Probability of Recurrence of Thrombosis in Patients with and without Factor V Leiden

Summary

Activated protein C (APC) resistance is a common risk factor for venous thromboembolism and is associated with the replacement of Arg 506 by Gin in the factor V gene (factor V Leiden). We investigated the risk of recurrence of venous thromboembolism in APC resistant patients heterozygous and homozygous for FV Leiden and compared these patient groups with a group of patients, who had a history of venous thromboembolism, but had neither APC resistance nor the FV Leiden mutation. APC resistance was determined in frozen blood samples from patients with a history of venous thromboembolism, who were not receiving oral anticoagulant (OAC) treatment. The plasma samples were collected between 1984 and 1991. Twenty-one patients in whom APC resistance was found in the stored plasma samples were reinvestigated in 1994 (5 males, 16 females, median [m] age 49 years, range 21-71 years). Twenty-one sex and age matched patients with venous thromboembolism (5 males, 16 females, age m = 50 years, range 25-73 years) investigated during the same time period who had a normal APC resistance test served as a control group. Patients with APC resistance as well as controls were reinvestigated for the presence of FV Leiden by genetic analysis in 1994. Of the 21 APC resistant patients, 5 were homozygous and 16 heterozygous for FV Leiden. Before the study entry homozygous patients had a significantly higher recurrence rate (5/5 patients) compared to the control group, in heterozygous patients (9/16) and controls (9/21) the recurrence rate was not significantly different.

The total observation time was 21 years in patients with homozygous FV Leiden, 83 years in patients with heterozygous FV Leiden and 108 years in controls, excluding the time when patients were on OAC treatment. During the observation time the recurrence rate was highest in patients with homozygous FV Leiden (9.5 % per patient per year), but was similar in patients with heterozygous FV Leiden (4.8% per patient per year) and controls (5% per patient per year). Two of five (40%) homozygous patients, 4/16 (25%) heterozygous and 5/21 (24%) controls had at least one recurrent event during the observation period. The probability for development of thrombosis in the Kaplan-Meyer-Plot analysis was not different between the three groups.

Bearing limitations of our study in mind (retrospective design, relatively small patient number) we conclude that the risk of recurrence after a thromboembolic event is not higher in patients with heterozygous FV Leiden than in patients without this mutation. Thus, it appears that the identification of heterozygous FV Leiden mutation is not an indication for long-term OAC treatment. Also, long-term OAC treatment cannot generally be recommended for homozygous patients with a single thromboembolic event. More definitive conclusions will require larger prospective studies.

• References

• 1 Thaler E, Lechner K. Antithrombin III deficiency and thromboembolism. Clin Haematol 1981; 10: 369-390
• 2 Bauer KA, Rosenberg RD. Role of antithrombin III as a regulator of in vivo coagulation. Semin Haematol 1991; 28: 10-18
• 3 Broekmans AW, Veltkamp JJ, Bertina RM. Congenital protein C deficiency and venous thromboembolism: a study in three Dutch families. N Engl J Med 1983; 309: 340-344
• 4 Engesser L, Broekmans AW, Briët E, Brommer EJP, Bertina RM. Hereditary protein S deficiency: clinical manifestations. Ann Intern Med 1987; 106: 677-682
• 5 Esmon CT. The protein C anticoagulant pathway. Arterioscler Thromb 1992; 12: 135-145
• 6 Pabinger I, Kyrle PA, Heistinger M, Eichinger S, Lechner K. The risk of thromboembolism in patients with protein S or protein C deficiency: prospective cohort study. Thromb Haemost 1994; 71 (04) 441-445
• 7 Dahlbäck 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
• 8 Svensson PJ, Dahlbäck B. Resistance to activated protein C as a basis for venous thrombosis. N Engl J Med 1994; 330: 517-522
• 9 Griffin JH, Evatt B, Wideman C, Fernandez J. Anticoagulant protein C pathway defective in majority of thrombophilic patients. Blood 1993; 82: 1989-1993
• 10 Koster T, Rosendaal FR, de Ronde H, 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
• 11 Faioni EM, Franchi F, Asti D, Sacchi E, Bemardi F, Mannucci PM. Resistance to activated protein C in nine thrombophilic families: interference in a protein S functional assay. Thromb Haemost 1993; 70: 1067-1071
• 12 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: 64-67
• 13 Greengard JS, Sun X, Xu X, Fernandez JY, Griffin JH, Evatt B. Activated protein C resistance caused by Arg 506 Gin mutation in FVa. Lancet 1994; 343: 1361-1362
• 14 Voorberg J, Roelse J, Koopman R, Büller H, Berends F, ten Cate JW, Mer-tens K, van Mourik JA. Association of idiopathic venous thromboembolism with single point mutation at Arg 506 of factor V. Lancet 1994; 343: 1535-1536
• 15 Rosendaal FR, Koster T, Vandenbrouke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85: 1504-1508
• 16 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thromboembolism in apparently healthy men. N Engl J Med 1995; 332: 912-917
• 17 Sarasin F, Bounameaux H. Duration of oral anticoagulant therapy after proximal deep vein thrombosis: a decision analysis. Thromb Haemost 1994; 71 (03) 286-291
• 18 De Stefano V, Leone G, Mastrangelo S, Tripodi A, Rodeghiero F, Castaman G, Barbui T, Finazzi G, Bizzi B, Mannucci PM. Clinical manifestations of inherited thrombophilia: a retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C, protein S. Thromb Haemost 1994; 72 (03) 352-358
• 19 Mannhalter C, Huber H, Löffler H, Faber V. Molekularbiologie in der me-dizinischen Diagnostik. In “Methoden der diagnostischen Hamatologie”. Springer Verlag; Berlin, Heidelberg, New York 1994: 215-261
• 20 Zöller B, Svensson P, He X, Dahlbäck B. Identification of the same factor V gene mutation in 47 out of 50 thrombosis prone families with inherited resistance to activated protein C. J Clin Invest 1994; 94: 2521-2524
• 21 Bovill EG, Bauer KA, Dickerman JD, Callas P, West B. The clinical spectrum of heterozygous protein C deficiency in a large New England kindred. Blood 1989; 73: 712-717
• 22 Khamashta MA, Cuadrano MJ, Mujic F, Taub NA, Hunt BJ, Hughes GR. The management of thrombosis in the anti-phospholipid-antibody syndrome. N Engl J Med 1995; 332 (15) 993-997
• 23 Kominger C, Lechner K, Niessner H, Gössinger H, Kundi M. Impaired fibrinolytic capacity predisposes for recurrence of venous thrombosis. Thromb Haemost 1984; 52 (02) 127-130
• 24 Schulman S, Rhedin AS, Lindmarker P, Carlsson A, Läfars G, Nicol P, Loogna E, Svensson E, Ljungeberg B, Walter H, Viering S, Nordlander S, Leijd B, Jönsson KA, Hlorth M, Linder O, Borberg J. and the duration of anticoagulant 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: 1661-1665