Association of factor V gene polymorphisms (Leiden; Cambridge; Hong Kong and HR2 haplotype) with recurrent idiopathic pregnancy loss in Tunisia

Summary

Inherited thrombophilia has been shown to be linked with fetal loss. We performed a case-control study on the association between thrombosis-related polymorphisms in the factor V (FV) gene (Leiden, Cambridge, Hong Kong; HR2 haplotype) and idiopathic recurrent pregnancy loss (RPL) in Tunisian women. A total of 348 women with RPL, and 203 control women were studied, corresponding to 1,250 pregnancy losses and 1,200 successful pregnancies. FV Leiden was seen in 19.4% of patients (4.3% in the homozygous state) and in 5.5% of controls. The prevalence of the FV HR2 haplotype was similar in patients and controls, but with 7 homozygous patients for 1 control. FV Cambridge and Hong Kong were absent from both patients and controls. The study of all pregnancy losses evidenced that the frequency of the factor V Leiden polymorphism was zero in women who had miscarried before7 weeks of gestation, and then sharply increased to a plateau. After categorization of pregnancy losses (before8 weeks of gestation; weeks 8 and 9; weeks 10 to 12; from the 13^th week of gestation onwards), heterozygous and homozygous factor V Leiden polymorphisms, and homozygous FV HR2 haplotype, were associated with significant and independent risks of pregnancy loss during weeks 8 and 9, which increased during weeks 10 to 12, then culminated after week 12. In Tunisian women with idiopathic RPL, factor V Leiden polymorphism and homozygous FV HR2 haplotype are not a risk factor for very early pregnancy loss, before 8 weeks of gestation, but are thereafter associated with significant clinical risks, which gradually increase from the 8^th week onwards.

Keywords

Pregnancy loss - Factor V Leiden mutation - Factor V HR2 haplotype

• References

• 1 Regan L, Rai R. Epidemiology and the medical causes of miscarriage. Bailleres Best Pract Res Clin Obstet Gynecol 2000; 14: 839-54.
• 2 Brenner B. Inherited thrombophilia and fetal loss. Curr Opin Hematol 2000; 07: 290-5.
• 3 Martinelli I, Taioli E, Cetin I. et al. Mutation in coagulation factors in women with unexplained fetal loss. N Engl J Med 2000; 343: 1015-8.
• 4 Lane DA, Grant PJ. Role of haemostatic gene polymorphisms in venous and arterial thrombotic disease. Blood 2000; 95: 1517-32.
• 5 Bertina RM. Genetic approach to thrombophilia. Thromb Haemost 2001; 86: 92-103.
• 6 Nicolaes GA, Dahlback B. Factor V and thrombotic disease: description of a janus faced protein. Arterioscler Thromb Vasc Biol 2002; 22: 530-8.
• 7 Rosendaal FR. Thrombosis series: venous thrombosis: a multi causal disease. Lancet 1993; 353: 1167-73.
• 8 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 65-7.
• 9 Lunghi B, Iacoviello L, Gemmanti D. et al. Detection of new polymorphic markers in the factor V gene: association with factor V levels in plasma. Thromb Haemost 1996; 75: 45-8.
• 10 Bernardi F, Faioni EM, Castoldi E. et al. A factor V genetic component differing from factor V R506Q contributes to activated protein C resistance phenotype. Blood 1997; 90: 1552-7.
• 11 De Visser MC, Guasch JF, Kamphuisen PW. et al. The HR2 haplotype of factor V: effects on factor V levels normalized activated protein C sensitivity ratios and the risk of venous thrombosis. Thromb Haemost 2000; 83: 577-82.
• 12 Faioni EM, Franchi F, Bucciarelli B. et al. Co-inheritance of the HR2 haplotype in the factor V gene confers an increased risk of venous thrombosis to carriers of factor V R506Q (Factor V Leiden). Blood 1999; 94: 3062-4.
• 13 Folsom AR, Cushman M, Tsai MY. et al. A prospective study of venous thromboembolism in relation to factor V Leiden and related factors. Blood 2002; 99: 2720-5.
• 14 Chan WP, Lee CK, Kwong YL. et al. A novel mutation of Arg306 of factor V gene in Hong Kong Chinese. Blood 1998; 91: 1135-9.
• 15 Williamson D, Brown K, Luddington R. et al. Factor V Cambridge: a new mutation (Arg306Thr) associated with resistance to activated protein C. Blood 1998; 91: 1140-4.
• 16 Liang R, Lee CK, Wat MS. et al. Clinical significance of Arg306 mutations of factor V gene. Blood 1998; 92: 2599-600.
• 17 Mtiraoui N, Borgi L, Hizem S. et al. Prevalence of antiphospholipid antibodies, factor V G1691A (Leiden) and prothrombin G20210A mutations in early and late recurrent pregnancy losses. Eur J Obstet Gynecol Reprod Biol 2005; 119: 164-70.
• 18 Lissalde-Lavigne G, Fabbro-Peray P, Cochery ENouvellon. et al. Factor V Leiden and Prothrombin G20210A polymorphisms as risk factors for miscarriage during a first intended pregnancy: the matched case-control “NOHA First” study. J Thromb Haemost 2005; 03: 2178-84.
• 19 Rey E, Kahn S R, David M. et al. Thrombophilic disorders and fetal loss:a meta-analysis. Lancet 2003; 361: 901-8.
• 20 Cohen J. Sorting out chromosome errors. Science 2002; 296: 2164-6.
• 21 Dudding TE, Attia J. The association between adverse pregnancy outcomes and factor V Leiden genotype: a meta-analysis. Thromb Haemost 2004; 91: 700-11.
• 22 Kovalevsky G, Gracia CR, Berlin JA. et al. Evaluation of the association between hereditary thrombophilias and recurrent pregnancy loss. Arch Intern Med 2004; 164: 558-63.
• 23 Roqué H, Paidas MJ, Funai EF. et al. Maternal thrombophilias are not associated with early pregnancy loss. Thromb Haemost 2004; 91: 290-5.
• 24 Makikallio K, Tekay A, Jouppila P. Yolk sac and umbilicoplacental hemodynamics during early human embryonic development. Ultrasound Obstet Gynecol 1999; 14: 175-9.
• 25 Meinardi JR, Middeldorp S, de Kam PJ. et al. Increased risk for foetal loss in carriers of the factor V Leiden mutation. Ann Intern Med 1999; 130: 736-9.
• 26 Brenner B, Sarig G, Weiner Z. et al. Thrombophilic polymorphisms are common in women with fetal loss without apparent cause. Thromb Haemost 2000; 83: 350-1.
• 27 Pabinger I, Nemes L, Rintelen C. et al. Pregnancyassociated risk for venous thromboemboilism and pregnancy outcome in women homozygous for factor V Leiden. HematolJ 2000; 01: 37-41.
• 28 Isermann B, Sood R, Pawlinski R. et al. The thrombomodulin-protein C system is essential for the maintenance of pregnancy. Nat Med 2003; 09: 331-7.
• 29 Komlosi K, Havasi V, Bene J. et al. Search for factor Arg306Cambridge and Hong Kong mutations in mixed Hungarian population samples. Acta Haematologica 2003; 110: 220-2.
• 30 Ruiz-Arguelles GJ, Poblete-Naredo I, Reyes-Nunes V. et al. Primary thrombophilia in Mexico IV: frequency of the Leiden, Cambridge, Hong Kong, Liverpool, and HR2 haplotype polymorphisms in the factor V gene of a group of thrombophilic Mexican Mestizo patients. Rev Invest Clin 2004; 56: 600-4.
• 31 Djordjevic V, Rakicevic LJ, Mkovic D. et al. Prevalence of factor V Leiden, factor II G20210A and methylenetetrahydrofolate reductase C677T mutations in healthy and thrombophilic Serbian populations. Acta Haematol 2004; 112: 227-9.
• 32 Franco RF, Elion J, Travella MH. et al. The prevalence of FV Arg306Thr (FV Cambridge) and factor V Arg306Gly mutations in different human populations. Thromb Haemost 1999; 81: 312-3.
• 33 Norman RJ, Clark AM. Obesity and reproductive disorders:a review. Reprod Fertil Dev 1998; 10: 55-63.
• 34 Lashen H, Fear K, Sturdee DW. Obesity is associated with increased risk of first trimester and recurrent miscarriage: matched case-control study. Human Reprod 2004; 19: 1644-6.
• 35 Nakabayashi M, Yamamoto S, Suzuki K. Analysis of thrombomodulin gene polymorphism in women with severe early onset preeclampsia. Semin Thromb Haemost 1999; 25: 473-9.
• 36 Franchi F, Biguzzi E, Cetin I. et al. Mutations in the thrombomodulin and endothelial protein C receptor genes in women with late fetal loss. Br J Haematol 2001; 114: 641-6.