Venous Thrombotic Risk in Family Members of Unselected Individuals with Factor V Leiden

Summary

The factor V Leiden mutation (FVL) leads to a seven-fold increased risk of venous thromboembolism (VTE). In thrombophilic families, 25% of carriers have experienced thrombosis before the age of 40 years. Aim of our study was to assess the association of FVL with VTE in first-degree family members of unselected symptomatic and asymptomatic carriers of FVL.

We tested 197 relatives of consecutive thrombosis patients with FVL and 36 relatives of asymptomatic carriers on the presence of FVL and the occurrence of VTE.

The incidence of VTE in relatives with FVL of symptomatic carriers was 0.34%/year. This was similar to the incidence in relatives with FVL of asymptomatic carriers. Kaplan Meier analysis in relatives of symptomatic propositi showed that at the age of 58 years, thrombosisfree survival was reduced to 75% in carriers and 93% in non-carriers (P < 0.05). Carriers of FVL had a three times higher thrombotic risk than non-carriers. In combination with environmental risk factors, FVL clearly adds to the risk of VTE. The thrombotic incidence rate in these unselected relatives with FVL, however, is considerably lower than was seen in carriers of thrombophilic families (1.7%/year). Therefore, special care should be paid to individuals with a positive family history of venous thrombosis while exposed to these risk factors.

Key words

Venous thromboembolism - thrombophilia - Factor V Leiden - hypercoagulability

• References

• 1 Nordström M, Lindblad B, Bergqvist 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.
• 2 Carter CJ. The natural history and epidemiology of venous thrombosis. Prog Cardiovasc Dis 1994; 36: 423-38.
• 3 Nachman RL, Silverstein R. Hypercoagulable states. Ann Intern Med 1993; 119: 819-27.
• 4 Griffin JH, Evatt B, Wideman C, Fernández JA. Anticoagulant protein C pathway defective in majority of thrombophilia patients. Blood 1993; 82: 1989-93.
• 5 Koster T, Rosendaal FR, Ronde deH, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
• 6 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-22.
• 7 Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995; 85: 607-14.
• 8 Lane DA, Mannucci PM, Bauer KA, Bertina RM, Bochkov NP, Boulyjenkov V, Chandy M, Dahlbäck B, Ginter EK, Miletich JP, Rosendaal FR, Seligsohn U. Inherited thrombophilia: Part 1&2. Thromb Haemost 1996; 76: 651-62. 824-34.
• 9 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 55: 1504-8.
• 10 Bertina RM, Koeleman RPC, Koster T, Rosendaal FR, Dirven RJ, Ronde deH, Velden van derPA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-7.
• 11 Greengard JS, Sun X, Xu X, Fernandez JA, Griffin JH, Evatt B. Activated protein C resistance causes by Arg 506 Gln mutation in factor Va. Lancet 1994; 343: 1361-2.
• 12 Voorberg J, Roelse J, Koopman R, Büller H, Berends F, ten Cate FW, Mertens K, van Mourik JA. Association of idiopathic venous thromboembolism with single point mutation at Arg506 of factor V. Lancet 1994; 343: 1535-6.
• 13 Zivelin A, Griffin JH, Xu X, Pabinger I, Samana M, Conard J, Brenner B, Eldor A, Seligsohn U. A single genetic origin for a common Caucasian risk factor for venous thrombosis. Blood 1997; 89: 397-402.
• 14 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346: 1133-4.
• 15 Zöller B, Svensson PJ, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 of 50 thrombosis-prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-4.
• 16 Lensen R, Rosendaal RF, Koster T, Allaart CF, Ronde deH, Vandenbroucke JP, Reitsma P, Bertina RM. Apparent different thrombotic tendency in patients with Factor V Leiden and Protein C deficiency due to selection of patients. Blood 1996; 88: 4205-8.
• 17 Ronde deH, Bertina RM. Laboratory diagnosis of APC-resistance: a critical evaluation of the test and the development of diagnostic criteria. Thromb Haemost 1994; 72: 880-6.
• 18 National Medical Registration of the Foundation Information Center for Health Care (SIG, Utrecht, the Netherlands). 1996
• 19 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.
• 20 Rosendaal FR, Walker ID, Preston FE, Briët E. European Prospective Cohort on Thrombophilia (EPCOT): An update. Thromb Haemost 1997; 78: 575 (abstract).
• 21 Miletich JP, Sherman L, Broze Jr GJ. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317: 991-6.
• 22 Tait RC, Walker ID, Perry DJ. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87: 106-12.
• 23 Martinelli I, Mannucci PM, De Stefano V, Taioli E, Rossi V, Crosti F, Paciaroni K, Leone G, Faioni EM. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92: 2353-8.
• 24 Middeldorp S, Henkens CMA, Koopman MMW, Pampus vanECM, Hamulyák K, Meer van derJ, Prins MH, Buller 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.
• 25 Simioni P, Sanson BJ, Prandoni P, Tormene D, Friederich PW, Girolami B, Gavasso S, Huisman MV, Büller HR, Cate tenJW, Girolami A, Prins MH. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81: 198-202.