Risk of Pregnancy-related Venous Thrombosis in Carriers of Severe Inherited Thrombophilia^[*]

Summary

Homozygous carriers of factor V Leiden have an approximately 80-fold increased risk of venous thrombosis. Also double heterozygous carriers of both the factor V Leiden and the prothrombin gene mutations are at high thrombotic risk. The magnitude of the risk of venous thrombosis in pregnant women with the two severe thrombophilic conditions has not been estimated so far. We performed a multicenter retrospective family study in women with homozygous factor V Leiden, double heterozygous factor V Leiden and the prothrombin gene mutation, and women with normal coagulation. Only relatives of index patients with thrombosis formed the study cohort. Fifteen homozygous and 39 double heterozygous women were compared to 182 women with normal coagulation. Venous thrombosis occurred in 3 of 19, 2 of 50 and 1 of 221 pregnancies, respectively. One thrombotic episode occurred in the third trimester, the remaining 5 in the postpartum. The prevalence of venous thrombosis was 15.8% (95% CI 3.4-39.6) for homozygotes, 4.0% (95% CI 0.5-13.7) for double heterozygotes and 0.5% for women with normal coagulation. The relative risk of pregnancy-related venous thrombosis was 41.3 (95% CI 4.1-419.7) for homozygous and 9.2 (95% CI 0.8-103.2) for double heterozygous carriers. In conclusion, homozygous carriers of factor V Leiden and, to a lesser extent, double heterozygous carriers of factor V Leiden and of the prothrombin mutation have an increased risk of venous thrombosis during pregnancy, particularly high during the postpartum period. On the basis of these findings we recommend that these women receive anticoagulant prophylaxis at least in the postpartum, that should perhaps be extended to the whole pregnancy in homozygous carriers.

Keywords

Coagulation - factor V Leiden - prothrombin mutation - pregnancy - puerperium

^* This work has been done within the frame of activity of the GIRTE (Italian Research Group on Inherited Thrombophilia).

• References

• 1 Rees DC. The population genetics of factor V Leiden (Arg506Gln). Br J Haematol 1996; 95: 579-86.
• 2 Rosendaal FR, Koster T, Vandenbrouke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-8.
• 3 Poort SR, Bertina RM, Vos HL. Rapid detection of the prothrombin 20210 A variation by allele-specific PCR. Thromb Haemost 1997; 78: 974-1163.
• 4 Martinelli I, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Mannucci PM. The risk of venous thromboembolism in family members with mutations in the genes of factor V, prothrombin or both. Br J Haematol 2001; 111: 1223-9.
• 5 Andersen BS, Steffensen FH, S¯rensen HT, Nielsen GL, Olsen J. The cumulative incidence of venous thromboembolism during pregnancy and puerperium. Acta Obstet Gynecol Scand 1998; 77: 170-3.
• 6 Lindqvist P, Dahlbäck B, Marsál K. Thrombotic risk during pregnancy: a population study. Obstet Gynecol 1999; 94: 595-9.
• 7 Ray JG, Chan WS. Deep vein thrombosis during pregnancy and the puerperium: a meta-analysis of the period of risk and the leg of presentation. Obstet Gynecol Surv 1999; 54: 265-71.
• 8 Dizon-Townson DS, Nelson LM, Jang H, Varner MW, Ward K. The incidence of the factor V Leiden mutation in an obstetric population and its relationship to deep vein thrombosis. Am J Obstet Gynecol 1997; 176: 883-6.
• 9 Middeldorp S, Henkens CMA, Koopman MMW. et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Int Med 1998; 128: 15-20.
• 10 Simioni P, Sanson BJ, Prandoni P. et al. The incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81: 198-202.
• 11 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: 1324-8.
• 12 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.
• 13 Simioni P, Prandoni P, Lensing AWA. et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000; 96: 3329-33.
• 14 De Stefano V, Martinelli I, Mannucci PM. et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999; 341: 801-6.
• 15 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.
• 16 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.
• 17 McColl MD, Walker ID, Greer IA. The role of inherited thrombophilia in venous thromboembolism associated with pregnancy. Br J Obstet Gynecol 1999; 106: 756-66.
• 18 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.
• 19 Lane DA, Mannucci PM, Bauer KA. et al. Inherited thrombophilia: part 1. Thromb Haemost 1996; 76: 651-62.
• 20 Ginsberg JS, Brill-Edwards P, Burrows RF. et al. Venous thrombosis during pregnancy: leg and trimester of presentation. Thromb Haemost 1992; 67: 519-20.