Conclusion: Patients with venous thromboses who are homozygous for factor V Leiden and/or prothrombin G20210A or are double heterozygous carriers of factor V Leiden and prothrombin G20210, do not have a high risk of recurrent venous thrombosis. Summary: Within the Caucasian population, factor V Leiden has a prevalence of approximately 5% and the prothrombin G20210A mutation has a prevalence of approximately 2%. The risk for initial venous thrombosis is clearly higher in heterozygote and homozygote carriers of factor V Leiden and prothrombin G20210A. Heterozygote carriers of factor V Leiden have an approximately a 5-fold increased risk for initial venous thrombosis, whereas homozygote carriers have an 18-fold increased risk for initial venous thrombosis. Individuals heterozygous for both factor V Leiden and prothrombin G20210A have approximately a 20-fold risk for initial venous thrombosis. It is generally assumed that patients with thrombophilia on the bases of factor V Leiden and/or prothrombin G20210A mutations would also have increased risk for recurrent venous thrombosis. This assumes the risk of recurrence is driven primarily by the same factors that prompted the initial venous thrombosis. However, some studies have suggested thrombophilia secondary to factor V Leiden and prothrombin G20210A mutations actually do not increase the risk of recurrent venous thrombosis. This would argue against testing for these genetic defects in individuals with an unprovoked first-time venous thrombosis (Christansen SC et al, JAMA 2005;293;2352-61; and Baglin T et al, Lancet 2003;362:523-6). The authors performed a case-control study using a large cohort of families with thrombophilia identified through three major university hospitals in the Netherlands. The goal was to calculate the risk of recurrent venous thrombosis in individuals with homozygosity or double heterozygosity of factor V Leiden and/or prothrombin G20210A. Controls were patients with only one episode of venous thrombosis, and cases were individuals with recurrent venous thrombosis. There were 788 individuals in the cohort with venous thrombosis: 357 had factor V Leiden, and 137 had prothrombin G20210A mutation, 27 had factor V Leiden and/or prothrombin G20210A homozygosity, and 49 were double heterozygotes for both mutations. The cohort comprised 463 “controls” with only one venous thrombosis and 325 “cases” with recurrent venous thrombosis. Compared with noncarriers, the crude odds ratio for recurrence was 1.2 (95% confidence interval [CI], 0.9-1.6) for heterozygote carriers of factor V Leiden, 0.7 (95% CI, 0.4-1.2) for prothrombin G20210A, 1.2 (95% CI, 0.5-2.6) for homozygous carriers of factor V Leiden and/or prothrombin G20210A, and 1.0 (95% CI, 0.6-1.9) for double heterozygous of both mutations. Risk estimates were not altered by adjustments for family status, sex, age, other natural anticoagulant deficiencies, or first event type. Comment: The study has major indications for the evaluation of patients with a first-time unprovoked venous thrombosis. It suggests evaluation for factor V Leiden and prothrombin G20210A mutations have little clinical implication or benefit for the individual with a first-time venous thrombosis. If recurrence of first-time venous thrombosis is not increased by the presence of these mutations, then there is no need to test for them in the patient with an initial unprovoked venous thrombosis. The information in this study does not apply to individuals with multiple recurrent venous thrombi. It is also important to consider, because these mutations are genetic, whether it is still reasonable to perform thrombophilia testing in the patients with first-time venous thrombosis so that family members can be appropriately counseled.