Danaparoid in der Schwangerschaft bei Heparinunverträglichkeit

Zusammenfassung

Unter Therapie mit unfraktioniertem oder niedermolekularem Heparin treten häufig unerwünschte Arzneimittelwirkungen auf, die eine Fortsetzung der Therapie unmöglich machen. Insbesondere bei Schwangeren mit thromboembolischen Komplikationen kann es schwierig sein, ein geeignetes alternatives Antikoagulans zu finden, wenn zusätzlich eine Heparinunverträglichkeit vorliegt. Für den Einsatz von Danaparoid in der Schwangerschaft gibt es nur wenige Daten. Die Hauptgründe in den untersuchten 59 Schwangerschaften für eine Heparinunverträglichkeit waren entweder eine HIT II bei 37/59 (62,7%) Schwangeren, oder eine kutane Nebenwirkung in 19/22 (86,4%) der nicht HIT-assoziierten Schwangerschaften (22/59, 37,3%). Ergebnisse: 40/59 Schwangerschaften konnten unter Danaparoid erfolgreich ausgetragen werden, bei 16/19 wurde die Therapie aufgrund unerwünschter Arzneimittelwirkungen beendet. Fünf Patientinnen zeigten Blutungskomplikationen, die ebenso wenig Danaparoid-assoziiert waren wie die berichteten sechs Aborte und eine Abruptio. In 31/59 (52,5%) Schwangerschaften traten unerwünschte Arzneimittelwirkungen auf, 14/31 (45,2%) ließen sich auf Danaparoid zurückführen. In fünf Nabelschnurblut- und vier Brustmilchproben konnte keine Anti- Xa-Aktivität gemessen werden. Schlussfolgerung: Danaparoid kann zur alternativen Antikoagulation bei Schwangeren mit hohem Thromboserisiko und Heparinunverträglichkeit eingesetzt werden.

Summary

During the use of fractionated or unfractionated heparin adverse events frequently occur that can endanger the continuation of therapy. Especially in pregnant patients with thromboembolic complications it may be difficult to find a suitable alternative anticoagulant when heparin-induced thrombocytopenia type II (HIT II) or allergic skin reactions occur. There are still limited data on the use of danaparoid in pregnancy. The main reason for heparin intolerance in the 59 reviewed pregnancies were either HIT II, described in 37/59 (62.7%) pregnancies, or cutaneous adverse effects in 19/22 (86.4%) of non-HIT-associated pregnancies (22/59, 37.3%). Results: 40/59 pregnancies were carried to term under use of danaparoid and resulted in the delivery of a healthy infant. In 16/19 pregnancies, danaparoid was stopped due to a major adverse event. Five patients showed bleeding complications, seven fetal losses were documented, but there was no association with the use of danaparoid. In 31/59 (52.5%) pregnancies adverse events were documented, 14/31 (45.2%) could be attributed to danaparoid. Anti-Xa-activity was not detected in five fetal cord blood samples and in four maternal breastmilk samples. Conclusion: Danaparoid can be used as an alternative anticoagulant in pregnant women with high risk for thrombosis and heparin intolerance.

Schlüsselwörter

Schwangerschaft - Danaparoid - heparininduzierte Thrombozytopenie - heparininduzierte Hautveränderungen - Heparinintoleranz

Keywords

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

• Literatur

• 1 Amiral J, Bridey F, Wolf M. et al. Antibodies to macromolecular platelet factor 4-heparin complexes in heparin-induced thrombocytopenia. Thromb Haemost 1995; 73: 21-28.
• 2 Bank I, Libourel EJ, Middeldorp S. et al. High rate of skin complications due to low-molecularweight heparins in pregnant women. J Thromb Haemost 2003; 1: 859-861.
• 3 Besien K van, Hoffman R, Golichowski A. Pregnancy associated with lupus anticoagulant and heparin- induced thrombocytopenia: management with a low molecular weight heparinoid. Thromb Res 1991; 62: 23-29.
• 4 Bjorge L, Ernst P, Haram KO. Paroxysmal nocturnal hemoglobinuria in pregnancy. Acta Obstet Gynecol Scand 2003; 82: 1067-1071.
• 5 Blickstein D, Hod M, Bar J. Eczematous plaques related to unfracionated and low-molecularweight heparin in pregnancy: cross-reaction with danaparoid sodium. Blood Coagul Fibrinolysis 2003; 765-768.
• 6 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. Allergol 1996; 19: 95.
• 7 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 S1 102b.
• 8 Chong BH, Castaldi PA. Heparin-induced thrombocytopenia: further studies of the effects of heparin- dependent antibodies on platelets. Br J Haematol 1986; 64: 347-354.
• 9 Deschamps A, Mathelier-Fusade P, Bernaille JL. Réaction cutanée à l’héparine pendant la grossesse: à propos d’un cas traité avec succès par le danaparoide. Rev Franc Allergol Immunol Clin 2003; 43: 131-134.
• 10 Dikensoy E, Dikensoy O, Graves C. et al. Heparin induced thrombocytopenia: how to manage when the patient is pregnant ?. Tuberk Toraks 2005; 53: 115-120.
• 11 Eichler P, Budde U, Haas S. et al. First workshop for detection of heparin-induced antibodies: validation of the heparin-induced platelet-activation test (HIPA) in comparison with PF4/heparin ELISA. Thromb Haemost 1999; 81: 625-629.
• 12 Enso MHH, Stephenson MD. Low molecular weight heparins in pregnancy. Pharmacotherapy 1999; 19: 1013-1025.
• 13 Fausett MB, Vogtlander M, Lee RM. et al. Heparininduced thrombocytopenia is rare in pregnancy. Am J Obstet Gynecol 2001; 185: 148-152.
• 14 Figarella I, Barbaud A, Lecompte T. et al. Cutaneous delayed hypersensitivity reactions to heparins and heparinoids. Ann Dermtol Venerol 2001; 128: 25-30.
• 15 Gerhardt A, Zotz RB, Scharf RE. Successful use of danaparoid in pregnant women with valve prosthesis and heparin-induced thrombocytopenia (HIT type II). Haemostaseology 2004; 24: A77 P151.
• 16 Gill J, Kovacs MJ. Successful use of danaparoid in treatment of heparin-induced thrombocytopenia during twin pregnancy. Obstet Gynecol 1997; 90: 648-650.
• 17 Grainger JD, Hay CRM. Heparin induced thrombocytopenia caused by danaparoid sodum. Thromb Haemost 2001; 86 S1 A3458.
• 18 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.
• 19 Greinacher A, Alban S. Heparinoide als eine Alternative für die parenterale Antikoagulation bei Patienten mit Heparin-induzierter Thrombozytopenie. Hämostaseologie 1996; 16: 41-49.
• 20 Greinacher A, Eckhardt TH, Mussmann J. et al. Pregnancy complicated by heparin-induced thrombocytopenia: management by a prospectively in-vitro selected heparinoid (Org 10172). Thromb Res 1993; 71: 123-126.
• 21 Halimeh S, Rott T, Trobisch H. Fondaparinux: a selective factor Xa inhibitor in pregnancy. Haemostaseologie 2004; 24: A40 P6.
• 22 Harenberg J, Huhle G, Wang L. et al. Association of heparin-induced skin lesions, intra-cutaneous tests and heparin-induced IgG. Allergy 1999; 54: 473-477.
• 23 Harrison SJ, Rafferty I, McColl MD. Management of heparin allergy during pregnancy with danaparoid. Blood Coagul Fibrinolysis 2001; 12: 157-159.
• 24 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.
• 25 Herzog S, Rath W, Kuhn W. Successful therapy of a heparin-induced thrombocytopenia with a lowsulphated heparinoid. Geburtsh Frauenheilk 1995; 55: 164-166.
• 26 Horellou MH, Conard J, Achkar A. et al. Treatment of thrombosis with low molecular heparins during 15 pregnancies in 14 women. Thromb Haemost 1997; 733 S1 A2992.
• 27 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 S1 A2997.
• 28 Koch P, Munssinger T, Rupp-John C. et al. Delayed- type hypersensitivity skin reactions caused by subcutaneous unfractionated and low molecular weight heparins: tolerance of a new recombinant hirudin. JAmAcad Dermatol 2000; 42: 612-619.
• 29 Lemesle FG, Mebroukine L, Ermacora P. et al. Thrombose, Thrombopénie sous HBPM et délivrance. Press Méd 1998; 27: 19.
• 30 Lindhoff-Last E, Kreutzenbeck HJ, Magnani HN. Treatment of 51 pregnancies with danaparoid because of heparin intolerance. Thromb Haemost 2005; 93: 63-69.
• 31 Ludwig RJ, Schindewolf M, Alban S. et al. Molecular weight determines the frequency of delayed type hypersensitivity reactions to heparin and synthetic oligosaccharides. Thromb Haemost 2005; 94: 1265-1269.
• 32 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: 187-189.
• 33 Magnani HN. Heparin-induced thrombocytopenia (HIT): an overview of 230 patients treated with Orgaran (Org 10172). Thromb Haemost 1993; 70: 554-561.
• 34 Magnani HN. Orgaran® (danaparoid) use in the syndrome of heparin-induced thrombocytopenia. Platelets 1997; 8: 74-81.
• 35 Meuleman DG. Orgaran (Org 10172): its pharmacological profile in experimental models. Haemostasis 1992; 22: 58-65.
• 36 Morikawa M, Yamada H, Kato EH. et al. Failure of thromboprophylaxis in pregnancy caused by dual deficiencies of protein S and protein C. Semin Thromb Hemost 2005; 31: 261-265.
• 37 Myers B, Westby J, Strong J. Prophylactic use of danaparoid in high-risk pregnancy with heparininduced thrombocytopenia-positive skin reaction. Blood Coagul Fibrinolysis 2003; 14: 485-587.
• 38 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: 277-283.
• 39 Porzelt C, Drummer B, Hoffmann A. Thromboprophylaxe in der Schwangerschaft nach Polytraumatisierung mit Splenektomie und Immobilisation bei heparininduzierter ,,relativer“ Thrombozytopenie Typ II. Geburtsh Frauenheilk 2002; 62: 784-786.
• 40 Rondeau M, Weber JC, Haffner C. et al. HELLP syndrome, catastrophic antiphospholipid syndrome or heparin-induced thrombocytopenia?. J Autoimmun 2000; 15: A68.
• 41 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: 751-754.
• 42 Schindewolf M, Erbe M, Klaeffling C. et al. Danaparoid in a pregnant patient with former HIT, homozygous factor V Leiden mutation and a history of pregnancy losses. VASA 2005; 34 (Suppl. 67) 32.
• 43 Schindewolf M, Ludwig RJ, Kroll H. et al. Cutaneous delayed-type IV-hypersensitivity reaction (DTH) to heparin and heparin-induced thrombocytopenia type II (HIT) – similar clinical picture, different pathogenesis. VASA 2005; 34: 44-45.
• 44 Schindewolf M, Mosch G, Bauersachs RM. et al. Safe anticoagulation with danaparoid in pregnancy and lactation. Thromb Haemost 2004; 92: 211.
• 45 Schinzel H, Buehler G, Peetz D. et al. Management der akuten heparininduzierten Thrombozytopenie Typ II währen der Schwangerschaft und peripartal. Geburtsh Frauenheilk 2004; 64: 1098-1105.
• 46 Sekiyama K, Itoh H, Sagawa N. et al. Successful management of a pregnant woman with heterozygous protein C deficiency using activated protein C concentrate. J Obstet Gynaecol Res 2003; 29: 412-415.
• 47 Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-idnuced thrombocytopenia. Blood 1986; 67: 27-30.
• 48 Taylor AA. Successful use of heparinods in a pregnancy complicated by allergy to heparin. Br J Obst Gyn 2001; 108: 1011-1012.
• 49 Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin III. Thromb Res 1977; 21: 169-173.
• 50 Warkentin TE, Chong BH, Greinacher A. Heparin- induced thrombocytopenia: Towards consensus. Thromb Haemost 1998; 79: 1-7.
• 51 Warkentin TE. Heparin-induced thrombocytopenia: pathogenesis and management. Br J Haematol 2003; 121: 535-555.
• 52 Wilhelm MJ, Schmid C, Kececioglu D. et al. Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia using Org 10172. Ann Thorac Surg 1996; 61: 920-924.
• 53 Woo YL, Allard S, Cohen H. et al. Danaparoid prophylaxis in pregnant women with heparin-induced thrombocytopenia. Br J Obst Gyn 2002; 109: 466-468.