Role of Thrombophilia in Deciding on the Duration of Anticoagulation

ABSTRACT

It is now possible to identify hereditary risk factors in a substantial percentage of patients presenting with a venous thrombotic event. Discovery of the factor V Leiden and prothrombin G20210A mutations has greatly increased the percentage of patients in whom venous thrombosis can be attributed to hereditary thrombophilia. There is considerable uncertainty, however, as to how this information should be used in patient management. Although prolonged anticoagulation at an international normalized ratio (INR) of 2 to 3 is highly effective in preventing thrombotic recurrences, this benefit is partially offset by the risk of major bleeding and the inconvenience associated with oral vitamin K antagonists. Although low-intensity anticoagulation at a target INR of 1.5 to 2 has recently been shown to be effective in preventing recurrent venous thromboembolism after 3 to 6 months of treatment at an INR of 2 to 3, it has not been demonstrated to reduce the risk of major bleeding complications. A decision as to the overall benefit of extended anticoagulation therefore continues to require clinical assessment of an individual patient's risk of recurrence in the absence of treatment and the risk of bleeding at the chosen INR target range.

KEYWORDS

Thrombophilia - thromboembolism - anticoagulants - INR - factor V Leiden - prothrombin G20210A mutation

REFERENCES

• 1 Heijboer H, Brandjes D PM, Büller H R, Sturk A, ten Cate J W. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep venous thrombosis.  N Engl J Med. 1990;  323 1512-1516
• 2 Bauer K A. The thrombophilias: well-defined risk factors with uncertain therapeutic implications.  Ann Intern Med. 2001;  135 367-373
• 3 Walker I D, Greaves M, Preston F E. Investigation and management of heritable thrombophilia.  Br J Haematol. 2001;  114 512-528
• 4 Prandoni P, Lensing A WA, Cogo A et al.. The long-term clinical course of acute deep venous thrombosis.  Ann Intern Med. 1996;  125 1-7
• 5 Schulman S, Rhedin A S, Lindmarker P et al.. A comparison of six weeks with six months of oral anticoagulation after a first episode of venous thromboembolism.  N Engl J Med. 1995;  332 1661-1665
• 6 Schulman S, Granqvist S, Holmström M et al.. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism.  N Engl J Med. 1997;  336 393-398
• 7 Agnelli G, Prandoni P, Santamaria M G et al.. Three months versus one year of oral anticoagulant therapy for idiopathic deep venous thrombosis.  N Engl J Med. 2001;  345 165-169
• 8 Ridker P M, Goldhaber S Z, Danielson E et al.. Long-term, low-intensity warfarin for the prevention of recurrent venous thromboembolism.  N Engl J Med. 2003;  348 1425-1434
• 9 Kearon C, Gent M, Hirsh J et al.. A comparison of three months of anticoagulation with extended anticoagulation for a first episode of idiopathic venous thromboembolism.  N Engl J Med. 1999;  340 901-907
• 10 Ridker P M, Miletich J P, Stampfer M J et al.. Factor V Leiden and risks of recurrent idiopathic venous thromboembolism.  Circulation. 1995;  92 2800-2802
• 11 Simioni P, Prandoni P, Lensing A WA et al.. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep vein thrombosis.  Blood. 2000;  96 3329-3333
• 12 Simioni P, Prandoni P, Lensing A WA et al.. The risk of recurrent venous thromboembolism in patients with an Arg⁵⁰⁶øGln mutation in the gene for factor V (factor V Leiden).  N Engl J Med. 1997;  336 399-403
• 13 Eichinger S, Minar E, Hirschl M et al.. The risk of early recurrent venous thromboembolism after oral anticoagulant therapy in patients with the G20210A transition in the prothrombin gene.  Thromb Haemost. 1999;  81 14-17
• 14 Eichinger S, Pabinger I, Schneider B et al.. The risk of recurrence of venous thromboembolism in patients with and without factor V Leiden.  Thromb Haemost. 1997;  77 624-628
• 15 Lindmarker P, Schulman S, Sten-Linder M et al.. 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.  Thromb Haemost. 1999;  81 684-690
• 16 Margaglione M, D'Andrea G, Colaizzo D et al.. Coexistence of factor V Leiden and factor II A20210 mutations and recurrent venous thromboembolism.  Thromb Haemost. 1999;  82 1583-1587
• 17 De Stefano V, Martinelli I, Mannucci P M et al.. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation.  N Engl J Med. 1999;  341 801-806
• 18 Baglin C, Brown K, Luddington R, Baglin T. Risk of recurrent venous thromboembolism in patients with the factor V Leiden (FVR506Q) mutation: effect of warfarin and prediction by precipitating factors. East Anglian Thrombophilia Study Group.  Br J Haematol. 1998;  100 764-768
• 19 Sarasin F P, Bounameaux H. Decision analysis model of prolonged oral anticoagulant treatment in factor V Leiden carriers with first episode of deep vein thrombosis.  BMJ. 1998;  316 95-99
• 20 Hille E T, Westendorp R G, Vandenbroucke J P, Rosendaal F R. Mortality and causes of death in families with the factor V Leiden mutation (resistance to activated protein C).  Blood. 1997;  89 1963-1967
• 21 Emmerich J, Rosendaal F R, Cattaneo M et al.. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism-pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Study Group for Pooled-Analysis in Venous Thromboembolism.  Thromb Haemost. 2001;  86 809-816
• 22 Koeleman B PC, Reitsma P H, Allaart C F, Bertina R M. Activated protein C resistance as an additional risk factor for thrombosis in protein C-deficient families.  Blood. 1994;  84 1031-1035
• 23 Gandrille S, Greengard J S, Alhenc-Gelas M et al.. Incidence of activated protein C resistance caused by ARG 506 GLN mutation in factor V in 113 unrelated symptomatic protein C-deficient patients.  Blood. 1995;  86 219-224
• 24 Van Boven H H, Reitsma P H, Rosendaal F R et al.. Factor V Leiden (R506Q) in families with inherited antithrombin deficiency.  Thromb Haemost. 1996;  75 417-421
• 25 Zöller B, Berntsdotter A, Garcia de Frutos P, Dahlbäck B. Resistance to activated protein C as an additional risk factor in hereditary deficiency of protein S.  Blood. 1995;  85 3518-3523
• 26 Meinardi J R, Middeldorp S, de Kam P J et al.. The incidence of recurrent venous thromboembolism in carriers of factor V Leiden is related to concomitant thrombophilic disorders.  Br J Haematol. 2002;  116 625-631
• 27 Khamashta M A, Cuadrado M J, Mujic F et al.. The management of thrombosis in the antiphosholipid-antibody syndrome.  N Engl J Med. 1995;  332 993-997
• 28 Schulman S, Svenungsson E, Granqvist S. Anticardiolipin antibodies predict early recurrence of thromboembolism and death among patients with venous thromboembolism following anticoagulant therapy. Duration of Anticoagulation Study Group.  Am J Med. 1998;  104 332-338
• 29 Crowther M A, Ginsberg J S, Julian J et al.. A comparison of two intensities of warfarin for the prevention of recurrent thrombosis in patients with the antiphospholipid antibody syndrome.  N Engl J Med. 2003;  349 1133-1138
• 30 Hutten B A, Prins M H, Gent M et al.. The incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved INR. A retrospective analysis.  J Clin Oncol. 2000;  18 3078-3083
• 31 Prandoni P, Lensing A WA, Piccioli A et al.. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis.  Blood. 2002;  100 3484-3488
• 32 Lee A YY, Levine M N, Baker R I et al.. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer.  N Engl J Med. 2003;  349 146-153
• 33 van den Belt A G, Sanson B J, Simioni P et al.. Recurrence of venous thromboembolism in patients with familial thrombophilia.  Arch Intern Med. 1997;  157 2227-2232
• 34 van den Belt A G, Hutten B A, Prins M H. Duration of oral anticoagulant treatment in patients with venous thromboembolism and a deficiency of antithrombin, protein C or protein S-a decision analysis.  Thromb Haemost. 2000;  84 758-763
• 35 Van Boven H H, Vandenbroucke J P, Westendorp R G, Rosendaal F R. Mortality and causes of death in inherited antithrombin deficiency.  Thromb Haemost. 1997;  77 452-455
• 36 Wählander K, Lundstrom T, Clason S, Schulman S, Eriksson H. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran.  N Engl J Med. 2003;  349 1713-1721