Danaparoid. A review of its pharmacology and clinical use in the management of heparin-induced thrombocytopenia

Drugs

Volumn 54, Issue 6, 1997, Pages 903-924

  Wilde, Michelle I ^a   Markham, Anthony ^a  

^a ADIS INTERNATIONAL LIMITED   (New Zealand)

Author keywords

[No Author keywords available]

Indexed keywords

ANCROD; ANTICOAGULANT AGENT; BLOOD CLOTTING FACTOR; BLOOD CLOTTING FACTOR 10A; CHLORTALIDONE; DANAPAROID; DEXTRAN; DIGOXIN; HEPARAN; THROMBOCYTE ANTIBODY;

AGE; BLEEDING; BODY WEIGHT; CLINICAL TRIAL; CONTROLLED CLINICAL TRIAL; CONTROLLED STUDY; CROSS REACTION; DELAYED HYPERSENSITIVITY; DRUG ABSORPTION; DRUG DISTRIBUTION; DRUG EFFICACY; DRUG ELIMINATION; FEMALE; FIBRINOLYSIS; HUMAN; INTRAVENOUS DRUG ADMINISTRATION; LIPOLYSIS; MAJOR CLINICAL STUDY; MALE; META ANALYSIS; MORTALITY; OSTEOPOROSIS; RASH; REVIEW; SEX DIFFERENCE; SUBCUTANEOUS DRUG ADMINISTRATION; THROMBOCYTE COUNT; THROMBOCYTE FUNCTION; THROMBOCYTOPENIA; TREATMENT OUTCOME;

EID: 0030715080     PISSN: 00126667     EISSN: None     Source Type: Journal    
DOI: 10.2165/00003495-199754060-00008     Document Type: Review

References (116)

1. Meuleman DG, Hobbelen PM, van Dedem G, et al. A novel anti-thrombotic heparinoid (Org 10172) devoid of bleeding inducing capacity: a survey of its pharmacological properties in experimental animal models. Thromb Res 1982; 27: 353-63
2. Van Dedem G, de Leeuw den Bouter H. The nature of the glucosaminoglycan in Orgaran (Org 10172) [abstract no. 397]. Thromb Haemost 1993; 69: 652
3. Organon Inc. Danaparoid sodium prescribing information. West Orange, USA
4. Dryjski M, Dryjski H. Heparin induced thrombocytopenia. Eur J Vasc Endovasc Surg 1996 Apr; 11: 260-9
5. Chong BH. Heparin-induced thrombocytopenia. Br J Haematol 1995; 89 (3): 431-9
6. Greinacher A. Antigen generation in heparin-associated thrombocytopenia: the nonimmunologic type and the immunologic type are closely linked in their pathogenesis. Semin Thromb Hemost 1995; 21 (1): 106-16
7. Green RM. Treatment of heparin-induced thrombocytopenia and thrombosis. Semin Vasc Surg 1996; 9 (4): 292-5
8. Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia Prog Hemost Thromb 1991; 10: 1-34
9. 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: 1330-5
10. Mikhailidis DP, Jagroop IA, Ganotakis ES. Pathophysiology of heparin-induced thrombocytopenia (HIT). Proceedings of a workshop held in London, 1996 Nov 1. Platelets 1997; 8: 66-7
11. Shorten GD, Comunale ME. Heparin-induced thrombocytopenia. J Cardiothoracic Vasc Anesth 1996 Jun; 10 (4): 521-30
12. 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
13. Amiral J, Wolf M, Fischer A-M, et al. Pathogenicity of IgA and/or IgM antibodies to heparin-PF4 complexes in patients with heparin-induced thrombocytopenia. Br J Haematol 1996; 92: 954-9
14. 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 Jan; 93: 81-8
15. 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 Dec 1; 84: 3691-9
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. Thromb Haemost 1994; 71 (2): 247-51
17. Kelton JG, Sheridan D, Santos A, et al. Heparin-induced thrombocytopenia: laboratory studies. Blood 1988 Sep; 72 (3): 925-30
18. Kelton JG, Smith JW, Warkentin TE. Immunoglobulin G from patients wtih heparin-induced thrombocytopenia binds to a complex of heparin and platelet factor 4. Blood 1994; 83 (11): 3232-9
19. Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: the antibody is not heparin specific. Thromb Haemost 1992; 67(5): 545-9
20. Greinacher A, Michels I, Liebenhoff U, et al. Heparin-associated thrombocytopenia: immune complexes are attached to the platelet membrane by the negative charge of highly sulphated oligosaccharides. Br J Haematol 1993; 84: 711-6
21. 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
22. 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
23. Meuleman DG. Orgaran (ORG 10172): its pharmacological profile in experimental models. Haemostasis 1992; 22: 58-65
24. Gordon DL, Linhardt R, Adams Jr HP. Low-molecular-weight heparins and heparinoids and their use in acute or progressing ischemic stroke. Clin Neuropharmacol 1990 Dec; 13: 522-43
25. Hirsh J, Ofosu FA, Levine M. The development of low molecular weight heparins for clinical use. In: Verstraete M, Vermylen J, Lijnen R, et al., editors. Thrombosis and haemostasis 1987. Leuven University Press: 325-48
26. Haines ST, Bussey HI. Thrombosis and the pharmacology of antithrombotic agents. Annals of Pharmacotherapy 1995; 29 (9): 892-905
27. Chong BH. Heparin-induced thrombocytopenia. Aust N Z J Med 1992; 22: 145-52
28. Keeling DM, Richards EM, Baglin TP. Platelet aggregation in response to four low molecular weight heparins and the heparinoid ORG 10172 in patients with heparin-induced thrombocytopenia. Br J Haematol 1994; 86: 425-6
29. Ramakrishna R, Manoharan A, Kwan YL. Heparin-induced thrombocytopenia: cross-reactivity between standard heparin, low molecular weight heparin, dalteparin (Fragmin) and heparinoid, danaparoid (Orgaran). Br J Haematol 1995; 91: 736-8
30. Vun CM, Evans S, Chong BH. Cross-reactivity study of low molecular weight heparins and heparinoid in heparin-induced thrombocytopenia. Thromb Res 1996; 81 (5): 525-32
31. Walenga JM, Silber I, Koza M, et al. Lack of heparin induced thrombocytopenia response with the use of new antithrombotic agents [abstract no. 669]. Blood 1991; 78 Suppl. 1: 145a
32. Makhoul RG, Greenberg CS, McCann RL. Heparin-associated thrombocytopenia and thrombosis: a serious clinical problem and potential solution. J Vasc Surg 1986; 4: 522-8
33. Kikta MJ, Keller MP, Humphrey PW. Can low molecular weight heparins and heparinoids be safely given to patients with heparin-induced thrombocytopenia syndrome? Surgery 1993; 114: 705-10
34. Savoia H, O'Malley C, Grigg A, et al. Haematological aspects of heparin-induced thrombocytopenia (HITS) and the incidence of cross-reactive platelet aggregation with low molecular weight heparin and organon 10172: the Royal Melbourne Hospital experience [abstract]. Aust N Z J Med 1993 Feb; 23: 120
35. Elalamy I, Lecrubier C, Potevin F, et al. Absence of in vitro cross-reaction of pentasaccharide with the plasma heparin-dependent factor of twenty-five patients with heparin-associated thrombocytopenia. Thromb Haemost 1995 Nov; 74: 1384-5
36. Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia (HAT): successful therapy of patients after prospective selection of a compatible heparinoid with the heparin-induced platelet activation test [in German]. Beitr Infusionsther 1992; 30: 408-12
37. Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554-61
38. Ockleford PA, Carter CJ, Mitchell L, et al. Discordance between the anti-Xa activity and the antithrombotic activity of ultra-low molecular weight heparin fraction. Thromb Res 1982; 28: 401-9
39. Ofosu FA. Anticoagulant mechanisms of Orgaran (ORG 10172) and its fraction with high affinity to antithrombin-III (ORG 10849). Haemostasis 1992 Mar-Apr; 22: 66-72
40. Mikhailidis DP, Fonseca VA, Barradas MA, et al. Platelet activation following intravenous injection of a conventional heparin: absence of effect with a low molecular weight heparinoid (Org 10172). Br J Clin Pharmacol 1987; 24: 415-24
41. Mikhailidis DP, Barradas MA, Mikhailidis AM, et al. Comparison of the effect of a conventional heparin and a low molecular weight heparinoid on platelet function. Br J Clin Pharmacol 1984; 17: 43-8
42. Smith PE, Dawes J. The effect of plasma on platelet interactions with heparin and the LMW heparinoid orgaran [abstract]. Aust N Z J Med 1995 Feb; 25: 106
43. 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
44. Bradbrook ID, Magnani HN, Moelker HC, et al. ORG 10172: a low molecular weight heparinoid anticoagulant with a long half-life in man. Br J Clin Pharmacol 1987; 23: 667-75
45. Stiekema JCJ, van Griensven JMT, van Dinther TG. A crossover comparison of the anti-clotting effects of three low molecular weight heparins and glycosaminoglycuronan. Br J Clin Pharmacol 1993 Jul; 36: 51-6
46. ten Cate H, Henny CP, ten Cate JW, et al. Anticoagulant effects of a low molecular weight heparinoid (Org 10172) in human volunteers and haemodialysis patients. Thromb Res 1985 Jul 15; 38: 211-22
47. Hobbelen PM, Vogel GM, Meuleman DG. Time courses of the antithrombotic effects, bleeding enhancing effects and interactions with factors Xa and thrombin after administration of low molecular weight heparinoid Org 10172 or heparin to rats. Thromb Res 1987; 48: 549-58
48. Suehiro A, Imaoka J, Kakishita E. Comparison of the antithrombotic effects of low molecular weight heparinoid KB-101 and heparin in a rat experimental model. Gen Pharmacol 1993 Mar; 24 (2): 341-4
49. Vogel GMT, Meuleman DG, Bourgondien FGM, et al. Comparison of two experimental thrombosis models in rats. Effects of four glycosaminoglycans. Thromb Res 1989; 54 (5): 399-410
50. Verstraete M, Zoldhelyi P. Novel antithrombotic drugs in development. Drugs 1995; 49 (6): 856-84
51. Zammit A, Dawes J. Low-affinity material does not contribute to the antithrombotic activity of Orgaran (Org 10172) in human plasma. Thromb Haemost 1994 Jun; 71: 759-67
52. Ockelford PA, Carter CJ, Hirsh J. In vivo activity of a new heparinoid. Pathology 1985; 17: 78-81
53. Warkentin TE. Danaparoid (Orgaran) for the treatment of heparin-induced 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 no. 2493]. Blood 1996 Nov 15; 88 (Pt 1) Suppl. 1: 626a
54. Hill GR, Hickton C, Henderson S, et al. The use of low dose Orgaran in heparin-induced thrombocytopenia associated with in vitro platelet aggregation at higher Orgaran concentrations. Clin Lab Haematol 1997; 19: 155-7
55. Van Barlingen HHJJ, Van Beck A, Erkelens DW, et al. Danaparoid: an antithrombotic agent without major impact on triglyceride hydrolysis capacity in humans. J Intern Med 1997; 242: 125-9
56. Stiekema JCJ, Wijnand HP, Van Dinther TG, et al. Safety and pharmacokinetics of the low molecular weight heparinoid Org 10172 administered to healthy elderly volunteers. Br J Clin Pharmacol 1989 Jan; 27: 39-48
57. Danhof M, De Boer A, Magnani HN, et al. Pharmacokinetic considerations on orgaran (ORG-10172) therapy. Haemostasis 1992; 22: 73-84
58. Kroon C, De Boer A, Kroon JM, et al. Comparison of the bioavailability of heparin and low molecular weight heparin(oids) after subcutaneous administration in healthy volunteers. Br J Clin Pharmacol 1993; 35 (5): 535
59. Insler SR, Kraenzler EJ, Bartholomew JR, et al. Thrombosis during the use of the heparinoid Organon 10172 in a patient with heparin-induced thrombocytopenia. Anesthesiology 1997 Feb; 86: 495-8
60. Organon. Data sheet, New Zealand, 1996. (data on file)
61. 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 [letter]. Thromb Haemost 1986; 55: 301
62. Greinacher A, Eckhardt T, Mussmann J. Pregnancy complicated by heparin associated thrombocytopenia: management by a prospectively in vitro selected heparinoid (ORG 10172). Thromb Res 1993; 71: 123-6
63. Peeters LL, Hobbelen PM, Verkeste CM, et al. Placental transfer of Org 10172, a low-molecular weight heparinoid, in the awake late-pregnant guinea pig. Thromb Res 1986; 44: 277-83
64. 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 (1): 74-81
65. Von Bonsdorff M, Stiekema J, Harjanne A, et al. A new low molecular weight heparinoid Org 10172 as anticoagulant in hemodialysis. Int J Artif Organs 1990 Feb; 13: 103-8
66. Massey EW, Biller J, Davis JN, et al. Large-dose infusions of heparinoid ORG 10172 in ischemic stroke. Stroke 1990; 21: 1289-92
67. Chong BH. LMW heparinoid and heparin-induced thrombocytopenia [abstract]. Aust N Z J Med 1996 Apr; 26: 331
68. Organon Inc. (data on file)
69. Tardy-Poncet B, Reynaud J, Tardy B, et al. Efficacy and safety of Orgaran anticoagulation in patients with heparin induced thrombocytopenia [abstract no. 1627]. Thromb Haemost 1995 Jun; 73: 1323
70. Mahul P, Raynaud J, Favre JP, et al. Heparin-induced thrombocytopenia: use of a low molecular weight heparinoid, ORG 10172 (Lomoparan). Am Fr Anesth Reanim 1993; 12 Suppl.: 29-32
71. Lamriben L, Tiberghien F, Delacour JL, et al. The important role of Orgaran in haemodialysis during heparin-induced thrombocytopenia. Presse Med 1996; 25 (28): 1303
72. Rowlings PA, Mansberg R, Rozenberg MC, et al. The use of a low molecular weight heparinoid (Org 10172) for extracorporeal procedures in patients with heparin dependent thrombocytopenia and thrombosis. Aust N Z J Med 1991; 21: 52-4
73. Greinacher A, Philippen KH, Kemkes-Matthes B, et al. Heparin-associated thrombocytopenia type II in a patient with endstage renal disease: successful anticoagulation with the low-molecular-weight heparinoid Org 10172 during haemodialysis. Nephrol Dial Transplant 1993; 8: 1176-7
74. Magnani HN, Beijering RJR, ten Cate JW, et al. Orgaran anticoagulation for cardiopulmonary bypass in patients with heparin-induced thrombocytopenia. In: Pifarré R, editor. New anticoagulants for the cardiovascular patient. Philadelphia (PA): Hanley & Belfus, Inc., 1997: 487-500
75. Burkhard-Meier U, Söhngen D, Schultheiss H-P, et al. Heparin-induced thrombocytopenia type II: successful use of Orgaran in intensive care patients [abstract]. Onkologie 1994 Oct; 17 Suppl. 2: 21
76. Hach-Wunderle V, Kainer K, Salzmann G, et al. Heparin-associated thrombosis despite normal platelet counts [abstract]. Thromb Haemost 1995 Jun; 73: 1449
77. Klement D, Rammos S, Von Kries R, et al. Heparin as a cause of thrombus progression - heparin-associated thrombocytopenia is an important differential diagnosis in paediatric patients even with normal platelet counts. Eur J Pediatr 1996 Jan; 155: 11-4
78. Rationale for the use of Orgaran in patients with heparin-induced thrombocytopenia (HIT). Organon Inc. (Data on file)
79. Warkentin TE. (Data on file)
80. Borris LC, Lassen MR. A comparative review of the adverse effect profiles of heparins and heparinoids. Drug Saf 1995 Jan; 12: 26-31
81. Sivakumaran M, Ghosh K, Munks R, et al. Delayed cutaneous reaction to unfractionated heparin, low molecular weight heparin and danaparoid. Br J Haematol 1994 Apr; 86: 893-4
82. Boehncke W-H, Weber L, Gall H. Tolerance to intravenous administration of heparin and heparinoid in a patient with delayed-type hypersensitivity to heparins and heparinoids. Contact Dermatitis 1996; 35: 73-5
83. Trautmann A, Kreienkamp M, Brocker E-B, et al. Delayed-type hypersensitivity to heparins and a heparinoid: a case report [in German]. H G Z Hautkr 1994; 69 (8): 534-6
84. de Boer A, Danhof M, Cohen AF, et al. Interaction study between Org 10172. a low molecular weight heparinoid, and acetylsalicyclic acid in healthy male volunteers. Thrombosis and Haemostasis 1991; 66 (2): 202-7
85. de Boer A, Stiekema JCJ, Danhof M, et al. Studies of interaction of a low-molecular-weight heparinoid (Org 10172) with cloxacillin and ticarcillin in healthy male volunteers. Antimicrob Agents Chemother 1991; 35 (10): 2110-5
86. de Boer A, Stiekema JCJ, Danhof M. The influence of Org 10172, a low molecular weight heparinoid, on antipyrine metabolism and the effect of enzyme induction on the response to Org 10172. Br J Clin Pharmacol 1991; 32: 23-9
87. de Boer A, Stiekema JC, Danhof M, et al. Influence of chlorthalidone on the pharmacokinetics and pharmacodynamics of Org 10172 (Lomoparan®), a low molecular weight heparinoid, in healthy volunteers, J Clin Pharmacol 1991; 31 (7): 611-7
88. de Boer A, Stiekema JCJ, Danhof M. Interaction of ORG 10172, a low molecular weight heparinoid, and digoxin in healthy volunteers. Eur J Clin Pharmacol 1991; 41: 245-50
89. Warkentin TE, Russett JI, Johnston M, et al. Warfarin treatment of deep vein thrombosis complicating heparin-induced thrombocytopenia (HIT) is a risk factor for initiation of venous limb gangrene: report of nine patients implicating the interacting procoagulant effects of two anticoagulant agents [abstract no. 804]. Thrombosis and Haemostasia 1995; 73 (6): 1110
90. Goh P, Rickard KA, Gibson J, et al. Laboratory monitoring of low molecular weight heparin ORG 10172 therapy [abstract]. Aust N Z J Med 1991 Feb; 21 Suppl. 1: 141
91. Goh P, Rickard K, Gibson J, et al. Monitoring of ORG 10172 or fragmin therapy using the Cohas Fara [abstract no. 834]. Thromb Haemost 1991; 65 Suppl.: 930
92. r heparin fragment, based on their anti-Xa activity. Clin Chem 1984 Jun; 30 (6): 860-4
93. Stiekema JCJ, Wijnand HP, ten Cate H, et al. Partial in vivo neutralisation of plasma anticoagulant effects of Lomoparan (Org-10172) by protamine chloride. Thromb Res 1991 Jul 1; 63: 157-67
94. Kleinschmidt S, Seyfert UT. Heparin-associated thrombocytopenia (HAT) still a diagnostic and therapeutical problem in clinical practice. Angiology 1995 Jan; 46: 37-44
95. Schmitt BP, Adelman B. Heparin-associated thrombocytopenia: a critical review and pooled analysis. Am J Med Sci 1993 Apr; 305: 208-15
96. 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 cerebrovasculur diseases. Br J Haemat 1997; 96: 442-6
97. Green D, Martin GJ, Shoichet SH, et al. Thrombocytopenia in a prospective randomized double-blind trial of bovine and porcine heparin. Am J Med Sci 1984; 288: 60-4
98. Street A, McPherson J. The new heparins. Aust Prescriber 1996; 19 (4): 104-8
99. Goad KE, Gralnick HR. Coagulation disorders in cancer. Hematol/Oncol Clin North Am 1996 Apr; 10 (2): 457-84
100. King DJ, Kelton JG. Heparin-associated thrombocytopenia. Ann Intern Med 1984; 100: 535-40
101. Warkentin TE, Kelton JG. A 14-year study of heparin-induced thrombocytopenia. Am J Med 1996 Nov; 101: 502-7
102. Baglin TP. Heparin-induced thrombocytopenia/thrombosis syndrome (HIT): diagnosis and treatment. Proceedings of a workshop held in London, 1996 Nov 1. Platelets 1997; 8: 72-4
103. Greinacher A, Michels I, Mueller-Eckhardt C. Diagnosis of heparin associated thrombocytopenia (HAT) and selection of a compatible heparin by a rapid and sensitive heparin induced platelet activation (HIP-) test [abstract no. 61]. Ann Hematol 1991; 62: A52
104. Greinacher A, Michels I, Kiefel V, et al. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 1991; 66: 734-6
105. Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30
106. Amiral J. Diagnostic tests in heparin-induced thrombocytopenia. Proceedings of a workshop held in London, 1996 Nov 1. Platelets 1997; 8: 65-82
107. Hach-Wunderle V, Kainer K, Krug B, et al. Heparin-associated thrombosis despite normal platelet counts [letter]. Lancet 1994 Aug 13; 344: 469-70
108. Boon DMS, Michiels JJ, Stibbe J, et al. Heparin-induced thrombocytopenia and antithrombotic therapy [letter]. Lancet 1994 Nov 5; 344: 1296
109. Krishnamurti C, Bolan CD, Reid III TJ, et al. Pharmacology and mechanism of action of ancrod: potential for inducing thrombosis [letter]. Blood 1992; 79: 2492
110. Schrör K. Antiplatelet drugs: a comparative review. Drugs 1995 Jul; 50: 7-28
111. Shetty HGM, Fennerty AJ, Routledge PA. Adverse effects of anticoagulants. Adverse Drug React Bull 1989 Aug; 137: 512-5
112. Greinacher A, Alban S. Heparinoids as one approach for parenteral anticoagulation in patients with heparin-induced thrombocytopenia [in German]. Hamostaseologie 1996; 16 (1): 41-9
113. Cola C, Ansell J. Heparin-induced thrombocytopenia and arterial thrombosis: alternative therapies. Am Heart J 1990 Feb; 119 (2 Pt 1): 368-74
114. Fondu P. Heparin-associated thrombocytopenia: an update. Acta Clin Belg 1995 Dec; 50: 343-57
115. Penner JA. Managing the hemorrhagic complications of heparin therapy. Hematol Oncol Clin North Am 1993 Dec; 7 (6): 1281-9
116. Eichler P, Greinacher A. Anti-hirudin antibodies induced by recombinant hirudin in the treatment of patients with heparin-induced thrombocytopenia (HIT) [abstract]. Ann Hematol 1996; 72: A4