Meta-analysis: Factor V Leiden mutation associated with recurrent VTE, VTE in family members

Despite the association between Factor V Leiden and the risk for recurrent venous thromboembolism, testing for Factor V Leiden or prothrombin G20210A mutation may not improve outcomes for adults with VTE or family members with the mutation, according to data from a systematic review.

“There is no direct evidence that testing for these mutations, and the resultant management, reduces VTE related-outcomes in individuals who have had VTE or in the probands’ family members who have been tested,” the researchers wrote.

The review included 46 articles that examined VTE rates in people with a history of VTE who were tested for Factor V Leiden or prothrombin G20210A mutation, or in family members of people with mutations. All studies included patients from European populations. Researchers used random-effects models to pool the odds of VTE associated with mutations.

Pooled ORs for recurrent thrombosis among individuals heterozygous for Factor V Leiden was 1.56 (95% CI, 1.14-2.12) and among those with homozygous for Factor V Leiden was 2.65 (95% CI, 1.2-6.0) compared with people without Factor V Leiden. Compared with family members of individuals without Factor V Leiden, both heterozygosity and homozygosity for Factor V Leiden predicted VTE in family members.

Prothrombin G20210A heterozygosity was not predictive of recurrent VTE in probands (OR=1.45; 95% CI, 0.96-2.2) and, due to insufficient data, the researchers were unable to determine whether homozygosity predicts recurrent VTE or VTE in family members. According to the researchers, superior evidence shows the reduction in recurrent VTE afforded by anticoagulation among individuals with either mutation, and inferior evidence demonstrates that the reduction in risk for VTE is similar to that among individuals with a history of VTE without mutations.

The researchers did not assess any studies that examined the effect of testing on outcomes.

Segal JB. JAMA. 2009;301:2472-2485.

This systematic review concludes that heterozygosity for the Factor V Leiden mutation is associated with a significant, albeit modest, increased relative risk for recurrent venous thromboembolism (RR 1.56); a similar trend was seen for heterozygosity for the prothrombin G20210A mutation, but the number of cases was smaller and did not reach statistical significance.

Clinical factors present at the time of a first venous thrombosis, specifically whether it was unprovoked or provoked (occurred in association with a transient risk factor), are the most important determinants of the recurrence risk following a minimum of three months of anticoagulant therapy. Testing for the Factor V Leiden and prothrombin G20210A mutations is performed frequently in patients with venous thromboembolism with little available evidence that their identification, save for homozygosity which is detected infrequently, should influence the duration of anticoagulant therapy. Furthermore there is no evidence that testing of their asymptomatic affected relatives leads to improved outcomes. Thrombophilia testing should no longer be a "reflex action" of physicians evaluating patients with thrombotic disorders, but undertaken following careful clinical assessment including a detailed family history and counselling of the patient.

– Kenneth Bauer, MD

HemOnc Today Editorial Board member