of a low molecular weight heparinoid. Thromb Haemost 1986; 55: 301
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Henny CP, ten Cate H, ten Cate JW. et al. Use of a new heparinoid as anticoagulant during acute haemodialysis of patients with bleeding complications. Lancet 1983; i: 890-3
    PubMedGoogle Scholar
  • 41 Hoppensteadt D, Walenga J, Fareed J. Effect of dermatan sulfate and heparan sulfate on platelet activity compared to heparin. Semin Thromb Hemost 1991; 17 (Suppl. 01) 60-4
    PubMedGoogle Scholar
  • 42 Horellou MH, Conard J, Lecrubier C. et al. Persistent heparin induced thrombocytopenia despite therapy with low molecular weight heparin. Thromb Haemost 1984; 51: 134
    PubMedGoogle Scholar
  • 43 John G, Shehabi Y, Mudaliar Y. Use of low molecular weight preparation of heparin-Org 10172 (Lomoparan) in the critically ill. Anaesth Intensive Care 1991; 588-91
    PubMedGoogle Scholar
  • 44 Kelton JG, Sheridan D, Santos A. et al. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925-30
    PubMedGoogle Scholar
  • 45 King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med 1984; 100: 535-40
    CrossrefPubMedGoogle Scholar
  • 46 Kiers L, Grigg LE, Cade JF. et al. Use of Org 10172 in the treatment of heparin-induced thrombocytopenia and thrombosis. Aust NZ J Med 1986; 16: 719
    CrossrefPubMedGoogle Scholar
  • 47 Klauser RJ. Interaction of the sulfated lacto-bionic acid amide LW 10082 with thrombin and its endogenous inhibitors. Thromb Res 1991; 62: 557-65
    CrossrefPubMedGoogle Scholar
  • 48 Klauser RJ, Meinetsberger E, Raake W. Biochemical studies on lactobionic acid amides. Semin Thromb Hemost 1991; 17 (Suppl. 01) 118-25
    PubMedGoogle Scholar
  • 49 Leroy J, Leclerc MH, Delahousse B. et al. Treatment of heparin-associated thrombocytopenia and thrombosis with low molecular weight heparin (CY 216). Semin Thromb Hemost 1985; 11: 326-9
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554-61 and 1072;
    Article in Thieme ConnectPubMedGoogle Scholar
  • 51 Mascellani G, Liverani L, Bianchini P. et al. Structure and contribution of the heparin co-factor Il-mediated inhibition of thrombin of naturally oversulphated sequences of dermatan sulfate. Biochem J 1993; 296: 639-48
    CrossrefPubMedGoogle Scholar
  • 52 Marcum JA, Rosenberg RD. Regulation of the blood coagulation mechanism by antico-agulantly active heparan sulfate proteoglycans. Biol Carbohydr 1991; 3: 47-73
    PubMedGoogle Scholar
  • 53 Merton RE, Thomas DP. Experimental studies on the relative efficacy of dermatan sulfate and heparin as antithrombotic agents. Thromb Haemost 1987; 58: 839-42
    Article in Thieme ConnectPubMedGoogle Scholar
  • 54 Messmore HL, Griffin B, Koza M. et al. Interaction of heparinoids with platelets: comparison with heparin and low molecular weight heparin. Semin Thromb Hemost 1991; 17: 57-64
    PubMedGoogle Scholar
  • 55 Meuleman DG. Orgaran (Org 10172): its pharmacological profile in experimental models. Haemostasis 1992; 22: 58-65
    PubMedGoogle Scholar
  • 56 Meuleman DG. Synopsis of the anticoagulant and antithrombotic profile of the low molecular weight heparinoid Org 10172 in experimental models. Semin Thromb Hemost 1989; 15: 370-2
    Article in Thieme ConnectPubMedGoogle Scholar
  • 57 Nader HB, Toma L, Pinhal MS. et al. Effect of heparin and dextran sulfate on the synthesis and structure of heparan sulfate from cultured endothelial cells. Semin Thromb Hemost 1991; 17: 47-56
    PubMedGoogle Scholar
  • 58 Nawa K, Sakano K, Fujiwara H. et al. Presence and function of chondroitin-4-sulfate on recombinant human soluble thrombomodulin. Biochem Biophys Res Commun 1990; 171: 729-37
    CrossrefPubMedGoogle Scholar
  • 59 Nieuwenhuis HK, Sixma JJ. Treatment of disseminated intravascular coagulation in acute promyelocytic leukemia with low molecular weight heparinoid Org 10172. Cancer 1986; 58: 761-4
    CrossrefPubMedGoogle Scholar
  • 60 Ofosu FA. Anticoagulant mechanisms of Orgaran (Org 10172) and its fractions affinity to antithrombin III (Org 10849). Haemostasis 1992; 22: 66-72
    PubMedGoogle Scholar
  • 61 Ofosu FA, Choay J, Anvari N. et al. Inhibition of factor X and factor V activation by dermatan sulfate and a pentasaccharide with high affinity for antithrombin III in human plasma. Eur J Biochem 1990; 193: 485-93
    CrossrefPubMedGoogle Scholar
  • 62 Ortel TL, Gockerman JP, Cliff RM. et al. Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin-induced thrombocytopenia and thrombosis. Thromb Haemost 1992; 292-6
    Article in Thieme ConnectPubMedGoogle Scholar
  • 63 Raake W, Klauser RJ, Meinetsberger E. et al. Pharmacological profile of the antithrombotic and bleeding actions of sulfated lactobionic acid amides. Semin Thromb Hemost 1991; 17 (Suppl. 01) 129-35
    PubMedGoogle Scholar
  • 64 Rowlings PA, Mansberg R., Rozenberg MC. et al. The use of a low molecular weight heparin (Org 10172) for extracorporeal procedures in patients with heparin-induced thrombocytopenia and thrombosis. Aust NZ J Med 1991; 21: 52-4
    CrossrefPubMedGoogle Scholar
  • 65 Roth B, Johnen M, Herkenrath P, Schütz F. Anwendung eines neuen Heparinoids zur Antikoagulation bei der Hämodialyse eines Kindes mit intrakranieller Blutung. Nieren und Hochdruckkrankheiten 1985; 14: 62-4
    PubMedGoogle Scholar
  • 66 Saivin S, Dol F, Caranobe C. et al. Influence of molecular weight upon the anticoagulant and pharmacokinetic properties of dermatan sulfate in the rabbit. Thromb Res 1992; 66: 527-35
    CrossrefPubMedGoogle Scholar
  • 67 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30
    PubMedGoogle Scholar
  • 68 Sina P, Jacquinet JC, Petitou M. et al. Total synthesis of a pentasaccharide fragment having high affinity for antithrombin III. Carbohydr Res 1984; 132: C5-C9
    CrossrefPubMedGoogle Scholar
  • 69 Tardy PB, Tardy B, Grelac F. et al. Pentosan polysulfate-induced thrombocytopenia and thrombosis. Am J Hematol 1994; 88 (04) 803-8
    PubMedGoogle Scholar
  • 70 Ten Cate H, Henny CP, Büller HR. et al. Use of a heparinoid in patients with haemorrhagic stroke and thromboembolic disease. Ann Neurol 1984; 15: 268-70
    CrossrefPubMedGoogle Scholar
  • 71 Visentin GP, Ford SE, Scott JP. et al. Antibodies from patients with heparin-induced thrombocytopenia/thrombosis are specific for platelet factor 4 complexe with heparin or bound to endothelial cells. J Clin Invest 1994; 93: 81-8
    CrossrefPubMedGoogle Scholar
  • 72 Volpi N, Cusmano M, Venturelli T. Qualitative and quantitative studies of heparin and chondroitin sulfates in normal human plasma. Biochim Biophys Acta 1995; 1243: 49-58
    CrossrefPubMedGoogle Scholar
  • 73 Wagenvoord R, Hendrix H, Soria C. et al. Localization of the inhibitory site(s) of pentosan polysulphate in blood coagulation. Thromb Haemost 1988; 60: 220-5
    Article in Thieme ConnectPubMedGoogle Scholar
  • 74 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Prog Hemost Thromb 1991; 10: 1-34
    PubMedGoogle Scholar
  • 75 Warkentin TE, Levine MN, Hirsh J, Hemker HC. Heparin-induced thrombocytopenia in patients treated with low molecular weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-4
    CrossrefPubMedGoogle Scholar