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Menopause Matters

Factor V Leiden Mutation, Venous Thromboembolism,
and Consideration of Hormone Therapy

Karen Novielli, MD

Factor V Leiden mutation, one of the most common inherited forms of thrombophilia, warrants careful consideration in postmenopausal health care—particularly with the short-term use of hormone replacement therapy (HRT) to alleviate vasomotor symptoms.

IDENTIFYING INHERITED THROMBOPHILIAS

When a patient presents with idopathic thromboembolic disease, recurrent thromboembolism, or a strong family history of thromboembolism, a laboratory evaluation for thrombophilia is often advisable. Such a workup typically involves measurement of the following blood factors:

• Antithrombin III
• Protein C
• Protein S
• Fibrinogen
• Antiphospholipid antibodies
• Prothrombin 20210A mutation
• Plasma homocysteine
• Factor V Leiden mutation.

BACKGROUND

Factor V Leiden mutation was first identified in 1993, when investigators in Sweden and the Netherlands uncovered a particular defect in the hemostatic pathway. These researchers initially referred to the defect as “resistance to activated protein C”¹ because it causes the activated form of factor V to be resistant to degradation by activated protein C. Such an effect is highly duplicable in the laboratory, and has been found to be responsible for most cases of resistance to activated protein C in humans.²

Clinical studies link factor V Leiden mutation with an increased risk of primary³ and recurrent VTE,⁴ as well as thrombosis during the use of oral contraceptives, ⁵ during pregnancy, ⁶ and in the presence of other risk factors for coagulation.⁷

PREVALENCE

Unlike other inherited coagulation defects (eg, disordered lupus anticoagulant and antiphospholipid antibodies), factor V Leiden mutation is relatively common. One large cross-sectional US study (N = 4047 men and women) determined the overall carrier frequency to be 3.71%, and the allele frequency to be 1.89%.⁸ Incidence of the mutation was highest in Caucasian participants (5.27%) and significantly lower in other ethnic groups, including Hispanic Americans (2.21%), African Americans (1.23%), and Asian Americans (0.45%).

THE RISK DURING MENOPAUSE

Factor V Leiden, as well as all other forms of inherited thromobophilia, represents a particular concern for health care providers prescribing short-term HRT for the relief of perimenopausal and postmenopausal vasomotor symptoms. This is because estrogen supplementation, regardless of duration of use, increases thrombosis risk.⁹ This subject is beginning to receive wider attention in the medical community.

Earlier this year, Rosendaal and colleagues investigated whether the increased risk of thrombosis posed by HRT is affected by carriership of factor V Leiden mutation and prothrombin 20210A mutation in 77 women aged 45 to 64 years.¹⁰ Among participants with a first venous thrombosis, 51% were receiving HRT at the time of the thrombosis, compared with 24% of those in the control group. Among the patients, 23% had a prothrombotic defect, versus 7% among those in the control group. The authors determined that women who had the factor V Leiden mutation and used HRT had a 15-fold increase in the risk for thrombosis compared with women who did not have the mutation and did not use HRT, and concluded that the thrombotic risk of HRT may particularly affect women with prothrombotic mutations.

Also this year, Herrington and associates analyzed data from the Heart and Estrogen/Progestin Replacement Study (HERS) and Effects of Estrogen Replacement on the Progression of Coronary-Artery Atherosclerosis (ERA)—two multicenter trials that examined HRT versus placebo in women with coronary artery disease.¹¹ In HERS, 47 women (1.7%) experienced deep-vein thrombosis or pulmonary embolism; in ERA, 8 women (2.6%) experienced a venous thromboembolism (VTE). After genotyping blood samples from these women and matched controls, these authors found the factor V Leiden mutation in 16.7% of the women with a VTE versus 6.3% of the controls. Data analysis revealed that the risk of VTE was 3.3 times higher in women who carried the mutation than in noncarriers. Based on the results of these investigations, efforts to avoid HRT in women with this mutation are recommended.

It is also important to note that estrogen-related compounds (eg, tamoxifen, raloxifene) confer the same increased risk of thromboembolism; therefore, similar efforts should be made to avoid these agents in patients with factor V Leiden mutation (and other inherited forms of thrombophilia).

SCREENING RECOMMENDATIONS

The decision to routinely screen patients for factor V Leiden mutation varies among patient populations. Standard screening of patients, including those in whom HRT is being considered, is not recommended: It has been estimated that in the United States, 376 women with coronary artery disease would have to be screened, at a cost of $150 to $600 per test, to prevent just one VTE over 5 years.¹¹ In addition, the risks associated with lifetime anticoagulation are considerable; therefore, the presence of this mutation does not warrant automatic anticoagulation as a practice standard. However, in women presenting with any personal or family history or thrombosis, screening for factor V Leiden mutation and other inherited forms of thrombophilia prior to the administration of systemic estrogen supplementation (ie, oral, transdermal, transvaginal) or the use of an estrogen-related compound, regardless of expected duration of use, should be considered.

Karen Novielli, MD, is clinical assistant professor of family medicine and assistant dean for faculty affairs, Jefferson Medical College, Philadelphia, Pa.

REFERENCES

1. Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C. Proc Natl Acad Sci U S A. 1993;90:1004-1008.
2. Bertina RM, Koeleman B, Koster T, et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature. 1994;369:64-67.
3. Koster T, Rosendaal FR, de Rhonde H, et al. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet. 1993;342:1503-1506.
4. Ridker PM, Miletich JP, Stampfer MJ, et al. Factor V Leiden and recurrent idiopathic venous thromboembolism. Circulation. 1995;92:2800-2802.
5. 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;344:1453-1457.
6. Boarewa MI, Bremme K, Blomback M. Arg506-Gln mutation in factor V and risk of thrombosis during pregnancy. Br J Haematol. 1996;92:473-478.
7. Zoller B, Bernstdotter A, Garcia de Frutos P, Dahlbäck B. Resistance to activated protein C as an additional genetic risk factor in hereditary deficiency of protein S. Blood. 1995;85: 3518-3523.
8. Ridker PM, Miletich JP, Hennekens CH, Buring JE. Ethnic distribution of factor V Leiden in 4047 men and women; implications for venous thromboembolism screening. JAMA. 1997;277:1305-1307.
9. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA. 2002;288(7):872-881.
10. Rosendaal FR, Vessey M, Rumley A, et al. Hormonal replacement therapy, prothrombotic mutations, and the risk of venous thrombosis. Br J Haematol. 2002;116(4):851-854.
11. Herrington DM, Vittinghoff E, Howard TD, et al. Factor V Leiden, hormone replacement therapy, and risk of venous thromboembolic events in women with coronary disease. Arterioscler Thromb Vasc Biol. 2002; 22(6):1012-1017.

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