Venöse Thrombose in der Schwangerschaft

R. B. Zotz; A. Gerhardt; R. E. Scharf

doi:10.1055/s-0037-1616881

Hämostaseologie, Inhaltsverzeichnis

Hamostaseologie 2006; 26(01): 63-71
DOI: 10.1055/s-0037-1616881

Original article

Schattauer GmbH

Venöse Thrombose in der Schwangerschaft

Prädiktion, Prävention und TherapiePregnancy-associated venous thromboembolic diseaseprediction, prevention, and therapy

R. B. Zotz

¹Institut für Hämostaseologie und Transfusionsmedizin, Universitätsklinikum Düsseldorf

,

A. Gerhardt

¹Institut für Hämostaseologie und Transfusionsmedizin, Universitätsklinikum Düsseldorf

,

R. E. Scharf

¹Institut für Hämostaseologie und Transfusionsmedizin, Universitätsklinikum Düsseldorf

› Institutsangaben

Abstract

Zusammenfassung

Thromboembolien sind nach wie vor führende Ursache für die mütterliche Letalität in Schwangerschaft und Wochenbett. Eine rationale und risikoadaptierte Heparin-Prophylaxe setzt 1. die Identifizierung von Frauen mit erhöhtem Thromboserisiko und 2. die genaue Quantifizierung dieses Risikos voraus.

Ohne Thrombose in der Vorgeschichte ist ein heterozygoter Faktor V Leiden oder eine heterozygote G20210A-Mutation im Prothrombin-Gen lediglich mit einem Thromboserisiko in der Schwangerschaft von ca. 1 : 400 assoziiert. Aufgrund dieses niedrigen absoluten Risikos für eine Venenthrombose ist eine Heparin-Prophylaxe in der Schwangerschaft deshalb nicht generell zu empfehlen. Bei kombiniertem Vorliegen der beiden genetischen Risikofaktoren in heterozygoter Konstellation steigt das Thromboserisiko überproportional auf ca. 1 : 25 an. Frauen mit vorausgegangener Thrombose in einer vorübergehenden definierten Risikosituation (Operation oder Trauma) ohne Nachweis eines genetischen Risikofaktors dürften ein niedriges Thromboserisiko in der Schwangerschaft haben. Die Datenlage hierzu ist jedoch widersprüchlich. Im Gegensatz dazu ist das Thromboserisiko bei Frauen mit vorausgegangenem thromboembolischen Ereignis und Nachweis hereditärer Risikomarker oder einer positiven Familienanamnese einer Thrombose deutlich erhöht (>10%). Eine Heparin-Prophylaxe anteund postpartal erscheint deshalb indiziert. Trotz des Fortschritts in der Risikostratifizierung schwangerschaftsassoziierter Thrombosen sind die genaue Beurteilung des absoluten Thromboserisikos und ein optimales Therapieregime noch in der Diskussion.

Summary

Thromboembolic disease remains a leading cause of maternal mortality during pregnancy and the puerperium. Rational and risk-adapted administration of heparin prophylaxis depends on 1. the identification of those women who have an increased risk of thrombosis and 2. the accurate quantification of this risk.

In women without prior thrombosis, the presence of a heterozygous factor V Leiden or heterozygous G20210A mutation in the prothrombin gene is associated with a pregnancy- associated thrombotic risk of approximately 1 in 400. Thus, in pregnant carriers of either one of these mutations the risk of venous thromboembolism is low. Therefore, no heparin prophylaxis is recommended. A combination of the two genetic risk factors can increase the risk to a modest level of 1 in 25. In women with a single episode of prior thrombosis associated with a transient risk factor, e. g. surgery or trauma, and no additional genetic risk factor, the probability of a pregnancy-associated thrombosis appears also to be low. However, data are sparse and conflicting. In contrast, in women with a prior idiopathic venous thrombosis who carry an additional hereditary risk factor or who have a positive family history of thrombosis, a high risk (>10%) can be expected supporting the indication for active antepartum and postpartum heparin prophylaxis. Despite the remarkable progress in risk stratification, the absolute magnitude of risk and the optimal management in many cases is an issue of ongoing debate. Pregnancy-associated venous thromboembolic disease: prediction, prevention, and therapy

Schlüsselwörter

Schwangerschaft - venöse Thrombose - Thromboseprophylaxe

Keywords

Pregnancy - venous thrombosis - prevention

Volltext

Referenzen

References
1 National Institute of Health Consensus Development Conference.. Prevention of venous thrombosis and pulmonary embolism. JAMA 1986; 256: 744-9.
2 Kierkegaard A. Incidence and diagnosis of deepvein thrombosis associated with pregnancy. Acta Obs Gynecol Scand 1983; 62: 239-43.
3 Treffers PE, Huidekoper BL, Weenink GH. et al. Epidemiological observations of thromboembolic disease during pregnancy and in the puerperium, in 56,022 women. Int J Gynecol Obs 1983; 21: 327-31.
4 Bergqvist A, Bergqvist D, Hallbook T. Deepvein thrombosis during pregnancy – a prospective-study. Acta Obs Gynecol Scand 1983; 62: 443-8.
5 Mccoll MD, Ramsay JE, Tait RC. et al. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemost 1997; 78: 1183-8.
6 The National Institute for Clinical Excellence Scottish Executive Health Department and Department of HealthSocial Services and Public Safety: Northern Ireland.. Confidential enquiries into maternal deaths in the United Kingdom 1997–99. London: TSO; 2001
7 Macklon NS, Greer IA. Venous thromboembolic disease in obstetrics and gynaecology: The Scottish experience. Scot Med J 1996; 41: 83-6.
8 Greer IA. Haemostasis and thrombosis in pregnancy. In: Bloom AL, Forbes CD, Thomas DP. et al (eds). Haemostasis and thrombosis. London: Churchill Livingstone; 1994: 987-1015.
9 Ware JA, Coller BS. Platelet morphology, biochemistry, and function. In: Beutler E, Lichtmann MA, Coller BS. et al (eds). Hematology. New York: McGraw-Hill; 1995: 1161-201.
10 Greer IA. Epidemiology, risk factors and prophylaxis of venous thrombo-embolism in obstetrics and gynaecology. Baill Clin Obs Gynaecol 1997; 11: 403-30.
11 Clark P, Brennand J, Conkie JA. et al. Activated protein C sensitivity, protein C, protein S and coagulation in normal pregnancy. Thromb Haemost 1998; 79: 1166-70.
12 Macklon NS, Greer IA, Bowman AW. An ultrasound study of gestational and postural changes in the deep venous system of the leg in pregnancy. Br J Obs Gynaecol 1997; 104: 191-7.
13 Gerhardt A, Scharf RE, Beckmann MW. et al. Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium. N Engl J Med 2000; 10 342 374-80.
14 Bergqvist D, Hedner U. Pregnancy and venous thromboembolism. Acta Obs Gynecol Scand 1983; 62: 449-53.
15 Cockett FB, Thomas ML, Negus D. Iliac vein compression – its relation to iliofemoral thrombosis and post-thrombotic syndrome. Br Med J 1967; 2: 214-9.
16 Greer IA. The challenge of thrombophilia in maternal- fetal medicine. N Engl J Med 2000; 342: 424-5.
17 Bertina RM, Koeleman BPC, Koster T. et al. Mutation in blood-coagulation factor-V associated with resistance to activated protein-C. Nature 1994; 369: 64-7.
18 Poort SR, Rosendaal FR, Reitsma PH. et al. A common genetic variation in the 3‘-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
19 Virchow R. Phlogose und Thrombose im Gefäßsystem. Gesammelte Abhandlungen zur Wissenschaftlichen Medizin. 1856
20 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353: 1453-7.
21 Conard J, Horellou MH, Vandreden P. et al. Thrombosis and pregnancy in congenital deficiencies in AT-III, protein-C or protein-S – study of 78 women. Thromb Haemost 1990; 63: 319-20.
22 DeStefano V, Leone G, Mastrangelo S. et al. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin- III, protein-C, protein-S. Thromb Haemost 1994; 71: 799-800.
23 Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency – A cooperative, retrospective study. Arteriosclerosis Thromb Vasc Biol 1996; 16: 742-8.
24 Friederich PW, Sanson BJ, Simioni P. et al. Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: Implications for prophylaxis. Ann Intern Med 1996; 125: 955-60.
25 Gerhardt A, Scharf RE, Zotz RB. Effect of hemostatic risk factors on the individual probability of thrombosis during pregnancy and the puerperium. Thromb Haemost 2003; 90: 77-85.
26 Dahlback B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein-C – prediction of a cofactor to activated protein-C. Proc Nat Acad Sci USA 1993; 90: 1004-8.
27 Koster T, Rosendaal FR, Briet E. et al. Protein-C deficiency in a controlled series of unselected outpatients – an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995; 85: 2756-61.
28 Van den Belt AGM, Prins MH, Huisman MV. et al. Familial thrombophilia: A review analysis. Clin Appl Thromb Hemost 1996; 2: 227-36.
29 Hellgren M, Svensson PJ, Dahlback B. Resistance to activated protein-C as a basis for venous thromboembolism associated with pregnancy and oralcontraceptives. Am J Obs Gynecol 1995; 173: 210-3.
30 Hallak M, Senderowicz J, Cassel A. et al. Activated protein C resistance (factor V Leiden) associated with thrombosis in pregnancy. Am J Obs Gynecol 1997; 176: 889-93.
31 Bokarewa MI, Bremme K, Blomback M. Arg(506)-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol 1996; 92: 473-8.
32 Grandone E, Margaglione M, Colaizzo D. et al. Genetic susceptibility to pregnancy-related venous thromboembolism: Roles of factor V Leiden, prothrombin G20210A, and methylenetetrahydrofolate reductase C677T mutations. Am J Obs Gynecol 1998; 179: 1324-8.
33 Mccoll MD, Ellison J, Reid F. et al. Prothrombin 20210 G -> A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy. Br J Obs Gynaecol 2000; 107: 565-9.
34 Martinelli I, De Stefano V, Taioli E. et al. Inherited thrombophilia and first venous thromboembolism during pregnancy and puerperium. Thromb Haemost 2002; 87: 791-5.
35 Rosendaal FR, Koster T, Vandenbroucke JP. et al. High-risk of thrombosis in patients homozygous for factor-V Leiden (activated protein-C resistance). Blood 1995; 85: 1504-8.
36 Emmerich J, Rosendaal FR, Cattaneo M. et al. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism – Pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Thromb Haemost 2001; 86: 809-16.
37 Pabinger I, Nemes L, Rintelen C. et al. Pregnancyassociated risk for venous thromboembolism and pregnancy outcome in women homozygous for factor V Leiden. Hematol J 2000; 1: 37-41.
38 Middeldorp S, Libourel EJ, Hamulyak K. et al. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden. Br J Haematol 2001; 113: 553-5.
39 Smirnov MD, Safa O, Esmon NL. et al. Inhibition of activated protein C anticoagulant activity by prothrombin. Blood 1999; 94: 3839-46.
40 Butenas S, van’t Veer C, Mann KG. ,,Normal“ thrombin generation. Blood 1999; 94: 2169-78.
41 Rosendaal FR, Doggen CJM, Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79: 706-8.
42 Seligsohn U, Lubetsky A. Medical progress: Genetic susceptibility to venous thrombosis. N Engl J Med 2001; 344: 1222-31.
43 Ginsberg JS, Wells PS, BrillEdwards P. et al. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-91.
44 Mateo J, Oliver A, Borrell M. et al. Laboratory evaluation and clinical characteristics of 2,132 consecutive unselected patients with venous thromboembolism – Results of the Spanish multicentric study on thrombophilia (EMET-study). Thromb Haemost 1997; 77: 444-51.
45 Khamashta MA, Cuadrado MJ, Mujic F. et al. The management of thrombosis in the antiphospholipid- antibody syndrome. N Engl J Med 1995; 332: 993-7.
46 Wilson WA, Gharavi AE, Koike T. et al. International consensus statement on preliminary classification criteria for definite antiphospholipid syndrome – Report of an international workshop. Arth Rheum 1999; 42: 1309-11.
47 Gharavi AE, Pierangeli SS. Origin of antiphospholipid antibodies: induction of aPL by viral peptides. Lupus 1998; 7: S52-4.
48 Gharavi AE, Sammaritano LR, Wen JY. et al. Characteristics of human-immunodeficiency-virus and chlorpromazine-induced antiphospholipid antibodies – effect of beta(2), glycoprotein-I on binding to phospholipid. J Rheum 1994; 21: 94-9.
49 Love PE, Santoro SA. Antiphospholipid antibodies – anticardiolipin and the lupus anticoagulant in systemic lupus erythematosus (Sle) and in non- Sle disorders – prevalence and clinical significance. Ann Intern Med 1990; 112: 682-98.
50 Long AA, Ginsberg JS, BrillEdwards P. et al. The relationship of antiphospholipid antibodies to thromboembolic disease in systemic lupus erythematosus – A cross-sectional study. Thromb Haemost 1991; 66: 520-4.
51 Ginsberg JS, BrillEdwards P, Johnston M. et al. Relationship of antiphospholipid antibodies to pregnancy loss in patients with systemic lupus erythematosus – A cross-sectional study. Blood 1992; 80: 975-80.
52 Simioni P, Prandoni P, Zanon E. et al. Deep venous thrombosis and lupus anticoagulant – A case-control study. Thromb Haemost 1996; 76: 187-9.
53 Zotz RB, Gerhardt A, Scharf RE. Prediction, prevention, and treatment of venous thromboembolic disease in pregnancy. Sem Thromb Hemost 2003; 29: 143-53.
54 Zotz RB, Gerhardt A, Scharf RE. Inherited thrombophilia and gestational venous thromboembolism. Best Pract Clin Haematol 2003; 16: 243-59.
55 Brill-Edwards P, Ginsberg JS, Gent M. et al. Safety of withholding heparin in pregnant women with a history of venous thromboembolism. N Engl J Med 2000; 343: 1439-44.
56 Pabinger I, Grafenhofer H, Kaider A. et al. Risk of pregnancy-associated recurrent venous thromboembolism in women with a history of venous thrombosis. J Thromb Haemost 2005; 3: 949-54.
57 Zotz RB, Gerhardt A, Scharf RE. Venöse Thrombose in der Schwangerschaft. Hämostaseologie 2006; 26: 63-71.
58 Pabinger I, Grafenhofer H, Kyrle PA. et al. Temporary increase in the risk for recurrence during pregnancy in women with a history of venous thromboembolism. Blood 2002; 100: 1060-2.
59 Bates SA, Greer IA, Hirsh J. et al. Use of antithrombotic agents during pregnancy. Chest 2004; 126: 627S-44S.
60 Greer IA. Thrombosis in pregnancy: maternal and fetal issues. Lancet 1999; 353 9160 1258-65.
61 Preston FE, Rosendaal FR, Walker ID. et al. Increased fetal loss in women with heritable thrombophilia. Lancet 1996; 348 9032 913-6.
62 Rushton ID. Placental pathology in spontaneous miscarriage. In: Beard RWSF. (ed.) Early pregnancy loss: mechanisms and treatment. London: RCOG; 1988: 149-58.
63 Warkentin TE, Levine MN, Hirsh J. et al. Heparininduced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin. N Engl J Med 1995; 332: 1330-5.
64 Sanson BJ, Lensing AWA, Prins MH. et al. Safety of low-molecular-weight heparin in pregnancy: A systematic review. Thromb Haemost 1999; 81: 668-72.
65 Douketis JD, Ginsberg JS, Burrows RF. et al. The effects of long-term heparin therapy during pregnancy on bone density – A prospective matched cohort study. Thromb Haemost 1996; 75: 254-7.
66 Pettila V, Kaaja R, Leinonen P. et al. Thromboprophylaxis with low molecular weight heparin (dalteparin) in pregnancy. Thromb Res 1999; 96: 275-82.
67 Elkayam U. Pregnancy through a prosthetic heart valve. J Am Coll Cardiol 1999; 33: 1642-5.
68 Chan WS, Anand S, Ginsberg JS. Anticoagulation of pregnant women with mechanical heart valves – A systematic review of the literature. Arch Intern Med 2000; 160: 191-6.
69 Guyatt G, Schunemann HJ, Cook D. et al. Applying the grades of recommendation for antithrombotic and thrombolytic therapy – The Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest 2004; 126: 179S-87S.
70 Gerhardt A, Zotz RB, Struve S. et al. Homozygous and combined heterozygous factor V G1691A and prothrombin G20210A mutations as predictors of venous thrombosis during pregnancy. Thromb Haemost 2001; (Suppl) A2982.
71 Lindqvist PG, Svensson PJ, Marsal K. et al. Activated protein C resistance (FV : Q(506)) and pregnancy. Thromb Haemost 1999; 81: 532-7.
72 Martinelli I, Legnani C, Bucciarelli P. et al. Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia. Thromb Haemost 2001; 86: 800-3.
73 Ginsberg JS, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy. Chest 2001; 119: 122S-31S.
74 Mccoll MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obs Gynaecol 1999; 106: 756-66.