Treatment of 51 pregnancies with danaparoid because of heparin intolerance

Edelgard Lindhoff-Last; Hans-Joachim Kreutzenbeck; Harry N. Magnani

doi:10.1160/TH04-06-0345

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2005; 93(01): 63-69
DOI: 10.1160/TH04-06-0345

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Treatment of 51 pregnancies with danaparoid because of heparin intolerance

Authors

Edelgard Lindhoff-Last

¹Division of Vascular Medicine, Department of Internal Medicine, University Hospital Frankfurt, Germany
Hans-Joachim Kreutzenbeck

²Medical Department, Celltech, Essen, Germany
Harry N. Magnani

³Clinical Consultant Marketing, Organon BV, Oss, The Netherlands

Abstract

Summary

Pregnant patients with acute venous thrombosis or a history of thrombosis may need alternative anticoagulation, when heparin intolerance occurs. Only limited data on the use of the heparinoid danaparoid are available in literature.We reviewed the use of danaparoid in 51 pregnancies of 49 patients identified in literature between 1981 and 2004.All patients had developed heparin intolerance (32 due to heparin-induced thrombocytopenia, 19 mainly due to heparin-induced skin rashes) and had a current and/or past history of thromboembolic complications.The initial danaparoid dose regimens ranged from 1000 to 7500 U/day administered s.c.or i.v..The median duration of danaparoid use was 10 weeks. Danaparoid was used until delivery of a healthy infant in 37 pregnancies. In the remaining 14 pregnancies it was stopped earlier, because anticoagulant treatment was no longer required (3/14) or an adverse event led to a treatment discontinuation (11/14). Four maternal bleeding events were recorded during pregnancy, delivery or postpartum, two of them were fatal due to placental problems. Three fetal deaths were recorded, all associated with maternal complications antedating danaparoid use. Danaparoid cross-reactivity was suspected in 4 HIT patients and 5 non-HIT patients with skin reactions and was confirmed serologically in one of the two HIT patients tested. In none of five fetal cord blood- and three maternal breast milksamples anti-Xa activity transfer was observed.In conclusion danaparoid can be used as an alternative antithrombotic agent in pregnant women with high thrombotic risk and intolerance to heparins.

Keywords

Pregnancy - heparin-induced thrombocytopenia - heparin-induced - skin rash - danaparoid - heparin-intolerance

Full Text

References

References
1 Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554-61.
2 Magnani HN. Orgaran® (danaparoid) use in the syndrome of heparin-induced thrombocytopenia. Platelets 1997; 8: 74-81.
3 Chong BH, Castaldi PA. Heparin-induced thrombocytopenia: further studies of the effects of heparindependent antibodies on platelets. Br J Haematol 1986; 64: 347-54.
4 Greinacher A, Michels I, Kiefel V. et al A rapid and sensitive test for diagnosing heparin-associated thrombocytopenia. Thromb Haemost 1991; 66: 734-6.
5 Amiral J, Bridey F, Wolf M. et al Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia. Thromb Haemost 1995; 73: 21-8.
6 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood 1986; 67/1: 27-30.
7 Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin III. Thromb Res 1977; 21: 169-73.
8 Boshkov LH, Hamilton P, Lee A. et al Successful therapy of heparin-induced thrombocytopenia with thrombosis (HITTS) in pregnancy with danaparoid sodium. Blood 1999; 94 (Suppl. 01) 102b.
9 Gerhardt A, Zotz RB, Scharf RE. Successful use of danaparoid in pregnant women with valve prosthesis and heparin-induced thrombocytopenia Type II (HIT type II). Haemostaseology 2004; 24: A77 Abstract P151.
10 Gill J, Kovacs MJ. Successful use of danaparoid in treatment of heparin-induced thrombocytopenia during twin pregnancy. Obstet Gynecol 1997; 90: 648-50.
11 Grainger JD, Hay CRM. Heparin induced thrombocytopenia caused by danaparoid sodium. Thromb Haemost 2001; 86 suppl Abstract 3458.
12 Harrison SJ, Rafferty I, McColl MD. Management of heparin allergy during pregnancy with danaparoid. Blood Coagul Fibrinolysis 2001; 12: 157-9.
13 Horellou MH, Elalamy I, Achkar A. et al Efficacy and safety of danaparoid (Orgaran® ) in venous thrombosis in pregnant women with thrombophilia and heparin- induced thrombocytopenia. Thromb Haemost 2001; 86 suppl Abstract 2997.
14 Macchi L, Sarfati R, Guicheteau M. et al Thromboembolic prophylaxis with danaparoid (Orgaran® ) in a high thrombosis risk pregnant woman with a history of heparin-induced thrombocytopenia (HIT) and Widal’s disease. Clin Appl Thromb Haemost 2000; 6: 187-9.
15 Rondeau M, Weber JC, Haffner C. et al HELLP syndrome, catastrophic antiphospholipid syndrome or heparin-induced thrombocytopenia?. J Autoimmun 2000; 15: A68.
16 Saint-Blanquat L de, Simon L, Toubas MF. et al Traitement par le danaparoide de sodium au cours de la grossesse chez une patiente présentant une allergie cutanée aux héparines de bas poids moleculaire. Ann Fr Anesth Reanim 2000; 19: 751-4.
17 Taylor AA. Successful use of heparinoids in a pregnancy complicated by allergy to heparin. BJOG 2001; 108: 1011-2.
18 Wilhelm MJ, Schmid C, Kececioglu D. et al Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996; 61: 920-4.
19 Woo Yl, Allard S, Cohen H. et al Danaparoid prophylaxis in pregnant women with heparin-induced thrombocytopenia. BJOG 2002; 109: 466-8.
20 Henny ChP, 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.
21 Besien K van, Hoffman R, Golichowski A. Pregnancy associated with lupus anticoagulant and heparininduced thrombocytopenia: management with a low molecular weight heparinoid. Thromb Res 1991; 62: 23-9.
22 Greinacher A, Eckhardt Th, Mussmann J. et al Pregnancy complicated by heparin-associated thrombocytopenia: management by a prospectively in-vitro selected heparinoid (Org 10172). Thromb Res 1993; 71: 123-6.
23 Porzelt C, Drummer B, Hoffmann A. Thromboprophylaxe in der Schwangerschaft nach Polytraumatisiering mit Splenektomie und Immobilisation bei heparininduzierter "relativer" Thrombozytopenie Typ II. Geburtsh Frauenheilk 2002; 62: 784-6.
24 Schindewolf M, Mosch G, Bauersachs RM. et al Safe anticoagulation with danaparoid in pregnancy and lactation. Thromb Haemost 2004; 92 (01) 211.
25 Gould J, Meyers B. Prophylactic danaparoid in heparin- induced thrombocytopenia presenting with skin manifestations in pregnancy. Blood Coagul Fibrinolysis 2002; 13/8: A18.
26 Deschamps A, Mathelier-Fusade P, Bernaille JL. Réaction cutanée a l’héparine pendant la grossesse: à propos d’un cas traité avec succès par le danaparoïde. Rev Française Allergol Immunol Clin 2003; 43: 131-4.
27 Horellou MH, Conard J, Achkar A. et al Treatment of thrombosis with low molecular weight heparins during 15 pregnancies in 14 women. Thromb Haemost 1997; 77 Suppl 733 Abstract 2992.
28 Lemesle FG, Mebroukine L, Ermacora P. et al Thrombose, thrombopénie sous HBPM et délivrance. La Presse Médicale 1998; 27: 19.
29 Herzog S, Rath W, Kuhn W. Successful therapy of a heparin-induced thrombocytopenia with a lowsulphated heparinoid. Geburtsh u Frauenheilk 1995; 55: 164-6.
30 Fausett MB, Vogtlander M, Lee RM. et al Heparin- induced thrombocytopenia is rare in pregnancy. Am J Obstet Gynecol 2001; 185: 148-52.
31 Peeters LLH, Vogel GMT, Hasenack HG. 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.
32 Warkentin TE, Chong BH, Greinacher A. Heparininduced thrombocytopenia: Towards consensus. Thromb Haemost 1998; 79: 1-7.
33 Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121: 535-55.
34 Greinacher A, Alban S. Heparinoide als eine Alternative für die parenterale Antikoagulation bei Patienten mit Heparin-induzierten Thrombozytopenie. Hämostaseologie 1996; 16: 41-9.
35 Grassegger A, Fritsch P, Reider N. Delayed-type Hypersensitivity and Cross-reactivity to heparins and heparinoids: a prospective study. Dermatol Surg 2001; 27: 47-52.
36 Harenberg J, Huhle G, Wang L. et al Association of heparin-induced skin lesions, intra-cutaneous tests and heparin-induced IgG. Allergy 1999; 54: 473-7.
37 Koch P Müßinger, Rupp-John C. et al Delayedtype hypersensitivity skin reactions caused by subcutaneous unfractionated and low molecular weight heparins: tolerance of a new recombinant hirudin. J Am Acad Dermatol 2000; 42: 612-9.
38 Boehncke WH, Weber L, Gall H. Toleranz gegenüber intravenöser Applikation von Heparin und Heparinoid bei einer Patientin mit Typ-IV Allergie auf Heparine und Heparinoide. Allergologie 1996; 19: 95.
39 Figarella I, Barbaud A, Lecompte T. et al Réaction cutanée d’hypersensibilité retardée avec polsensibilisation aux héparines et héparinoides. Ann Dermatol Venereol 2001; 128: 25-30.
40 Enso MHH, Stephenson MD. Low molecular weight heparins in pregnancy. Pharmacotherapy 1999; 19: 1013-25.