The Risk of Recurrent Venous Thromboembolism in Carriers and Non-carriers of the G1691A Allele in the Coagulation Factor V Gene and the G20210A Allele in the Prothrombin Gene

Summary

The results concerning the risk of recurrent venous thromboembolism (VTE) in carriers of the G1691A mutation in the coagulation factor V gene are not consistent and this risk in carriers of the G20210A polymorphism in the prothrombin gene has hitherto not been reported. We followed 534 patients for 48 months after their first episode of objectively documented VTE. The prevalence of the G1691A allele in 467 (87.5%) of the patients and in 207 controls was 25.3% and 8.2%, respectively, in heterozygote form and 2.4% and 0.5%, respectively, in homozygote form. The adjusted odds ratio (OR) for the first VTE was 4.4 (95% CI 2.6-7.8). The risk of recurrent VTE in heterozygotes was not statistically different from non-carriers (17.8% vs 17.6%), with 85% power to detect a hazard ratio of 2.35. Homozygotes had a significantly increased risk (p = 0.036) of recurrent VTE. The prevalence of the G20210A allele in 456 patients and 207 controls was 6.1% and 1.4%, respectively. The adjusted OR was 4.6 (95% CI 1.6-19.3) for the first VTE in 28 carriers of this polymorphism. The risk of recurrent VTE for these was not statistically different from non-carriers with an OR of 0.9 (95% CI 0.2-2.9).

^* The investigators and institutions in the Duration of Anticoagulation (DURAC) Trial Study Group are listed in the Appendix (p. 688).

• References

• 1 Hansson P-O, Welin L, Tibblin G, Eriksson H. Deep vein thrombosis and pulmonary embolism in the general population.. Arch Intern Med 1997; 157: 1665-70.
• 2 Nordström M, Lindblad B, Bergquist D, Kjellström T. A prospective study of the incidence of deep-vein thrombosis within a defined urban population.. J Int Med 1992; 232: 155-60.
• 3 Schulman S, Rhedin A-S, Lindmarker P, Carlsson A, Lärfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H, Viering S, Nordlander S, Leijd B, Jönsson K-Å, Hjorth M, Linder O. Boberg J and the Duration of Anticoagulation Trial Study Group. A comparison of six weeks with sex months of oral anticoagulant therapy after the first episode of venous thromboembolism. N Engl J Med 1995; 332:: 1661-5.
• 4 Dahlbäck B, Hillarp A, Rosen S, Zöller B. Resistance to activated protein C, the FV:Q ⁵⁰⁶ allele and venous thrombosis.. Ann Hematol 1996; 72: 166-76.
• 5 Zöller B, Berntsdotter A, Garcia de Frutos P, Dahlbäck B. Resistance to activated Protein C as an additional genetic risk factor in hereditary deficiency of Protein S.. Blood 1995; 85: 3518-23.
• 6 Dahlbäck B, Carlsson M, Svensson P. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: Prediction of a co-factor to activated protein C.. Proc Natl Acad Sci USA 1993; 90: 1004-8.
• 7 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de Ronde H, van der Velden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C.. Nature 1994; 369: 64-7.
• 8 Svensson P, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis.. N Eng J Med 1994; 330: 517-22.
• 9 Emmerich J, Alhenc-Gelas M, Ailaud M-F, Juhan-Vague I, Jude B, Garcin J-M, Dreyfus M, de Moerloose P, Le Querrec A, Priollet P, Berruyer M, Vallantin X, Wolf M, Aiach M, Fiessinger J-N.. Clinical features in 36 patients homozygous for the ARG 506 → GLN factor V mutation.. Thromb Haemost 1997; 77:: 620-3.
• 10 Vandenbroucke JP, Bertina RM, Holmes ZR, Spaargaren C, van Krieken J, Manten B, Reitsma PH. Factor V Leiden and fatal pulmonary embolism.. Thromb Haemost 1998; 79: 511-6.
• 11 Koster T, Rosendaal FR, de Ronde H, Briêt E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study.. Lancet 1993; 342: 1503-6.
• 12 Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism.. Circulation 1995; 92: 2800-2.
• 13 Rintelen C, Pabinger I, Knöbl P, Lechner K, Mannhalter C. Probability of recurrence of thrombosis in patients with and without factor V Leiden.. Thromb Haemost 1996; 75: 229-32.
• 14 Eichinger S, Pabinger I, Stüpflen A, Hirschl M, Bialonzyk C, Schneider B, Mannhalter C, Minar E, Lechner K, Kyrle PA. The risk of recurrent venous thromboembolism in patients with and without the factor V Leiden.. Thromb Haemost 1997; 77: 624-8.
• 15 Simioni P, Prandoni P, Lensing AW, Scudeller A, Sardella C, Prins MH, Villalta S, Dazzi F, Girolami A. The risk of recurrent venous thromboembolism in patients with an Arg506–>Gln mutation in the gene for factor V (Factor V Leiden).. N Engl J Med 1997; 336: 399-403.
• 16 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. 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.
• 17 Hillarp A, Zöller B, Svensson PJ, Dahlbäck B. The G20210A allele of the prothrombin gene is a common risk factor among Swedish outpatients with verified deep venous thrombosis.. Thromb Haemost 1997; 78: 990-2.
• 18 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the G20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia.. Thromb Haemost 1997; 78: 1426-9.
• 19 Kapur RK, Mills LA, Spitzer SG, Hiltin MB. A prothrombin gene mutation is significantly associated with venous thrombosis.. Arterioscler Thromb Vasc Biol 1997; 17: 2875-9.
• 20 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in a U.K. anticoagulant population.. Br J Haemat 1997; 89: 353-5.
• 21 Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210G/A pro-thrombin genotype is associated with early venous thrombosis in inherited thrombophilias and is not increased in frequency in artery disease.. Arterioscler Thromb Vasc Biol 1997; 17: 2418-22.
• 22 Gandrille S, Alhenc-Gelas M, Aiach M. A rapid screening method for the factor V Arg ⁵⁰⁶ → Gln mutation.. Blood Coag Fibr 1995; 6: 245-8.
• 23 Middeldorp S, Henkens C, Koopman M, van Pampus E, Hamulyák K, van der Meer J, Prins MH, Büller HR. 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.
• 24 Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer MJ, Henne-kens CH. Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation.. Ann Intern Med 1997; 126: 528-31.
• 25 Hille E, Westendorp R, Vandenbroucke J, Rosendaal F. Mortality and causes of death in families with the factor V Leiden mutation (Resistance to activated Protein C).. Blood 1997; 89: 1963-7.
• 26 Martinelli I, Cattaneo M, Panzeri D, Mannucci PM. Low prevalence of factor V:Q506 in 41 patients with isolated pulmonary embolism.. Thromb Haemost 1997; 77: 440-3.
• 27 Manten B, Westendorp R, Koster T, Reitsma PH Rosendaal FR. Risk factor profiles in patients with different clinical manifestations of venous thromboembolism: a focus on the factor V Leiden mutation.. Thromb Haemost 1996; 76: 510-3.
• 28 Baglin TP, Brown K, Williamson Baker P, Luddington R. Relative risk of pulmonary embolism and deep vein thrombosis in association with the factor V Leiden mutation in a United Kingdom population.. Thromb Haemost 1997; 77: 1219 (letter).
• 29 Schulman S. Optimal duration of oral anticoagulant therapy in venous thromboembolism.. Thromb Haemost 1997; 78: 693-8.