Heparin-Induced Thrombocytopenia (HIT): An Overview of 230 Patients Treated with Orgaran (Org 10172)

H N Magnani

doi:10.1055/s-0038-1649626

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 1993; 70(04): 554-561
DOI: 10.1055/s-0038-1649626

Original Article

Clinical Studies

Schattauer GmbH Stuttgart

Heparin-Induced Thrombocytopenia (HIT): An Overview of 230 Patients Treated with Orgaran (Org 10172)

H N Magnani

The Medical Research and Development Unit, Organon International BV, Oss, The Netherlands

› Author Affiliations

Abstract

PDF Download

Summary

Heparin-induced thrombocytopenia (HIT) with thrombosis occurs in about 1 in 2,000 heparin-treated patients. The arterial or venous thromboses may threaten life and limb hence alternative anticoagulation is needed. Some alternative treatments are possible i.e. LMWH, Ancrod, prostacyclin analogues, Dextran, aspirin and oral anticoagulants, but each has its drawbacks. This report reviews treatment of HIT patients with Orgaran (Org 10172), a low molecular weight heparinoid.

Because of its proven antithrombotic activity Orgaran was used to treat 230 HIT patients. One hundred and fifty, nine patients presented with at least one thrombotic problem, which in 88 was due to the heparin use. 92.8% of the patients were considered to have adequately responded to Orgaran during the treatment period. Fifty-nine deaths (25.7%) occurred of which 7 (3.0%) were attributed to Orgaran use. The remaining 52 deaths, 27 of which occurred after Orgaran treatment was successfully terminated, were due to the severe underlying disorders in these patients. These results and the lower cross-reactivity rate (≈10%) with the heparin-induced antibody compared with that of the LMWH (>90%) suggest that although problems remain, Orgaran can be a valuable alternative treatment for patients who suffer from HIT and who require anticoagulation.

PDF (1740 kb)

References

References
1 Meuleman DG, Hobbelen P, Van Dedem G, Moelker H. A novel anti-thrombotic heparinoid (Org 10172) devoid of bleeding inducing capacity. Thromb Res 1982; 27: 353-363
2 Boneu D, Buchanan MR, Cade JF. et al Effects of heparin and its low molecular weight fractions and other glycosaminoglycans on thrombus growth in-vivo. Thromb Res 1985; 40: 81-89
3 Ireland H, Lane DA, Flynn A, Anastassiades E, Curtis JR. The anticoagulant effect of heparinoid Org 10172 during haemodialysis: an objective assessment. Thromb Haemostas 1986; 55: 271-275
4 Baruch D, Franssen J, Hemker HC, Lindhout T. Effect of heparin and low molecular weight heparins on thrombin-induced blood platelet activation in the absence of AT-III. Thromb Res 1985; 38: 447-458
5 Mikhailidis DP, Barradas MA, Mikhailidis AM, Magnani HN, Dandona P. Comparison of the effects of a conventional heparin and a low molecular weight heparinoid fraction on platelet function. Br J Clin Pharmacol 1984; 17: 43-48
6 Wester J, Van Mensvoort FWJ, Meuleman DG, Ten CateH, Henny CP, Ten CateJW. Effects of Org 10172, a novel heparinoid on primary haemostasis in rats and humans; a morphological study. Thromb Haemostas 1987; 58: 123
7 Henny ChP, Ten CateH. The morphology of human haemostatic plug formation following administration of heparin or the low molecular weight heparinoid Org 10172. Thesis, University of Amsterdam, Amsterdam 1987; 77-94
8 Hobbelen PMJ, Vogel GMT, Meuleman DG. Time courses of the antithrombotic effects, the bleeding effects and the interaction with factor Xa and thrombin after administration of the low molecular weight heparinoid, Org 10172, or heparin. Thromb Res 1987; 48: 549-558
9 Hirsh J. In-vivo effects of low molecular weight heparins on experimental thrombosis and bleeding. Heamostasis 1986; 16: 82-86
10 Cade JF, Wood M, Magnani HN, Westlake GW. Early clinical experience of a new heparinoid, Org 10172, in the prevention of deep vein thrombosis. Thromb Res 1987; 45: 497-503
11 Turpie AG, Hirsh J, Jay RM. A double-blind randomised trial of Org 10172, a low molecular weight heparinoid, in the prevention of deep vein thrombosis in thrombotic stroke. Lancet 1987; i: 523-526
12 Makhoul RG, Greenberg CS, McCann RL. Heparin associated thrombocytopenia and thrombosis: a serious clinical problem and potential solution. J Vasc Surg 1986; 4: 522-528
13 Chong BH, Ismail F, Cade JF, Gallus AS, Gordon S, Chesterman CN. Heparin-induced thrombocytopenia: Studies with a new low molecular weight heparinoid, Org 10172. Blood 1989; 73: 1592-1596
14 Böttinger LE. Heparin-induced thromboytopenia. Acta Med Scand 1985; 218: 257-259
15 King DE, Kelton J. Heparin-induced thrombocytopenia. Ann Intern Med 1984; 100: 535-540
16 Towne JB, Bernard VM, Hussey C, Garancis JC. White clot syndrome, peripheral vascular complications of heparin therapy. Arch Surg 1979; 114: 372-377
17 Rankin JA. Heparin-induced thrombosis (white-clot syndrome) secondary to prophylactic subcutaneous administration of heparin. Can J Surg 1988; 31: 33-34
18 Leehey DL, Kanak RJ, Messmore HL, Nawab ZM, Popli S, Ing TS. Heparin-associated thrombocytopenia in maintenance haemodialysis patients. Int J Artificial Organs 1987; 10: 390-392
19 Atkinson JLD, Sundt TM, Kazmier FJ, Bowie EJW, Whisnant JP. Heparin-induced thrombocytopenia and thrombosis in acute stroke. Mayo Clin Proc 1988; 63: 353-361
20 Anonymous. Heparin-induced thrombocytopenia. Australian Adverse Drug Reactions Bulletin. August 1989
21 Harenberg J, Zimmerman R. Treatment of heparin-induced thrombocytopenia with thrombosis by a new heparinoid. Lancet 1983; 8331: 986-987
22 Greinacher A, Michels I, Mueller-Eckhardt C. Heparin-associated thrombocytopenia: The antibody is not heparin specific. Thromb Haemostas 1992; 67: 545-549
23 Kiers L, Grigg LE, Cade JF, Street PR, Chong BH. Use of Org 10172 in the treatment of heparin-induced thrombocytopenia and thrombosis. Aust NZ J Med 1986; 16: 719
24 Henny ChP, Ten CateH, Ten CateJW, Prummel FM, Peters J, Büller HR. Thrombosis prophylaxis in an AT-III deficient pregnant woman: application of the low molecular weight heparinoid Org 10172. Thromb Haemostas 1986; 55: 301-304
25 Doherty DC, Ortel TL, De Bruijn N, Greenberg CS, Van Trigt III P. “Heparin-free” cardiopulmonary by-pass: First reported use of heparinoid Org 10172 to provide anticoagulation for cardiopulmonary by-pass. Anesthesiology 1990; 73: 562-565
26 Rowlings PA, Mansberg R, Rozenberg MC, Evans S, Murray B. The use of a low molecular weight heparinoid (Org 10172) for extracorporeal procedures in patients with heparin-dependent thrombocytopenia and thrombosis. Aust NZ J Med 1991; 21: 52-54
27 Ortel TL, Gockerman JP, Califf RM. et al Parenteral anticoagulation with the heparinoid Lomoparan (Org 10172) in patients with heparin induced thrombocytopenia and thrombosis. Thromb Haemostas 1992; 67: 292-296
28 Greinacher A, Drost W, Michels I. et al Heparin associated thrombocytopenia successful therapy with ther heparinoid Org 10172 in a patient showing cross-reaction to LMW heparins. Ann Haematol 1992; 64: 40-42
29 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67: 27-30
30 Bradbrook I, Magnani HN, Moelker HCT. et al Org 10172: a low molecular weight anticoagulant with a long half-life in man. Br J Clin Pharmacol 1987; 23: 667-675
31 Stiekema J, Wijnand HP, Van Dinther ThG. Safety and pharmacokinetics of the low molecular weight heparinoid Org 10172 administered to healthy elderly volunteers. Br J Clin Pharmacol 1989; 27: 39-48
32 Teien AN, Lie M, Abildgaard U. Assay of heparin in plasma using a chromogenic substrate for activated factor X. Thromb Res 1976; 8: 413-416
33 Van Bessien K, Hoffman R, Golichowski A. Pregnancy associated with lupus anti-coagulant and heparin-induced thrombocytopenia: management with a low molecular weight heparinoid. Thromb Res 1991; 62: 23-29
34 Peeters LH, Hobbelen PMJ, 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: 277-283
35 Greinacher A, Michels I, Kiefer V, Mueller-Eckhardt C. A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia (HAT) and selecting a compatible heparin. Thromb Haemostas 1991; 66: 734-736
36 Harbrecht NM, Ankrig CJ. Heparin-induced thrombocytopenia type II: platelet aggregation studies with low molecular weight heparins and heparinoid (Org 10172). Thromb Haemostas 1991; 65: 1302
37 Kelton J. Heparin-induced thrombocytopenia. Haemostasis 1986; 16: 173-186
38 Kyritsis AP, Williams EC, Schutta HS. Cerebral Venous Thrombosis due to Heparin-induced Thrombocytopenia. Stroke 1990; 21: 1503-1505
39 Prull A, Nechwatal R, Maurer W. Fulminante venöse und arterielle Thrombosen unter Heparintherapie. Dtsch Med Wschr 1990; 115: 456-459
40 Henny ChP, Ten CateH, Ten CateJW. et al Use of a new heparinoid as anticoagulant during acute haemodialysis of patients with bleeding complications. Lancet 1983; i: 890-893
41 Ten CateH, Henny ChP, Buller HR, Ten CateJW, Magnani HN. Use of heparinoid in haemorrhagic stroke patients with thromboembolic disease. Ann Neurol 1984; 15: 268-270
42 Biller J, Massey EW, Marler JR. et al A dose escalation study of Org 10172 (low molecular weight heparinoid) in stroke. Neurology 1989; 39: 262-265
43 Guittard M, Pradalier A, Vincent D, Dry J. Thrombosis of the Right Ventricle and Thrombopenia Induced by Heparin. Presse Med 1988; 17: 871
44 Borg JY, Flechet B, Legendre M, Toulemonde F, Piguet H, Moncon-duit M. Severe heparin and pentosan polysulphate-induced thrombocytopenia: clinical aspects in-vitro effects of pentosan polysulphate, low molecular weight (LMW) heparins and oligosaccharides. Thromb Res. 1986 Suppl. VI 96
45 Dalger J, Dussarat GV, Dumoulin M. Infarctus myocardique compliquant une thrombopénie induite par le polysulfate de pentosane. Ann Cardiol Angeiol 1988; 37/4: 191-193
46 Maiza D, Derlon A, Khayat MC, Coulhon JP, Leporrier M. Rôle du polysulfate de pentosane dans le déclanchement de deux accidents thrombopéniques. Presse Med 1985; 14: 1289-1290
47 Follea G, Hamandjian I, Trzeciak MC, Nedey C, Streichenberger R, Dechavanne M. Pentosane polysulfate associated thrombocytopenia. Thromb Res 1986; 42: 413-418
48 Papazian L, Alazia M, Levy G, François G. Multiple arterial and venous thromboses associated with thrombocytopenia. Rôle of pentosan polysulphate and heparins. Presse Med 1986; 15: 1246-1247
49 Blockmans D, Bounameaux H, Vermylen J, Verstraete M. Heparin-induced thrombocytopenia, platelet aggregation studies in the presence of heparin fractions or semi-synthetic analogues of various molecular weights and anticoagulant activities. Thromb Haemostas 1986; 55: 90-93
50 Gouault-Heilmann M, Huet Y, Adnot S. et al Low molecular weight heparin fractions as an alternative therapy in heparin-induced thrombocytopenia. Haemostasis 1987; 17: 134-140
51 Copplestone A, Oscier DG. Heparin-induced thrombocytopenia in pregnancy. Br J Haematol 1987; 65: 248
52 Brace LD, Fareed J. Heparin-induced platelet aggregation: Dose response relationships for a low molecular weight derivative (PK 10169) and its subfractions. Thromb Res 1986; 42: 769-782
53 Le Querrec A, Derlon A, Tobelem G, Thomas M. Pentosane polysulphate like heparin may induce severe thrombocytopenia. Thromb Res. 1986 Suppl. VI 90
54 Paille F, Boccaccini A, DeKorwin JD. et al Thrombopénie sous héparine de bas poids moléculaire aprè traitement par pentosane polysulphate. Therapie 1988; 43: 322-323
55 Roussi JH, Houbouyan LL, Goguel AF. Use of low molecular weight heparin in heparin-induced thrombocytopenia with thrombotic complications. Lancet 1984; ii: 1183
56 Horellou MH, Conard J, Lecrubier C. et al Persistent heparin-induced thrombocytopenia despite therapy with low molecular weight heparin. Thromb Haemostas 1984; 51: 134
57 Vitoux JF, Mathieu JF, Roncato M, Fiessinger JN, Aiach M. Heparin-associated thrombocytopenia treatment with low molecular weight heparin. Thromb Haemostas 1986; 55: 37-39
58 Troussard X, Mosquet B, Bigot MC, Derlon A, Khayat MC, Moulin MA. Thrombopénie sous héparine. Therapie 1986; 41: 69-72
59 Gouault-Heilmann M, Huet Y, Contant G, Payen D, Bloch G, Rapin M. Cardiopulmonary by-pass with a low molecular weight heparin fraction. Lancet 1983; ii: 1374
60 Faivre R, Kieffer Y, Bassand JP, Maurat JP. Les thrombopénies graves à l’héparine: Intérêt de l’utilisation de l’héparine à bas poids moleculaire. Arch Mal Coeur 1985; 78: 27-30
61 Huisse MG, Huet Y, Zygelman M, Guillin MC. Une tentative thérapeutique dans une cas de thrombopénie enduite par l’héparine. Nouv Rev Fr Haematol 1983; 25: 139
62 Roussi J, Houbouyan L, Rosenthal D, Toulemonde F, Goguel A. Success du traitement par une fraction d’héparin de bas poids moléculaire dans un cas d’embolie pulmonaire compliquant une thrombopénie induite par l’héparine. Nouv Rev Fr Haematol 1983; 25: 273-274
63 Gruel Y, Guerois C, Delahousse B. et al Traitement des thrombopénies et thromboses sous héparins Standard: Résultats obtenus par l’utilisation de fractions des bas poids moléculaire (26 cas). Nouv Rev Fr Haematol 1984; 26: 135
64 Grau E, Fontucuberta J, Martinez R, Latorre J, Felez J, Rutllant MC. Thrombopénie sévère précoce induite par l’héparine non-fractionée: Tentative thérapeutique par une héparine de bas poids moléculaire. Nouv Rev Fr Haematol 1985; 27: 385-387
65 Gruel Y, Lerou J, Guerois C. et al Thrombopénie et thrombose sous héparine. Necessité des tests d’aggregation ayant le traitement par l’héparine de bas poids moleculaire. La presse Médicale 1985; 14: 166
66 Huisse MG, Guillin MC, Bezeaud A, Toulemonde F, Kitzis M, Andreassian B. Heparin-associated thrombocytopenia. In-vitro effects of different low molecular weight heparin fractions. Thromb Res 1982; 27: 485
67 Cornu P, Scalet M, Sternberg CI, Racine S. Thrombopénies induites par l’héparine (TIH): Etude in vitro des héparines de bas poids moleculaires (HBPM) et du polysulfate de pentosane (PSP-Hemoclar). Nouv Rev Fr Haematol 1984; 26: 135
68 Horrellou MH, Conard J. Lecrubier. et al Thrombopénie induite par l’héparine, entretenue par l’héparine de bas poids moleculaire. Nouv Rev Fr Haematol 1984; 26: 134
69 Sardin B, Gouille D, Desport JC. et al Thrombopénies immunoallergiques induites par l’héparine: Diagnostic, traitement et prévention. J Chir (Paris) 1987; 124: 349-350
70 Bollaert PE, Laprevoté-Heully MC, Mourizi M, Lambert H, Larcan A. Thrombopénie grave associée au traitement par polysulfate de pentosane. Ann Fr Anesth Réanim 1986; 5: 539-541
71 Leroy J, Leclerc MH, Delahousse B. et al Treatment of heparin-associated thrombocytopenia and thrombosis with low molecular weight heparin (CY 216). Semin Thromb Hemostas 1985; 11: 326-329
72 Gouault-Heilmann M, Payen D, Contant G, Intrator L, Huet Y, Schaeffer A. Thrombocytopenia related to synthetic heparin an analogue therapy. Thromb Haemostas 1985; 54: 557
73 Gouault-Heilmann M, Contant G, Intrator L, Brun-Ney D, Huet Y. Thrombopénie à l’heparin, circulation extra-corporelle et héparine de bas poids moleculaire. Nouv Rev Fr Haematol 1984; 26: 134
74 Delagardelle C, Harf C, Dondelinger RF. et al Traitement par thrombolyse locale d’une thrombose artérielle massive par thrombopénie induite par l’heparine. Arch Mal Coeur 1990; 83: 113-115
75 Leclercq C, De Place C, Rioux C, Mabo P, Paillard F, Daubert JC. Infarctus du myocarde et thrombose biventriculaire massive au cours d’une thrombopénie induite par le pentosan polysulfate et l’héparine. Arch Mal Coeur 1990; 83: 117-120
76 Tardy B, Page Y, Tardy-Poncet B, Comtet C, Zeni F, Bertrand JC. Thrombopénie induite par une héparine de bas poids moleculaire. Therapie 1990; 45: 453
77 Warkentin TE, Kelton JG. Heparin-induced thrombocytopenia. Progr Haemostas Thromb 1991; 10: 1-34