Factor V Leiden by Polymerase Chain Reaction

Factor V Leiden is a 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. 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 has not been detected 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. The presence of factor V Leiden mutation in hemophiliac patients may lessen their bleeding tendency.

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.

The clinical utility of genetic testing depends on the ability of testing results to change patient management in a way that improves clinical outcomes. The clinical utility of genetic tests for thrombophilia is based on the overall risk of thromboembolism and the risk to benefit ratio of anticoagulant therapy. Two medical societies have issued position statements that question the value of genetic testing.

The American College of Chest Physicians (ACCP) published guidelines for the treatment of thromboembolic disease in 2008. They stated that the presence of hereditary thrombophilia has not been used as a major factor to guide duration of anticoagulation therapy for venous thromboembolism because it is not a major risk factor for recurrence.

In 2011, the Evaluation of Genomic Applications in Practice and prevention Working Groups (EGAPP) stated that:

  • There is no evidence that knowledge of Factor V Leiden mutation status affects anticoagulation therapy to avoid recurrence
  • There is convincing evidence that treatment beyond three months reduces the recurrence of venous thromboembolism regardless of mutation status.
  • There is no evidence that knowledge of Factor V Leiden mutation status among asymptomatic family members of patients with venous thromboembolism leads to prophylactic anticoagulation therapy.

Factor V Leiden mutation analysis may be ordered separately or as part of the hypercoagulability panel.  Some laboratories perform a coagulation screening test for 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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