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Factor V Leiden is a recently discovered point mutation in the factor V gene involving a glutamine to arginine substitution at position 506. This mutation renders activated factor V relatively resistant to the proteolytic activity of activated protein C (APC), resulting in a hypercoagulable state. Heterozygotes have a 5 to 10-fold increased risk of venous thrombosis and homozygotes have a 50 to 100-fold increased risk. This primary hypercoagulable disorder accounts for 71% of deep vein thrombi in patients under 70 years of age, and for up to 50% of cases of familial venous thrombosis, making it by far the commonest hereditary cause of thrombosis. Approximately 3 to 8% of Caucasians are heterozygous for factor V Leiden and 0.1% (1 in 1000) are homozygous. Recently, the distribution of Factor V Leiden in other world populations was studied and reported.
Factor V Leiden is confined to persons of European extraction apart from rare cases among Asian Indians. Among Europeans, the highest carrier rates were among Greeks (15%) and U.K. whites (8.8%). The relatively high carrier rate in the U.S. reflects European ancestry. It is likely that this mutation occurred approximately 32,000 years ago in the European population, and has been dispersed by migration. It is interesting that the mutation was not detected at all in indigenous populations from Asia, Africa, Australia or America. Although environmental factors may play a role, it is possible that the absence of Factor V Leiden may partly explain the relative rarity of venous thromboembolic disease in these populations. The widespread prevalence of this mutation, in spite of its association with an increased risk for venous thromboembolism, suggests that some advantage may have been enjoyed by heterozygotes. It is possible that the mild hypercoagulability associated with the mutation may have conferred a survival advantage in pre-modern times, when death from bleeding associated with childbirth or warfare was a significant risk. A recent report that the presence of the factor V Leiden mutation in hemophiliac patients may lessen their bleeding tendency lends support to this hypothesis. In modern society, however, factor V Leiden is recognized as a significant risk factor for thromboembolic events. Young women who are either homozygous or heterozygous for the factor V Leiden gene and take oral contraceptives are at increased risk for thrombosis. A young woman who is heterozygous and taking oral contraceptives has a 30 fold relative risk of venous thrombosis. Older women with factor V Leiden who receive hormonal replacement therapy are also at increased risk of venous thromboembolic events. Approximately 45% of venous thromboembolic events that occur during pregnancy are associated with factor V Leiden. The odds ratio of pregnancy loss is increased 3.5 fold in women with factor V Leiden. Age-specific incidence rates of thrombosis and Factor V Leiden status were prospectively studied in a subset of participants in the Physicians' Health Study. The data indicated that the risk for venous thromboembolism in heterozygous carriers of factor V Leiden increased with age at a rate significantly greater than in men without the mutation. This difference was greatest in men over 70 years of age, whereas the incidence of thrombosis in men younger than 50 years of age was similar in both groups. This finding supports the hypothesis that the pathogenesis of venous thromboembolism is multifactorial, requiring interaction between both inherited and acquired risk factors. Heterozygosity for factor V Leiden alone may be a relatively weak risk factor for thrombosis unless a concomitant acquired risk factor is present, such as older age. This study also indicates that testing for factor V Leiden status should not be limited to younger patients. Laboratory screening for Factor V Leiden mutation is indicated in patients with a history of unexplained recurrent of familial thrombosis. The test may be ordered separately or as part of the hypercoagulability panel. The laboratory performs a coagulation screening test for APC resistance, the Activated Protein C Resistance ratio. All positive results are automatically confirmed by molecular analysis for the Factor V Leiden mutation by PCR. Results are reported as "not present", "present - heterozygous", or "present - homozygous". The reference value is not present. Specimen requirement is one 5 mL lavender top (EDTA) tube of blood. |
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