The Risk of Recurrent Venous Thromboembolism in Patients with and without Factor V Leiden

Summary

Thromboprophylaxis with oral anticoagulants up to six months is established in patients after a first venous thromboembolic event (VTE). The risk of recurrent VTE is still considerable thereafter, and it is uncertain whether some patients might benefit from extended anticoagulation. We performed a prospective, multicenter trial (4 thrombosis centers) and evaluated in 380 patients with a first or recurrent VTE (patients with a deficiency of antithrombin, protein C, protein S or plasminogen; cancer; or an antiphospholipid antibody syndrome were excluded) the risk of recurrence after discontinuation of secondary thromboprophylaxis with oral anticoagulants. It was the aim of the study to evaluate whether patients with factor V Leiden are at an increased risk of recurrent VTE. 112 (29.5%) patients were carriers of factor V Leiden (26.9% heterozygous, 2.6% homozygous). After a median observation time of 19.3 months the overall recurrence rate of VTE was 9.9%. Recurrent deep vein thrombosis and/or pulmonary embolism occurred in 26 of 268 patients without factor V Leiden (9.7%) and in 10 of 112 patients with factor V Leiden (8.9%). The probability of recurrent VTE two years after discontinuation of oral anticoagulants was 12.4% (95% Cl 7.8-17) in patients without factor V Leiden and was 10.6% (95% Cl 3.8-17.4) in carriers of the mutation. This difference was statistically not significant. Patients with factor V Leiden are not at a higher risk of recurrent VTE within two years after discontinuation of oral anticoagulants than patients without factor V Leiden. Balancing the risk of recurrent VTE and bleeding from oral. anticoagulants, patients with factor V Leiden are not likely to benefit from oral anticoagulant therapy extended beyond six months.

• References

• 1 Hyers TM, Hull RD, Weg JG. Antithrombotic therapy for venous thromboembolic disease. Chest 1992; 102 (Suppl): 408-425
• 2 Research Committee of the British Thoracic Society. Optimum duration of anticoagulation for deep-vein thrombosis and pulmonary embolism. Lancet 1992; 340: 873-876
• 3 Sarasin FP, Bounameaux H. Duration of oral anticoagulant therapy after proximal deep vein thrombosis: a decision analysis. Thromb Haemost 1994; 71: 286-291
• 4 Shulman S, Rhedin AS, Lindmarker P, Carlsson A, Lӓrfars G, Nicol P, Loogna E, Svensson E, Ljungberg B, Walter H, Viering S, Nordlander S, Leijd B, Kjell-Ake J, 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 Med 1982; 307: 1676-1681
• 5 Levine MN, Hirsh J, Gent A, Turpie AG, Weitz J, Ginsberg J, Geerts W, LeClerc J, Neemeh J, Powers P, Piovella F. Optimal duration of oral anticoagulant therapy: a randomized trial comparing four weeks to three months of warfarin in patients with a proximal deep vein thrombosis. Thromb Haemost 1995; 74: 606-611
• 6 Hull R, Delmore T, Carter C, Hirsh J, Genton E, Gent M, Turpie G, McLaughlin D. Adjusted subcutaneous heparin vs. warfarin sodium in the long-term treatment of venous thrombosis. N Engl J Med 1982; 306: 189-194
• 7 Hull R, Hirsh J, Jay R, Carter C, England C, Gent M, Turpie AG, McLaughlin D, Dodd P, Thomas M, Raskob G, Ockelford P. Different intensities of oral anticoagulant therapy in the treatment of proximal-vein thrombosis. N Engl J Med 1982; 307: 1676-1681
• 8 Dahlbӓck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci USA 1993; 90: 1004-1008
• 9 Bertina RM, Koeleman BPC, Koster T, Rosendaal FR, Dirven RJ, de RondeH, van derVelden PA, Reitsma PH. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369: 64-67
• 10 Voorberg J, Roelse J, Koopman R, Buller H, Berends F, ten Cate JW, Mertens K, van MourikJA. Association of idiopathic venous thromboembolism with a single point-mutation at Arg506 of factor V. Lancet 1994; 343: 1535-1536
• 11 Sun X, Evatt B, Griffin JH. Blood coagulation factor Va abnormality associated with resistance to activated protein C in venous thrombophilia. Blood 1994; 83: 3120-3125
• 12 Koster T, Rosendaal FR, de RondeH, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden thrombophilia study. Lancet 1993; 342: 1503-1506
• 13 Halbmayer WM, Haushofer A, Schön R, Fischer M. The prevalence of poor anticoagulant response to activated protein C (APC resistance) among patients suffering from stroke or venous thrombosis and among healthy subjects. Blood Coagulation Fibrinolysis 1994; 05: 51-57
• 14 Griffin JH, Evatt B, Wideman C, Fernández JA. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-1993
• 15 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522
• 16 Dahlbäck B. Inherited thrombophilia: resistance to activated protein C as a pathogenic factor of venous thromboembolism. Blood 1995; 85: 607-614
• 17 The PIOPED Investigators. Value of the ventilation/perfusion scan in acute pulmonary embolism. JAMA 1990; 263: 2753-2759
• 18 Pabinger I, Brücker S, Kyrle PA, Schneider B, Kominger HC, Niessner H, Lechner K. Hereditary deficiency of antithrombin III, protein C, and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagulation Fibrinolysis 1992; 03: 547-553
• 19 Kalbfleisch JD, Prentice RL. The statistical analysis of failure time data. John Wiley and Sons. 1980
• 20 Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53: 457-481
• 21 Coon WW, Willis PW. Hemorrhagic complications of anticoagulant therapy. Arch Intern Med 1974; 133: 386-392
• 22 Bounameaux H, de MoerlooseP, Sarasin FP. Optimal duration of oral anticoagulant therapy following deep vein thrombosis of lower limbs. Blood Coagulation Fibrinolysis 1996; 07: 507-514
• 23 Nordstrom M, Lindblad B, Bergqvist D, Kjellström TA. A prospective study of the incidence of deep vein thrombosis with a defined urban population. J Intern Med 1992; 232: 155-160
• 24 Anderson FA, Wheeler HB, Goldberg RJ, Hosmer DW, Patwardhan NA, Jovanovic B, Forcier A, Dalen JE. A population based perspective of the hospital incidence and case-fatality rates of deep vein thrombosis and pulmonary embolism: the Worcester DVT Study. Arch Intern Med 1991; 151: 933-938
• 25 Prandoni P, Lensing AWA, Cogo A, Cuppini S, Villalta S, Carta M, Cattelan AM, Polistena P, Bemardi E, Prins MH. The long-term clinical course of acute deep venous thrombosis. Ann Int Med 1996; 125: 01-07
• 26 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: 2800-2802
• 27 den HeijerM, Koster T, Blom HJ, Bos GMJ, Briët E, Reitsma PH, Vandenbroucke JP, Rosendaal FR. Hyperhomocysteinemia as a risk factor for deep-vein thrombosis. N Engl J Med 1996; 334: 759-762
• 28 Heijboer H, Brandjes DPM, Büller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323: 1512-1526
• 29 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: 229-232
• 30 Palaretti G, Leali N, Coccheri S, Poggi M, Manotti C, d’Angelo A, Pengo V, Erba N, Moia M, Ciavarella N, Devoto G, Berrettini M, Musolesi S. on behalf of the Italian Study on Complications of Oral Anticoagulant Therapy. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Lancet 1996; 348: 423-428
• 31 Stroke Prevention in Atrial Fibrillation Investigators. Adjusted-dose warfarin versus low-intensity, fixed-dose warfarin plus aspirin for high risk patients with atrial fibrillation: Stroke Prevention in Atrial Fibrillation III randomised clinical trial. Lancet 1996; 348: 633-638
• 32 Fihn S, Callahan C, Martin DC, McDonell MB, Henikoff JG, White RH. For the National Consortium of Anticoagulation. The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996; 124: 970-979
• 33 Levine MN, Hirsh J, Landefeld S, Raskob G. Hemorrhagic complications of anticoagulant treatment. Chest 1992; 102 (Suppl): 352-363