November 7, 2001 Access past issues

Reviewed by: Marta Gwinn, MD, MPH Office of Genomics and Disease Prevention Centers for Disease Control and Prevention

The Health Outcome

Venous thromboembolism (VTE) is an important cause of morbidity and mortality.  More than 200,000 new cases of venous thrombosis occur in the United States each year; a small proportion of these cases result in pulmonary embolism, which can be fatal.  The risk for recurrent VTE remains elevated for many years after the initial event.  However, use of anticoagulant prophylaxis to prevent recurrence introduces a significant risk for hemorrhagic complications.  Prevention of VTE has attracted renewed interest ever since the discovery of certain predisposing “thrombophilic” genetic variants.  The most common genetic variant is a point mutation in the gene for factor V, known as F5 R506Q, or factor V Leiden (FVL).  This variant is found in about 5% of people of northern European descent and in 20-60% of people with VTE, depending on selection criteria.

The Finding

Middeldorp et al. report results of a prospective study of 470 asymptomatic people with factor V Leiden who were identified by screening first-degree relatives of people with VTE.(1)   The mean age of participants was 43 years; mean follow-up was 3.3 years (range 1.5 – 4.8 years), yielding a total of 1,564 person-years of observation.  Nine venous thromboembolic events were observed, resulting in an overall annual incidence of 0.58% (95% confidence interval [CI] 0.26 – 1.10%).  Four “spontaneous” events occurred in the absence of other predisposing factors (surgery, trauma, immobilization, pregnancy, oral contraceptive use, or hormone replacement therapy), from which the authors calculated an annual incidence of 0.26%, (95% CI 0.07 – 0.65%).  Three other events occurred in women who used oral contraceptives, and one event occurred in a woman on hormone replacement therapy.  The remaining event occurred 3 weeks post-surgery, despite 1 week of anticoagulant prophylaxis.

Public Health Implications

The authors concluded that in the absence of other predisposing factors, the absolute risk for VTE in asymptomatic carriers of factor V Leiden is too low to justify routine screening for families of symptomatic people.  Results of this study corroborate those from an earlier, retrospective cohort study conducted in the same population.(2)    In that study, 8/29 (approximately 30%) of first episodes of VTE among factor V Leiden carriers were associated with pregnancy or oral contraceptive use; information about hormone replacement therapy was not reported.

Data from the prospective study were not presented separately for men and women or by age; however, a crude analysis (Table) suggests that  women who used exogenous hormones had about a fivefold increased risk for VTE compared with other factor V Leiden carriers.  A crude estimate of the attributable fraction (exposed; see Table) suggests that use of exogenous hormones accounted for 80% of the risk of VTE in factor V Leiden carriers who took them.

As the authors acknowledged, this study had limited power to measure incidence in “high-risk” situations.  Few studies have examined the risk for VTE associated with hormone replacement therapy in factor V Leiden carriers.(3)   This question deserves further study, given that the baseline risk of VTE increases with age, as does the risk difference for factor V Leiden carriers.(4)  More systematic evaluation is needed to evaluate the risks and benefits of testing for thrombophilic variants in various settings; such evaluations should include cost information for each of the associated interventions and outcomes.(5)

References

1. Middeldorp S, Meinardi JR, Koopman MMW, et al.  A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism.  Ann Intern Med 2001;135:322-327.
2. Middeldorp S, Henkens CM, Koopman MM, et al.  The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis.  Ann Intern Med 1998;128:15-20.
3. Hoibraaten E, Abdelnoor M, Sandset PM.  Hormone replacement therapy with estradiol and risk of venous thromboembolism—a population-based case-control study.  Thromb Haemost 1999;82:1218-21.
4. Ridker PM, Glynn RJ, Miletich JP, Goldhaber SZ, Stampfer MJ, Hennekens CH.  Age-specific incidence rates of venous thromboembolism among heterozygous carriers of factor V Leiden mutation.  Ann Intern Med 1997;126:528-31.
5. Marchetti M, Quaglini S, Barosi G.  Cost-effectiveness of screening and extended anticoagulation for carriers of both factor V Leiden and prothrombin G20210A.  Q J Med 2001;94:365-72.
6. E-journal club abstraction template.