Coexistence of Factor V Leiden and Factor II A20210 Mutations and Recurrent Venous Thromboembolism

Summary

Patients carrying the FV Leiden or the FII A²⁰²¹⁰ mutation have a high risk of venous thromboembolism. Among 542 patients with a documented diagnosis of deep venous thrombosis in one leg consecutively referred for a thrombophilic work-up, we have retrospectively assessed the rate of objectively documented previous recurrence in carriers of both FV Leiden and FII A²⁰²¹⁰ mutations. Eighty-two patients had experienced 115 episodes of recurrent venous thromboembolism. The rate of recurrent venous thromboembolism was 29.2% among subjects with and 14.5% in those without deficiencies of natural anticoagulant proteins (p = 0.055), and 24.6% among patients with and 14.0% in those without antiphospholipid antibodies (p = 0.036). The frequency of having a recurrent thromboembolism was 16.2%, 20.0%, and 36.4% among carriers of FV Leiden, FII A²⁰²¹⁰ mutation, or both gene defects, respectively, and 12.8% in subjects carrying neither mutation (p for trend = 0.004). When adjusted for age, sex, and thrombophilic risk factors, the rate was higher among patients with than in those without deficiencies of natural anticoagulant proteins (OR: 3.0; 95% CI: 1.2-7.5), aPL 2.5 (95% CI: 1.3-4.9), or both FV Leiden and FII A²⁰²¹⁰ gene mutations (OR 4.8; 95% CI: 1.9-12.2).

The rate of previous recurrent venous thromboembolism was significantly higher in subjects carrying both FV Leiden and FII ²⁰²¹⁰ mutations and was comparable to that observed in subjects with deficiencies of natural anticoagulant proteins or antiphospholipid antibodies.

Key Words

FV Leiden - FII A²⁰²¹⁰ - thrombosis - veins - risk factors

• References

• 1 Kniffin WD, Baron JA, Barret J, Birkmeyer JD, Anderson Jr. FA. The epidemiology of diagnosed pulmonary embolism and deep venous thrombosis in the elderly. Arch Intern Med 1994; 154: 861-6.
• 2 Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bernardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Intern Med 1996; 125: 1-7.
• 3 Hirsh J. The optimal duration of anticoagulation therapy for venous thromboembolism. N Engl J Med 1995; 332: 1710-1.
• 4 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia. Pathogenesis, clinical syndromes and management. Blood 1996; 87: 3531-44.
• 5 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. Thromb Haemost 1996; 76: 651-62.
• 6 Bertina RM, Koeleman BPC, Koester 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.
• 7 Dahlbäck B. Physiological anticoagulation. Resistance to activated protein C and venous thromboembolism. J Clin Invest 1994; 94: 923-7.
• 8 Poort SR, Rosendaal FP, Reitsma PH, Bertina RM. A common genetic variation in the 3’untraslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996; 88: 3698-703.
• 9 Cumming AM, Keeney S, Salden A, Bhavnani M, Shwe KH, Hay CRM. The prothrombin gene G20210A variant: prevalence in an U.K. anticoagulant clinic population. Br J Haematol 1997; 98: 353-5.
• 10 Margaglione M, Brancaccio V, Giuliani N, D’Andrea G, Cappucci G, Iannaccone L, Vecchione G, Grandone E, Di Minno G. Increased risk of venous thrombosis in carriers of the prothrombin A²⁰²¹⁰ gene variant. Ann Intern Med 1998; 129: 89-93.
• 11 De Stefano S, Leone G, Mastrangelo S, Tripodi A, Rodeghiero F, Castaman G, Barbui T, Finazzi G, Bizzi B, Mannucci PM. Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C protein S. Thromb Haemost 1994; 72: 352-8.
• 12 Ridker PM, Miletich JP, Stampfer MJ, Goldhaber SZ, Lindpaintner K, Hennekens CH. Factor V Leiden and risk of recurrent idiopathic venous thromboembolism. Circulation 1995; 92: 2800-2.
• 13 Simioni P, Prandoni P, Lensing AWA, 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.
• 14 Ginsberg JS, Wells PS, Brill-Edwards P, Donovan D, Moffatt K, Johnston M, Stevens P, Hirsh J. Antiphospholipid antibodies and venous thromboembolism. Blood 1995; 86: 3685-91.
• 15 Finazzi G, Brancaccio V, Moia M, Ciavarella N, Mazzucconi MG, Schinco PC, Ruggeri M, Pogliani EM, Gamba G, Rossi E, Baudo F, Manotti C, D’Angelo A, Palareti G, De Stefano V, Berrettini M, Barbui T. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four years prospective study from the Italian registry. Am J Med 1996; 100: 530-6.
• 16 Krnic-Barrie S, O’Connor CR, Looney SW, Pierangeli SS, Harris NE. A retrospective review of 61 patients with antiphospholipid syndrome. Analysis of factors influencing recurrent thrombosis. Arch Intern Med 1997; 157: 2101-8.
• 17 Ames PRJ, Pyke S, Iannaccone L, Brancaccio V. Antiphospholipid antibodies, haemostatic variables and thrombosis. A survey of 144 patients. Thromb Haemost 1995; 73: 768-73.
• 18 Ames PRJ, Catello T, Iannaccone L, Brillante M, Cimino R, Brancaccio V. Coagulation activation and fibrinolytic imbalance in subjects with idiopathic antiphospholipid antibodies. A crucial role for acquired free protein S deficiency. Thromb Haemost 1996; 76: 190-4.
• 19 Margaglione M, Di Minno G, Grandone E, Vecchione G, Celentano E, Cappucci G, Giordano M, Grilli M, Simone P, Fusilli S, Panico S, Mancini M. Raised plasma fibrinogen concentrations in subjects attending a metabolic ward. Relation to family history and vascular risk factors. Thromb Haemost 1995; 73: 579-83.
• 20 Koeleman BPC, Reitsma PH, Allart CF, Bertina RM. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families. Blood 1994; 84: 1031-5.
• 21 Margaglione M, D’Andrea G, Cappucci G, Grandone E, Giuliani N, Colaizzo D, Vecchione G, Di Minno G. Detection of factor V Leiden mutation using SSCP. Thromb Haemost 1996; 76: 814-5.
• 22 Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Lärfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H, Viering S, Nordlander S, Leijd B, Jönsson KA, Hjorth M, Linder O, Boberg J. and the Duration of Anticoagulation Trial Study Group. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. N Engl J Med 1995; 332: 1661-5.
• 23 Kearon C, Gent M, Hirsh J, Weitz J, Kovacs MJ, Anderson DR, Turpie AG, Green D, Ginsberg JS, Wells P, MacKinnon B, Julian JA. A comparison of three month of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism. N Engl J Med 1999; 340: 901-7.
• 24 Koster T, Rosendaal FR, de Ronde H, Briet E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulation response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342: 1503-6.
• 25 Svensson JP, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-22.
• 26 Gandrille S, Greengard JS, Alhenc-Gelas M, Juhan-Vague I, Abgrall JF, Jude B, Griffin JH, Aiach M. and the French Network on behalf of INSERM. Incidence of activated protein C resistance caused by the ARG ⁵⁰⁶ GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients. Blood 1995; 86: 219-24.
• 27 Koeleman BPC, van Rumpt D, Halmulyàk K, Reitsma PH, Bertina RM. Factor V leiden. An additional risk factor for thrombosis in protein S deficient families?. Thromb Haemost 1995; 74: 580-3.
• 28 van Boven HH, Reitsma PH, Rosendaal FR, Bayston TA, Chowdhury V, Bauer KA, Scharre I, Conard J, Lane DA. Factor V Leiden (FV R506Q) in families with inherited antithrombin deficiency. Thromb Haemost 1996; 75: 417-21.
• 29 Makris M, Preston FE, Beauchamp NJ, Cooper PC, Daly ME, Hampton KK, Bayliss P, Peake IR, Miller GJ. Co-inheritance of the 20210A allele of the prothrombin gene increases the risk of thrombosis in subjects with familial thrombophilia. Thromb Haemost 1997; 78: 1426-9.
• 30 Ferraresi P, Marchetti G, Legnani C, Cavallari E, Castoldi E, Mascoli F, Ardissino D, Palareti G, Bernardi F. The heterozygous 20210 G/A prothrombin 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.
• 31 Rintelen C, Pabinger I, Knöbl P, Lechner K, Mannhalter Ch. Probability of recurrence of thrombosis in patients with and without factor V Leiden. Thromb Haemost 1996; 75: 229-32.
• 32 Eichinger S, Pabinger I, Stümpflen A, Hirschl M, Bialonczyk C, Schneider B, Mannhalter C, Minar E, Lechner K, Kyrle PA. The risk of recurrent venous thromboembolism in patients with and without factor V Leiden. Thromb Haemost 1997; 77: 624-8.
• 33 Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. and the DURAC Trial Study Group. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in coagulation factor V gene and the G20210A allele in the prothrombin gene. Thromb Haemost 1999; 81: 684-9.