BioDrugs

, Volume 14, Issue 2, pp 109–125 | Cite as

Heparin-Induced Thrombocytopenia

Recommendations for Optimal Use of Recombinant Hirudin
  • Norbert Lubenow
  • Andreas Greinacher
Disease Management

Abstract

Recombinant hirudins have a definite role in the treatment of patients with heparin-induced thrombocytopenia (HIT). The most important adverse effects are haemorrhages and the induction of antihirudin antibodies. Major haemorrhages were not significantly increased in patients with HIT compared with a historical control group, but prospective data comparing hirudin and heparinoids such as danaparoid are lacking. The definition of the optimal method for monitoring and the availability of an antidote for hirudin would probably increase safety with this drug. To date, haemofiltration using high-flux filter systems is the only way to remove an overdosage of hirudin from the circulation. In patients with renal impairment requiring hirudin treatment, it therefore seems safer to start with a low dose that is subsequently adjusted according to the activated partial prothromboplastin time or ecarin clotting time.

Even in special circumstances, such as cardiopulmonary bypass or dialysis, hirudins can be applied successfully if care is taken to monitor their effects meticulously.

There are many other indications in which hirudins have shown feasibility (e.g. acute coronary syndromes) but available data preclude definite conclusions.

References

  1. 1.
    Haycraft JB. Über die Einwirkung eines Sekretes des officinellen Blutegels auf die Gerinnbarkeit des Blutes. Arch Exp Pathol Pharmakol 1884; 18: 209–17 and Proc R Soc Lond 1884; 36: 478-85CrossRefGoogle Scholar
  2. 2.
    Schultze E. Über die Verwendung von Blutegelextrakt bei der Transfusion des Blutes [dissertation]. Greifswald: University of Greifswald, 1891Google Scholar
  3. 3.
    Blobel P. Versuche über Transfusion mit dem vom Blutegel gesogenen Blute und über die Verwendung frisch bereiteten Egeldecoctes zur Transfusion [dissertation]. Greifswald: University of Greifswald, 1892Google Scholar
  4. 4.
    Sahli H. Über den Einfluβ intravenös injizierten Blutegelex-traktes auf die Thrombenbildung. Centralblatt Innere Med 1894; 22: 498Google Scholar
  5. 5.
    Eguet J. Über den Einfluβ des Blutegelinfuses auf die Thrombenbildung [dissertation]. Bern: University of Bern, 1894Google Scholar
  6. 6.
    Franz F. Über den die Blutgerinnung aufhebenden Bestandteil des medizinischen Blutegels. Naunyn Schmiedebergs Arch Exp Pathol Pharmakol 1903; 49: 342–57CrossRefGoogle Scholar
  7. 7.
    Jacobi Y. Über Hirudin. Dtsch Med Wochenschr 1904; 30: 1786–7Google Scholar
  8. 8.
    Engelmann F, Stade C. Über die Bedeutung des Blutegelextraktes für die Therapie der Eklampsie. Münch Med Wochenschr 1909; 43: 2203–7Google Scholar
  9. 9.
    Haas G. Über Versuche der Blutauswaschung am Lebenden mit Hilfe der Dialyse. Arch Pharmacol 1926; 116: 158–72CrossRefGoogle Scholar
  10. 10.
    Markwardt F. Untersuchungen über Hirudin. Naturwissen-schaften 1955; 42: 537–8CrossRefGoogle Scholar
  11. 11.
    Markwardt F. Untersuchungen über den Mechanismus der Blutgerinnungshemmenden Wirkung des Hirudins. Arch Exp Pathol Pharmakol 1956; 229: 389–99CrossRefGoogle Scholar
  12. 12.
    De la Llosa P, Tertrin C, Justisz M. Composition en acides aminés de lhirudine. Indentification du résidu N-terminal. Bull Soc Chim Biol 1963; 45: 69–74Google Scholar
  13. 13.
    De la Llosa P, Tertrin C, Justisz M. Lenchainemant C-terminal de lhirudin. Biochim Biophys Acta 1964; 93: 40–4CrossRefGoogle Scholar
  14. 14.
    Dodt J, Müller HP, Seemüller U, et al. The complete amino acid sequence of hirudin, a thrombin specific inhibitor. FEBS Lett 1984; 162: 180–3CrossRefGoogle Scholar
  15. 15.
    Markwardt F. Past, present and future of hirudin. Haemostasis 1991; 21 Suppl. 1: 11–26PubMedGoogle Scholar
  16. 16.
    Warkentin TE, Levine MN, Hirsh J, et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330–5PubMedCrossRefGoogle Scholar
  17. 17.
    Warkentin TE, Chong BH, Greinacher A. Heparin-induced thrombocytopenia: towards consensus. Thromb Haemost 1998; 79: 1–7PubMedGoogle Scholar
  18. 18.
    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: 21–82PubMedGoogle Scholar
  19. 19.
    Amiral J, Marfaing-Koka A, Wolf M, et al. Presence of auto-antibodies to interleucin-8 or neutrophil-activating peptide-2 in patients with heparin-associated thrombocytopenia. Blood 1996; 88: 410–6PubMedGoogle Scholar
  20. 20.
    Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992; 67: 545–9PubMedGoogle Scholar
  21. 21.
    Cines DB, Tomaski A, Tannenbaum S. Immune endothelial-cell injury in heparin-associated thrombocytopenia. N Engl J Med 1987; 316: 581–9PubMedCrossRefGoogle Scholar
  22. 22.
    Visentin GP, Ford SE, Scott JP, et al. 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: 81–8PubMedCrossRefGoogle Scholar
  23. 23.
    Greinacher A, Poetzsch 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: 247–51PubMedGoogle Scholar
  24. 24.
    Chong BH, Fawaz I, Chestermann CN, et al. Heparin-induced thrombocytopenia: mechanism of interaction of the heparin-dependent antibody with platelets. Br J Haematol 1989; 73: 235–40PubMedCrossRefGoogle Scholar
  25. 25.
    Kelton JG, Sheridan D, Santos A, et al. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988; 72: 925–30PubMedGoogle Scholar
  26. 26.
    Chong BH, Murray B, Berndt M, et al. Plasma P-selectin is increased in thrombotic consumptive platelet disorders. Blood 1994; 83: 1535–41PubMedGoogle Scholar
  27. 27.
    Warkentin TE, Hayward CP, 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: 3691–9PubMedGoogle Scholar
  28. 28.
    Warkentin TE. Limitations of conventional treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35: 17–25PubMedGoogle Scholar
  29. 29.
    Greinacher A, Völpel H, Janssens U, et al. Recombinant hirudin (lepirudin) provides safe and effective anticoagulation in patients with the immunologic type of heparin-induced thrombocytopenia: a prospective study. Circulation 1999; 99: 73–80PubMedCrossRefGoogle Scholar
  30. 30.
    Greinacher A, Janssens U, Berg G, et al. Lepirudin (recombinant hirudin) for parenteral anticoagulation in patients with heparin-induced thrombocytopenia. Circulation 1999; 100: 587–93PubMedCrossRefGoogle Scholar
  31. 31.
    Eriksson BI, Ekman S, Lindbratt S, et al. Prevention of thromboembolism with use of recombinant hirudin: results of a double-blind, multicenter trial comparing the efficacy of desirudin (Revasc) with that of unfractionated heparin in patients having a total hip replacement. J Bone Joint Surg Am 1997; 79: 326–33PubMedGoogle Scholar
  32. 32.
    Hoechst Marion Roussel. Refludan lepirudin: scientific monograph. Frankfurt: Hoechst Marion Roussel, 1997Google Scholar
  33. 33.
    Novartis Pharma GmbH. Desirudin (Revasc) product information. Nuremberg: Novartis Pharma GmbH, 1998Google Scholar
  34. 34.
    Markwardt F. The development of hirudin as an antithrombotic drug. Thromb Res 1994; 74: 1–23PubMedCrossRefGoogle Scholar
  35. 35.
    Hirsh J, Warkentin, TE, Raschke R, et al. Heparin and low molecular weight heparin: mechanisms of action, pharmacokinetics, dosing considerations, monitoring, efficacy and safety. Chest 1998; 114: 489S–510SPubMedCrossRefGoogle Scholar
  36. 36.
    Weitz JI, Hudoba M, Massel D, et al. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385–91PubMedCrossRefGoogle Scholar
  37. 37.
    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: 544–52PubMedCrossRefGoogle Scholar
  38. 38.
    Hogg PJ, Jackson CM, Labanowski JK, et al. Binding of fibrin monomer and heparin to thrombin in a ternary complex alters the environment of the thrombin catalytic site, reduces affinity for hirudin, and inhibits cleavage of fibrinogen. J Biol Chem 1996; 271: 26088–95PubMedCrossRefGoogle Scholar
  39. 39.
    Hogg PJ, Bock PE. Modulation of thrombin and heparin activities by fibrin. Thromb Haemost 1997; 77: 424–33PubMedGoogle Scholar
  40. 40.
    Vindigni A, White CE, Komives EA, et al. Energetics of thrombin-thrombomodulin interaction. Biochemistry 1997; 36: 6674–81PubMedCrossRefGoogle Scholar
  41. 41.
    Markwardt F, Nowak G, Stürzebecher J, et al. Clinicopharmacological studies with recombinant hirudin. Thromb Res 1988; 52: 393–400PubMedCrossRefGoogle Scholar
  42. 42.
    Markwardt F, Fink G, Kaiser B, et al. Pharmacological survey of recombinant hirudin. Pharmazie 1988; 43: 202–7PubMedGoogle Scholar
  43. 43.
    Behringwerke AG. Lepirudin (HBW 023): investigators’ brochure. 6th ed. Marburg/Lahn: Behringwerke AG, 1997 Jan 31Google Scholar
  44. 44.
    Schiele F, Vuillemenot A, Kramarz P, et al. A pilot study of subcutaneous recombinant hirudin (HBW 023) in the treatment of deep vein thrombosis. Thromb Haemost 1994; 71: 558–62PubMedGoogle Scholar
  45. 45.
    Nowak G, Markwardt F, Fink E. Pharmacokinetic studies with recombinant hirudin in dogs. Folia Haematol 1988; 115: 70–4Google Scholar
  46. 46.
    Markwardt F. Development of hirudin as an antithrombotic agent. Semin Thromb Haemost 1989; 15: 269–82CrossRefGoogle Scholar
  47. 47.
    Nowak G, Bucha E, Gööck T, et al. Pharmacology of r-hirudin in renal impairment. Thromb Res 1992; 66: 707–15PubMedCrossRefGoogle Scholar
  48. 48.
    Nowak G, Bucha E, Gööck T, et al. Pharmakokinetik von Hirudin beigestörter Nierenfunktion. Hämostaseologie 1991; 11: 152–7Google Scholar
  49. 49.
    Nowak G, Bucha E, Brauns I, et al. 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. Wien Klin Wochenschr 1997; 109: 354–8PubMedGoogle Scholar
  50. 50.
    Vanholder R, Camez A, Veys N, et al. Pharmacokinetics of recombinant hirudin in hemodialyzed end-stage renal failure patients. Thromb Haemost 1997; 77: 650–5PubMedGoogle Scholar
  51. 51.
    Vanholder R, Camez A, Veys NM, et al. Recombinant hirudin: a specific thrombin-inhibiting anticoagulant for hemodialysis. Kidney Int 1994; 45: 1754–9PubMedCrossRefGoogle Scholar
  52. 52.
    Lange U, Lehr A, Nowak G. Biologically active metabolites of recombinant and PEG-hirudin in rat urine: isolation and biochemical characterization [abstract]. Ann Hematol 1996; 72 Suppl. I: P233Google Scholar
  53. 53.
    van Wyk V, Badenhorst PN, Luus HG, et al. A comparison between the use of recombinant hirudin and heparin during hemodialysis. Kidney Int 1995; 48: 1338–43PubMedCrossRefGoogle Scholar
  54. 54.
    Hempel S, Lubenow N, Greinacher A. Nierenersatztherapie unter r-hirudin (Refludan) bei Heparin-induzierter Thrombo-zytopenie Typ II [abstract]. Infusionsther Transfusionsmed 1998; 25: 5/7pGoogle Scholar
  55. 55.
    Pötzsch B, Madiener K. Management of cardiopulmonary bypass anticoagulation in patients with heparin-induced thrombocytopenia. In: Warkentin TE, Greinacher A, editors. Heparin-induced thrombocytopenia. New York (NY): Marcel Decker, 2000: 355–69Google Scholar
  56. 56.
    Organization to Assess Strategies for Ischemic Syndromes (OASIS-2) Investigators. Effects of recombinant hirudin (lepirudin) compared with heparin on death, myocardial infarction, refractory angina, and revascularization procedures in patients with acute myocardial ischaemia without ST elevation: a randomized trial. Lancet 1999; 353: 429–38CrossRefGoogle Scholar
  57. 57.
    Hafner G, Rupprecht HJ, Luz M, et al. Recombinant hirudin as a periprocedural antithrombotic in coronary angioplasty for unstable angina pectoris. Eur Heart J 1996; 17: 1207–15PubMedCrossRefGoogle Scholar
  58. 58.
    Rupprecht HJ, Terres W, Ozbek C, et al. Recombinant hirudin (HBW 023) prevents troponin T release after coronary angioplasty in patients with unstable angina. J Am Coll Cardiol 1995; 26: 1637–42PubMedCrossRefGoogle Scholar
  59. 59.
    Neuhaus KL, Molhoek GP, Zeymer U, et al. Recombinant hirudin (lepirudin) for the improvement of thrombolysis with streptokinase in patients with acute myocardial infarction: results of the HIT-4 trial. J Am Coll Cardiol 1999; 34: 966–73PubMedCrossRefGoogle Scholar
  60. 60.
    Antman EM. Hirudin in acute myocardial infarction: Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9B trial. Circulation 1996; 94: 911–21PubMedCrossRefGoogle Scholar
  61. 61.
    Schiffmann H, Unterhalt M, Hanns K, et al. Successful treatment of heparin-induced thrombocytopenia (HIT) type II in childhood with recombinant hirudin. Monatsschr Kinderheilkd 1997; 145: 606–12CrossRefGoogle Scholar
  62. 62.
    Eriksson BI, Wille-Jörgensen P, Kälebo P, et al. A comparison of recombinant hirudin with a low-molecular weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329–35PubMedCrossRefGoogle Scholar
  63. 63.
    Hoet B, Tornai I, Arnout J, et al. Open study of intravenous recombinant hirudin (CGP 39393) on platelet function and coagulation in healthy volunteers. Drug Invest 1994; 7: 127–33CrossRefGoogle Scholar
  64. 64.
    Breddin HK. Neue Aspekte zu Hirudin. Medwelt 1997; 48: 64–6Google Scholar
  65. 65.
    Zoldhelyi P, Webster MWI, Fuster V, et al. Recombinant hirudin in patients with chronic, stable coronary artery disease: safety, half-life, and effect on coagulation parameters. Circulation 1993; 88: 2015–22PubMedCrossRefGoogle Scholar
  66. 66.
    Nowak G, Bucha E. Quantitative determination of hirudin in blood and body fluids. Semin Thromb Haemost 1996; 22: 197–202CrossRefGoogle Scholar
  67. 67.
    Verstraete M, Nurmohamed M, Kienast J, et al., European Hirudin in Thrombosis Group. Biologic effects of recombinant hirudin (CGP 39393) in human volunteers. J Am Coll Cardiol 1993; 22: 1080–8PubMedCrossRefGoogle Scholar
  68. 68.
    Marbet GA, Verstraete M, Kienast J, et al. Clinical pharmacology of intravenously administered recombinant desulfatohirudin (CGP 39393) in healthy volunteers. J Cardiovasc Pharmacol 1993; 22: 364–72PubMedCrossRefGoogle Scholar
  69. 69.
    Bridey F, Dreyfus M, Parent F, et al. Recombinant hirudin (HBW 023): biological data of ten patients with severe venous thrombo-embolism. Am J Hematol 1995; 49: 67–72PubMedCrossRefGoogle Scholar
  70. 70.
    Zeymer U, von Essen R, Tebbe U, et al. Recombinant hirudin and front-loaded alteplase in acute myocardial infarction: final results of a pilot study. HIT-I (hirudin for the improvement of thrombolysis). Eur Heart J 1995; 16 Suppl. D: 22–7PubMedCrossRefGoogle Scholar
  71. 71.
    Zeymer U, von Essen R, Tebbe U, et al., ALKK Study Group. Frequency of ‘optimal anticoagulation’ for acute myocardial infarction after thrombolysis with front-loaded recombinant tissue-type plasminogen activator and conjunctive therapy with recombinant hirudin (HBW 023). Am J Cardiol 1995; 76: 997–1001PubMedCrossRefGoogle Scholar
  72. 72.
    Nurmohamed MT, Berckmans RJ, Morrien-Salomons WM, et al. Monitoring anticoagulant therapy by activated partial thromboplastin time: hirudin assessment. Thromb Haemost 1994; 72: 685–92PubMedGoogle Scholar
  73. 73.
    Pötzsch B, Hund S, Madiener K, et al. Monitoring of recombinant hirudin: assessment of a plasma-based ecarin clotting time assay. Thromb Res 1997; 86: 373–83PubMedCrossRefGoogle Scholar
  74. 74.
    Pötzsch B, Madlener K, Seelig C, et al. Monitoring of r-hirudin anticoagulation during cardiopulmonary bypass: assessment of the whole blood ecarin clotting time. Thromb Haemost 1997; 77: 920–5PubMedGoogle Scholar
  75. 75.
    Kornalik F, Blombäck B. Prothrombin activation induced by ecarin: a prothrombin converting enzyme from Echis car-inatus venom. Thromb Res 1975; 6: 57–63PubMedCrossRefGoogle Scholar
  76. 76.
    Nishida S, Fujita T, Kohno N, et al. cDNA cloning and deduced amino acid sequence of prothrombin activator (ecarin) from Kenyan Echis carinatus venom. Biochemistry 1995; 34: 1771–8PubMedCrossRefGoogle Scholar
  77. 77.
    Morita T, Iwanaga S, Suzuki T. The mechanism of activation of bovine prothrombin by an activator isolated from Echis car-inatus venom and characterization of the new active intermediates. J Biochem 1976; 79: 1089–108PubMedGoogle Scholar
  78. 78.
    Novoa E, Seegers WH. Mechanisms of alpha-thrombin and beta-thrombin-E formation: use of ecarin for isolation of meizothrombin 1. Thromb Res 1980; 18: 657–68PubMedCrossRefGoogle Scholar
  79. 79.
    Greinacher A, Eichler P, Lubenow N, et al. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of two prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood 2000. In pressGoogle Scholar
  80. 80.
    von Essen R, Zeymer U, Tebbe U, et al. HBW 023 (recombinant hirudin) for the acceleration of thrombolysis and prevention of coronary reocclusion in acute myocardial infarction: results of a dose-finding study (HIT II) by the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausärzte. Coron Artery Dis 1998; 9: 265–72CrossRefGoogle Scholar
  81. 81.
    Butler KD, Dolan SL, Talbot MD, et al. Factor VIII and DDAVP reverse the effect of recombinant desulphatohirudin (CGP 39393) on bleeding in the rat. Blood Coagul Fibrinolysis 1993; 4: 459–64PubMedCrossRefGoogle Scholar
  82. 82.
    Bove CM, Casey B, Marder VJ. DDAVP reduces bleeding during continued hirudin administration in rabbit. Thromb Haemost 1996; 75: 471–5PubMedGoogle Scholar
  83. 83.
    Dickneite G, Friesen HJ, Kumpe G, et al. Reduction of r-hirudin induced bleeding in pigs by the administration of von Willebrand factor. Platelets 1996; 7: 283–90PubMedCrossRefGoogle Scholar
  84. 84.
    Dickneite G, Nicolay U, Friesen HJ, et al. Development of antibleeding agent for recombinant hirudin induced skin bleeding in the pig. Thromb Haemost 1998; 80: 192–8PubMedGoogle Scholar
  85. 85.
    Ibbotson SH, Grant PJ, Kerry R, et al. The influence of infusions of 1-desamino-8-D-arginine vasopressin (DDAVP) in vivo on the anticoagulant effect of recombinant hirudin (CGP39393) in vitro. Thromb Haemost 1991; 65: 64–6PubMedGoogle Scholar
  86. 86.
    Amin DM, Mant TG, Walker SM, et al. Effect of a 15 minute infusion of DDAVP on the pharmacokinetics and pharmaco-dynamics on Revasc during a four-hour intravenous infusion in healthy volunteers. Thromb Haemost 1997; 77: 127–32PubMedGoogle Scholar
  87. 87.
    Diehl KH, Romisch J, Hein B, et al. Investigation of activated prothrombin complex concentrate as potential hirudin antidote in animal models. Haemostasis 1995; 25: 182–92PubMedGoogle Scholar
  88. 88.
    Irami MS, Harvey JW, Sexon RG. Reversal of hirudin-induced bleeding diathesis by prothrombin complex concentrate. Am J Cardiol 1995; 75: 422–3CrossRefGoogle Scholar
  89. 89.
    Riess FC, Pötzsch B, Jäger K, et al. Elimination von rekombinanten Hirudin aus der Blutzirkulation mittels Hämofiltration. Hämostasiologie 1997; 17: 200–4Google Scholar
  90. 90.
    Markwardt F, Nowak G, Bucha E. Hirudin as anticoagulant in experimental hemodialysis. Haemostasis 1991; 21 Suppl. 1: 149–55PubMedGoogle Scholar
  91. 91.
    Frank RD, Farber H, Stefanidis I, et al. Hirudin elimination by hemofiltration: a comparative in vitro study of different membranes. Kidney Int 1999; 56: 41–6Google Scholar
  92. 92.
    Bucha E, Kreml R, Nowak G. In vitro study of transmembrane r-hirudin passage using different types of dialyzers [abstract]. Ann Hematol 1997; 74 Suppl. II: 159Google Scholar
  93. 93.
    Bruggener E, Walsmann P, Markwardt F. Neutralization of hirudin anticoagulant action by DIP-thrombin. Pharmazie 1989; 44: 648–9PubMedGoogle Scholar
  94. 94.
    Nakagomi K, Ajisaka K, Yokata I. Effects of acetylthrombin on protein C activation and fibrinogen clotting. Thromb Res 1990; 59: 713–22PubMedCrossRefGoogle Scholar
  95. 95.
    Nowak G, Bucha E. Prothrombin conversion intermediate effectively neutralizes toxic levels of hirudin. Thromb Res 1995; 80: 317–25PubMedCrossRefGoogle Scholar
  96. 96.
    Walenga JM, Pifarre R, Fareed J. Recombinant hirudin as an antithrombotic agent. Drugs Future 1990; 15: 267–80Google Scholar
  97. 97.
    Krupinski K, Breddin HK. Effects of different hirudins and combinations of low doses of hirudin, heparin and acetylsalicylic acid in a rat microcirculatory thrombosis model. Haemostasis 1991; 21 Suppl. 1: 88–92PubMedGoogle Scholar
  98. 98.
    Breddin HK, Radziwon P, Eschenfelder V, et al. PEG-hirudin and acetylsalicylic acid show a strong interaction on bleeding time [abstract]. Ann Haemat 1996; 72: 53CrossRefGoogle Scholar
  99. 99.
    Laubenthal FCA, Grosch B, Szurawitzki G, et al. Heparin-induced thrombocytopenia type II with early aortocoronary bypass occlusion and stent thrombosis after PTCA of the RCA: treatment with lepirudin (Refludan) and abciximab (Reopro) during recanalization of the RCA. Z Kardiol 1999; 88: 141–6PubMedCrossRefGoogle Scholar
  100. 100.
    Hirsh J, Weitz JI. New antithrombotic agents. Lancet 1999; 353: 1431–6PubMedCrossRefGoogle Scholar
  101. 101.
    Keularts IMLW, Béguin S, de Zwaan C, et al. Treatment with a GPIIb/III antagonist inhibits thrombin generation in platelet rich plasma from patients. Thromb Haemost 1998; 80: 370–1PubMedGoogle Scholar
  102. 102.
    Hérault JP, Peyrou V, Savi P, et al. Effect of SR 121566A, a potent GP IIb-IIIa antagonist on platelet-mediated thrombin generation in vitro and in vivo. Thromb Haemost 1998; 79: 383–8PubMedGoogle Scholar
  103. 103.
    Eichler P, Olbrich K, Pötzsch B, et al. Antihirudin antibodies in patients treated with recombinant hirudin for more than five days, a prospective study [abstract]. Thromb Haemost 1997 Jun; Suppl. : 493Google Scholar
  104. 104.
    Huhle G, Song X, Wang LC, et al. Generation and disappearance of antihirudin antibodies during treatment with r-hirudin. Fibrinol Proteol 1998; 12 Suppl. 2: 91–113Google Scholar
  105. 105.
    Huhle G, Hoffmann U, Song XH, et al. Immunantwort auf rekombinantes Hirudin: Eine Übersicht [Immune response to recombinant hirudin: an overview]. Haemostaseologie 1999; 19: 50–4Google Scholar
  106. 106.
    Huhle G, Hoffmann U, Song X, et al. Immunologic response to recombinant hirudin in HIT type II patients during long-term treatment. Br J Haematol 1999; 106: 195–201PubMedCrossRefGoogle Scholar
  107. 107.
    Eichler P, Eriksson BI, Pötzsch B, et al. Anti-hirudin antibodies following low dose subcutaneous application of desirudin for thrombosis prophylaxis after hip-replacement surgery. Incidence and clinical relevance [abstract]. Thromb Haemost 1999 Aug;Suppl. : 855Google Scholar
  108. 108.
    Close P, Bichler J, Kerry R, et al. Weak allergenicity of recombinant hirudin CGP 39393 (REVASC) in immunocompetent volunteers. The European Hirudin in Thrombosis Group (HIT) Group. Coron Artery Dis 1994; 5: 943–9PubMedGoogle Scholar
  109. 109.
    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: 20–5PubMedCrossRefGoogle Scholar
  110. 110.
    Madei W, Klieser HP, Hoerauf K. Heparin-induced thrombocytopenia as a cause of persistent bleeding after cardiac pacemaker implantation. Dtsch Med Wochenschr 1999; 124: 487–90PubMedCrossRefGoogle Scholar
  111. 111.
    Wagner AD, Kleber G, Lindner A, et al. 19jähriger Patient mit generalisiertem Krampfanfall und rezidivierenden Thrombosen unter Heparintherapie. Internist 1998; 39: 766–9CrossRefGoogle Scholar
  112. 112.
    Schmidt OH, Lang W. Heparin-induced thrombocytopenia with thromboembolic arterial occlusion treated with recombinant hirudin [letter]. N Engl J Med 1997; 337: 1389PubMedCrossRefGoogle Scholar
  113. 113.
    Harenberg J, Huhle G, Piazolo L, et al. Anticoagulation in patients with heparin-induced thrombocytopenia type II. Semin Thromb Hemost 1997; 189-96Google Scholar
  114. 114.
    Olbrich K, Wiersbitzky M, Wacke W, et al. Atypical heparin-induced thrombocytopenia complicated by intracardiac thrombus, effectively treated with ultra-low-dose rt-PA lysis and recombinant hirudin (Lepirudin). Blood Coagul Fibrinolysis 1998; 9: 273–7PubMedCrossRefGoogle Scholar
  115. 115.
    JanssensU, Breithardt OA, Greinacher A. Successful thrombolysis of right atrial and ventricle thrombi encircling a temporary pacemaker lead in a patient with heparin-induced thrombocytopenia type II. Pacing Clin Electrophysiol 1999; 22: 678–81CrossRefGoogle Scholar
  116. 116.
    Warkentin TE, Elavathil LJ, Hayward CP, et al. The pathogenesis of venous limb gangrene associated with heparin-induced thrombocytopenia. Ann Intern Med 1997; 127: 804–12PubMedGoogle Scholar
  117. 117.
    van Wyk V, Badenhorst PN, Kotzé HF. The effect of r-hirudin vs heparin on blood-membrane interactions during haemodialysis. Clin Nephrol 1997; 8: 381–7Google Scholar
  118. 118.
    Vanholder R, Dhondt A. Recombinant hirudin: clinical pharmacology and potential applications in nephrology. BioDrugs 1999; 11:417–29PubMedCrossRefGoogle Scholar
  119. 119.
    Walenga JM, Bakhos M, Messmore HL, et al. Comparison of recombinant hirudin and heparin as an anticoagulant in a cardiopulmonary bypass model. Blood Coagul Fibrinolysis 1991; 2: 105–11PubMedCrossRefGoogle Scholar
  120. 120.
    Riess FC, Bleese N, Kormann J, et al. Recombinant hirudin is a heparin alternative in cardiac surgery [[letter]. Cardiothorac Vasc Anesth 1997; 11:538–9CrossRefGoogle Scholar
  121. 121.
    Thannheimer A, Preuner JG, Pötzsch B, et al. Heparin-associated thrombocytopenia in open-heart surgery: heparin or hirudin as anticoagulant: the antibody decides [abstract]. Ann Hematol 1996; 72 Suppl. I: P222Google Scholar
  122. 122.
    Koster A, Kuppe H, Hetzer R, et al. Emergent cardiopulmonary bypass in five patients with heparin-induced thrombocytopenia type II employing recombinant hirudin. Anesthesiology 1998; 89: 777–80PubMedCrossRefGoogle Scholar
  123. 123.
    Pötzsch B, Iversen S, Riess FC, et al. Recombinant hirudin as an anticoagulant in open-heart surgery: a case report [abstract]. Ann Hematol 1993; 68 Suppl. 2: A46Google Scholar
  124. 124.
    Pötzsch B, Riess FC, Völpel H, et al. Recombinant hirudin as anticoagulant during open-heart surgery [abstract]. Thromb Haemost 1995; 73: 1456Google Scholar
  125. 125.
    Pötzsch B, Greinacher A, Riess FC, et al. Recombinant hirudin as anticoagulant in cardiac surgery: experiences with eleven patients [abstract]. Ann Hematol 1996; 72: A4Google Scholar
  126. 126.
    Riess FC, Löwer C, Seelig C, et al. Recombinant hirudin as a new anticoagulant during cardiac operations instead of heparin: successful for aortic valve replacement in man. J Thorac Cardiovasc Surg 1995; 110: 265–7PubMedCrossRefGoogle Scholar
  127. 127.
    Riess FC, Pötzsch B, Bader R, et al. A case report on the use of recombinant hirudin as an anticoagulant for cardiopulmonary bypass in open heart surgery. Eur J Cardiothorac Surg 1996; 10: 386–8PubMedCrossRefGoogle Scholar
  128. 128.
    Riess FC, Poetzsch B, Mueller-Berghaus G. Recombinant hirudin as an anticoagulant during cardiac surgery. In: Pifarré R, editor. New anticoagulants for the cardiovascular patient. Philadelphia (PA): Hanley & Belfus, Inc., 1997: 197–222Google Scholar
  129. 129.
    Ranze O, Ranze P, Magnani HN, Greinacher A. Heparin-induced thrombocytopenia in paediatric patients: a review of the literature and a new case treated with danaparoid sodium. Eur J Pediatr 1999; 158 Suppl. 3: S130–3PubMedCrossRefGoogle Scholar
  130. 130.
    Huhle G, Geberth M, Hoffmann U, et al. Management of heparin-associated thrombocytopenia in pregnancy with subcutaneous r-hirudin. Gynecol Obstet Invest 2000; 49: 67–9PubMedCrossRefGoogle Scholar
  131. 131.
    Lindhoff-Last E, Willeke A, Mosch G, et al. Hirudin is not detectable in human breast milk [abstract]. Ann Hematol 1999; 78 Suppl. 1: A82Google Scholar
  132. 132.
    Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554–61PubMedGoogle Scholar
  133. 133.
    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: 74–81Google Scholar
  134. 134.
    Ortel TL, Chong BH. New treatment options for heparin-induced thrombocytopenia. Semin Hematol 1998; 35 (4 Suppl. 5): 26–34 [discussion 35-6]PubMedGoogle Scholar
  135. 135.
    Greinacher A. Treatment of heparin-induced thrombocytopenia. Thromb Haemost 1999; 82: 457–67PubMedGoogle Scholar
  136. 136.
    Fox KAA. r-Hirudin in unstable angina pectoris: rationale and preliminary data from the APT pilot study. Eur Heart J 1995: 16: 28–32PubMedCrossRefGoogle Scholar
  137. 137.
    Organization to Assess Strategies for Ischemic Syndromes (OASIS) Investigators. Comparison of the effects of two doses of recombinant hirudin compared with heparin in patients with acute myocardial ischaemia without ST elevation: a pilot study. Circulation 1997; 96: 769–77CrossRefGoogle Scholar
  138. 138.
    The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIb investigators. A comparison of recombinant hirudin with heparin for the treatment of acute coronary syndromes. N Engl J Med 1996; 335: 775–82CrossRefGoogle Scholar
  139. 139.
    Zeymer U, Mateblowski M, Neuhaus K–L. Thrombin generation in patients with acute myocardial infarction treated with front-loaded rt-PA and recombinant hirudin (HBW 023). J Thromb Thrombol 1998; 5: 203–7CrossRefGoogle Scholar
  140. 140.
    Neuhaus KL, von Essen R, Tebbe U, et al. Safety observations from the pilot phase of the randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) study: a study of the Arbeitsgemeinschaft Leitender Kardiologischer Krankenhausarzte (ALKK). Circulation 1994; 90: 1638–42PubMedCrossRefGoogle Scholar
  141. 141.
    Molhoek GP, Laarman GJ, Lok DJ, et al. Effects of recombinant hirudin on early and late coronary patency in acute myocardial infarction patients treated with streptokinase (The HIT-SK study) [abstract]. Circulation 1995; 82:I–415–416Google Scholar
  142. 142.
    Molhoek GP, Laarman GJ, Lok DJ, et al. Angiographic dose-finding study with r-hirudin (HBW 023) for the improvement of thrombolytic therapy with streptokinase (HIT-SK): interim results. Eur Heart J 1995; 16 Suppl. D: 33–7PubMedCrossRefGoogle Scholar
  143. 143.
    The Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO) IIa Investigators. Randomized trial of intravenous heparin versus recombinant hirudin for acute coronary syndromes. Circulation 1994; 90: 1631–7CrossRefGoogle Scholar
  144. 144.
    Antman EM. Hirudin in acute myocardial infarction: safety report from the Thrombolysis and Thrombin Inhibition in Myocardial Infarction (TIMI) 9A Trial. Circulation 1994; 90: 1624–30PubMedCrossRefGoogle Scholar
  145. 145.
    Serruys PW, Herrman JP, Simon R, et al., Helvetica Investigators. A comparison of hirudin with heparin in the prevention of restenosis after coronary angioplasty. N Engl J Med 1995; 333: 757–63PubMedCrossRefGoogle Scholar
  146. 146.
    Parent F, Bridey F, Dreyfus M, et al. Treatment of severe thromboembolism with intravenous hirudin (HBW 023): an open pilot study. Thromb Haemost 1993; 70: 386–8PubMedGoogle Scholar
  147. 147.
    Schiele F, Lindgaerde F, Eriksson H, for the International Multicentre Hirudin Study Group, et al. 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: 834–8PubMedGoogle Scholar

Copyright information

© Adis International Limited 2000

Authors and Affiliations

  • Norbert Lubenow
    • 1
  • Andreas Greinacher
    • 1
  1. 1.Department of Immunology and Transfusion MedicineErnst-Moritz-Arndt-UniversityGreifswaldGermany

Personalised recommendations