Inherited Thrombophilia and Gestational Venous Thromboembolism

ABSTRACT

Inherited thrombophilias are associated with an increased risk of venous thromboembolism (VTE) and the risk is further increased during pregnancy. However, not all pregnancies or all thrombophilias carry the same risk. Deficiencies in coagulation inhibitors and especially in antithrombin are rare but are associated with a higher risk than the most frequent factor V Leiden or prothrombin (factor II) 20210A mutations. Differences may be observed depending on heterozygosity or homozygosity of the defects and on the presence of combined thrombophilias. Although we now have more information on the global risk of thrombosis in thrombophilia, the magnitude of the risk is unknown in women who do or do not have a history of VTE, and in those who are the propositus or family members. Additional risk factors may be taken into account such as age of the mother, cesarean section, obesity, and immobilization during pregnancy. Recommendations of the American College of Chest Physicians (ACCP) concerning prophylaxis during pregnancy published in 2001 are mostly 1C recommendations; they are based on observational studies and subject to changes when more information becomes available. There is now a consensus about prevention in the postpartum period in women with thrombophilia. In contrast, prophylaxis in the antepartum period is often determined on an individual basis. We give some indications of the appropriate prophylaxis on the basis of the ACCP recommendations and personal experience.

KEYWORDS

Thrombophilia - pregnancy - venous thrombosis - prophylaxis - anticoagulants

REFERENCES

• 1 Lane D A, Mannucci P M, Bauer K A. et al . Inherited thrombophilia: part 1.  Thromb Haemost . 1996;  76 651-662
• 2 Lane D A, Mannucci P M, Bauer K A. et al . Inherited thrombophilia: part 2.  Thromb Haemost . 1996;  76 824-834
• 3 Rosendaal F R. Risk factors for venous thrombotic disease.  Thromb Haemost . 1999;  82 610-619
• 4 Seligsohn U, Lubetsky A. Genetic susceptibility to venous thrombosis.  N Engl J Med . 2001;  344 1222-1231
• 5 Tilburg N HV, Rosendaal F R, Bertina R M. Thrombin activatable fibrinolysis inhibitor and the risk for deep vein thrombosis.  Blood . 2000;  95 2855-2859
• 6 Rosendaal F R, Vessey M, Rumley A. et al . Hormone replacement therapy, prothrombotic mutations and the risk of venous thrombosis.  Br J Haematol . 2002;  116 851-854
• 7 Bucciarelli P, Rosendaal F R, Tripodi A. et al . Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance.  Arterioscler Thromb Vasc Biol . 1999;  19 1026-1033
• 8 Lensen R PM, Rosendaal F R, Köster T. et al . Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients.  Blood . 1996;  88 4205-4208
• 9 Martinelli I, Bucciarelli P, Margaglione M. et al . The risk of venous thromboembolism in family members with mutations of the genes of factor V or prothrombin or both.  Br J Haematol . 2000;  111 1223-1229
• 10 Emmerich J, Rosendaal F R, Cattaneo M. et al . Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism.  Thromb Haemost . 2001;  86 809-816
• 11 De Stefano V, Martinelli I, Mannucci P M. et al . The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and G20210A prothrombin mutation.  N Engl J Med . 1999;  341 214-215
• 12 Conard J, Horellou M H, Van Dreden P. et al . Homozygous protein C deficiency with late onset and recurrent coumarin induced skin necrosis.  Lancet . 1992;  339 743-744
• 13 The Procare Group. Comparison of thrombotic risk between 85 homozygotes and 481 heterozygotes carriers of the factor V Leiden mutation: retrospective analysis from the Procare Study.  Blood . 2000;  11 511-518
• 14 Greer I A. Thrombosis in pregnancy: maternal and fetal issues.  Lancet . 1999;  353 1258-1265
• 15 Brandt P. Observations during the treatment of antithrombin III deficient women with heparin and antithrombin concen/trate during pregnancy, parturition and abortion.  Thromb Res . 1981;  22 15-24
• 16 Mathieux V, Conard J, Horellou M H, Elalamy I, Samama M. Pregnancy in hereditary antithrombin deficient women. Single center study of 162 pregnancies in 59 women. In preparation. 
• 17 Gompel A, Levy D, Conard J. Ovarian hyperstimulation and thrombosis. In: Brenner B, Marder VJ, Conard J, eds. Women's Issues in Thrombosis and Hemostasis London: Martin Dunitz 2002: 143-150
• 18 Conard J, Horellou M H, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women.  Thromb Haemost . 1990;  63 319-320
• 19 Pabinger I, Schneider B. Thrombotic risk in hereditary antithrombin III, protein C and protein S deficiency.  Arterioscl Thromb Vasc Biol . 1996;  16 742-748
• 20 Friederich P W, Sanson B J, Simioni P. et al . Frequency of pregnancy-related venous thromboembolism in anticoagulant factor-deficient women: implications for prophylaxis.  Ann Intern Med . 1996;  125 955-960
• 21 Simioni P, Sanson B J, Prandoni P. et al . Incidence of venous thromboembolism in families with inherited thrombophilia.  Thromb Haemost . 1998;  81 198-202
• 22 Middeldorp S, Henkens C MA, Koopman M MW. et al . The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.  Ann Intern Med . 1998;  128 15-20
• 23 Martinelli I, Legnani C, Bucciarelli P. et al . Risk of pregnancy-related venous thrombosis in carriers of severe inherited thrombophilia.  Thromb Haemost . 2001;  86 300-303
• 24 Samama M, Conard J, Nassiri S. et al . Comparaison de deux groupes de 22 femmes homozygotes ou hétérozygotes pour la mutation du facteur V Leiden.  Bull Acad Natle Méd . 1997;  181 919-937
• 25 Middledorp S, Libourel E J, Hamulyak K, van der Meer J, Büller H R. The risk of pregnancy-related venous thromboembolism in women who are homozygous for factor V Leiden.  Br J Haematol . 2001;  113 553-555
• 26 Hellgren M, Tengborn L, Abildgaard U. Pregnancy in women with congenital antithrombin III deficiency. Experience of treatment with heparin and antithrombin.  Gynecol Obstet Invest . 1982;  14 127-141
• 27 Green P J. Antithrombin III and subcutaneous heparin.  Lancet . 1980;  1 103-104
• 28 Samson D, Stirling Y, Wolf L. et al . Management of planned pregnancy in a patient with congenital antithrombin III deficiency.  Br J Haematol . 1984;  56 243-249
• 29 Pabinger I, Kyrle P A, Heistinger M. et al . The risk of thromboembolism in asymptomatic patients with protein C and protein S deficiency: a prospective cohort study.  Thromb Haemost . 1994;  71 441-445
• 30 Sanson B J, Simioni P, Tormene D. et al . The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C or protein S: a prospective cohort study.  Blood . 1999;  94 3702-3706
• 31 McColl M D, Ramsay J E, Tait R C. et al . Risk factors for pregnancy associated venous thromboembolism.  Thromb Haemost . 1997;  78 1183-1188
• 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 Obstet Gynecol . 1998;  179 1324-1328
• 33 Gerhardt A, Scharf R E, Beckmann M W. et al . Prothrombin and factor V mutations in women with a history of thrombosis during pregnancy and the puerperium.  N Engl J Med . 2000;  342 374-380
• 34 McColl M D, Ellison J, Reid F. et al . Prothrombin 20210 G→A, MTHFR C677T mutations in women with venous thromboembolism associated with pregnancy.  Br J Obstet Gynaecol . 2000;  107 565-569
• 35 Martinelli I, Taioli E, Bucciarelli P, Akhavan S, Mannucci P M. Interaction between the G20210A mutation of the prothrombin gene and oral contraceptive use in deep vein thrombosis.  Arterioscler Thromb Vasc Biol . 1999;  19 700-703
• 36 Brill-Edwards P, Ginsberg J, Gent M. et al . Safety of withholding heparin in pregnant women with a history of venous thromboembolism.  N Engl J Med . 2000;  343 1439-1444
• 37 Ginsberg J S, Greer I, Hirsh J. Use of antithrombotic agents during pregnancy.  Chest . 2001;  119 122S-131S
• 38 Sanson B J, Lensing A WA, Prins M H. et al . Safety of low-molecular-weight heparin in pregnancy: a systematic review.  Thromb Haemost . 1999;  81 668-672
• 39 Lepercq J, Conard J, Borel-Derlon A. et al . Venous thromboembolism during pregnancy: a retrospective study of enoxaparin safety in 624 pregnancies.  Br J Obstet Gynaecol . 2001;  108 1134-1140
• 40 Macchi L, Sarfati R, Guicheteau M. et al . Thromboembolic prophylaxis with danaparoid (Orgaran;rM) in a high-thrombosis-risk pregnant woman with a history of heparin-induced thrombocytopenia (HIT) and Widal's disease.  Clin Appl Thromb Hemost . 2000;  6 187-189
• 41 Harrison S J, Rafferty I, McColl M D. Management of heparin allergy during pregnancy with danaparoid.  Blood Coagul Fibrinolysis . 2001;  12 157-159
• 42 McColl M D, Walker I D, Greer I A. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy.  Br J Obstet Gynaecol . 1999;  106 756-766
• 43 Walker I D, Greaves M, Preston F E. Investigation and management of hereditable thrombophilia.  Br J Haematol . 2001;  114 512-528
• 44 Mannucci P M, Boyer C, Wolf M, Tripodi A, Larrieu M J. Treatment of congenital antithrombin III deficiency with concentrates.  Br J Haematol . 1982;  50 531-535
• 45 Handeland G F, Abildgaard U. In vivo recovery of antithrombin concentrates.  Thromb Res . 1985;  39 133-138