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Etiology

Review: Factor V Leiden mutation increases risk for thromboembolism

ACP J Club. 1998 Mar-April; 128:52. doi:10.7326/ACPJC-1998-128-2-052


Source Citation

Price DT, Ridker PM. Factor V Leiden mutation and the risks for thromboembolic disease: a clinical perspective. Ann Intern Med. 1997 Nov 15;127:895-903.


Abstract

Objective

To determine whether an association exists between factor V Leiden mutation and thromboembolism.

Data sources

English-language studies were identified using MEDLINE (1993 to April 1997) with the search terms factor V, mutation, protein C, resistance, thromboembolism, prevalence, diagnosis, screening, therapy, and prevention. Bibliographies of relevant papers were also reviewed.

Study selection

Studies were selected if they were prospective cohort or case-control studies. Case reports and case series were included if no analytic studies were available.

Data extraction

Data were extracted on prevalence, screening, diagnosis, and the relation between factor V mutation and venous or arterial thromboembolism alone and in combination with other risk factors (thrombophilia, oral contraceptive use, postmenopausal hormone therapy, and pregnancy).

Main results

The relation between factor V mutation and risk for venous thromboembolism was confirmed in a prospective study of 14 916 men with no history of cardiovascular disease or cancer followed for a mean of 8.6 years. 11.6% of men with venous thromboembolism had the mutation compared with 6.0% of those with no thromboembolism (relative risk [RR] 2.7, 95% CI 1.3 to 5.6, P = 0.008). Risks were higher for patients with idiopathic events (RR 3.5, CI 1.5 to 8.4, P = 0.004) and for men > 60 years of age (adjusted RR 4.0, CI 1.6 to 9.7, P = 0.003). A prospective study showed that men with both factor V mutation and moderate hyperhomocystinemia had an increased risk for any form of venous thromboembolism (RR 9.7, P = 0.009) and for idiopathic venous thromboembolism (RR 21.8, P < 0.001) compared with men who had neither abnormality. In a case-control study comparing 155 premenopausal women who had deep venous thrombosis unrelated to a malignant condition with 169 women who had no history of thrombosis, the combination of oral contraceptive use and factor V mutation increased the risk for thromboembolism (RR 34.7, CI 7.8 to 154). No studies examined the interaction between factor V mutation and postmenopausal hormone therapy. Data from observational studies suggested a link between factor V and venous thromboembolism during pregnancy. 2 prospective studies of patients followed after a first thrombotic episode each reported increased risks for recurrent thromboembolism in patients with factor V mutation (RR 4.1, P = 0.04 in one study; hazard ratio 2.4, P < 0.01 in the other study). Population-based and case-control studies report no difference in the prevalence of factor V mutation in men with or without cardiovascular disease. No randomized controlled trials show that long-term prophylaxis prevents recurrent thrombosis in patients with factor V mutation.

Conclusion

Factor V mutation is associated with increased risk for venous thromboembolism, particularly in men > 60 years of age, men with hyperhomocystinemia, and women receiving oral contraceptives.

Source of funding: Not stated.

For article reprint: Dr. P.M. Ridker, Division of Cardiovascular Diseases, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA. FAX 617-732-7134.


Commentary

The review by Price and Ridker attempted to answer the following questions: 1) What is the prevalence of factor V Leiden mutation? 2) What is the risk for thromboembolism? and 3) What are the clinical implications for screening and management? The review was thorough and well done, and reliable answers were obtained to the first 2 questions but not the third.

The management of asymptomatic heterozygous persons and those with a single episode of venous thrombosis is influenced by 3 factors: the annual incidence of thrombosis, the effectiveness of treatment, and the risk for bleeding with anticoagulant drug use. The annual incidence of thrombosis is influenced by age. A study of women aged 15 to 45 years reported that factor V mutation was associated with an annual risk for thrombosis of 0.06% (1). This risk increased about 5-fold to 0.3% per year among women receiving oral contraceptives. Therefore, the absolute incidence of venous thrombosis remained low when women with factor V mutation received oral contraceptives.

Anticoagulants are remarkably effective in preventing thrombosis and recurrent thrombosis, with a risk reduction of about 90% (2, 3). The risk for major bleeding with oral anticoagulant use has been reported to be about 2% per year, with a fatal rate of bleeding of 0.4% per year (2, 3). On the basis of these considerations, long-term anticoagulant therapy is not indicated in asymptomatic carriers.

Price and Ridker conclude that routine screening for factor V mutation before surgery, before or during pregnancy, or before beginning an oral contraceptive regimen is not warranted because of the low detection rate and the uncertain clinical benefits of detection. Their recommendations for clinical trials to evaluate the relative benefit-to-risk ratio for screening patients with thrombosis and the subsequent use of long-term anticoagulation are reasonable.

Jack Hirsh, MD
Hamilton Civic Hospitals Research CentreHamilton, Ontario, Canada


References

1. Vandenbroucke JP, Koster T, Briet E, et al. Increased risk of venous thrombosis in oral-contraceptive users who are carriers of factor V Leiden mutation. Lancet. 1994;344:1453-7.

2. Schulman S, Rhedin AS, Lindmarker P, et al. A comparison of six weeks with six months of oral anticoagulant therapy after a first episode of venous thromboembolism. Duration of Anticoagulation Trial Study Group. N Engl J Med. 1995;332:1661-5.

3. Schulman S, Granqvist S, Holmstrom M, et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med. 1997;336:393-8.