What is the Factor V Leiden (Factor 5) test?

Factor V Leiden Test: Genetic Testing for Thrombophilia Risk

The Factor V Leiden test is a genetic test that detects a specific mutation (R506Q) in the factor V gene, which is the most common inherited risk factor for venous thrombosis, causing resistance to activated protein C and increasing thrombosis risk. 1, 2

What is Factor V Leiden?

Factor V Leiden is a genetic disorder characterized by:

• A mutation in the F5 gene (R506Q mutation) that makes Factor V resistant to inactivation by activated protein C (APC)
• Present in approximately 5% of Caucasian Americans 1
• Accounts for 20% of idiopathic first venous thrombosis cases 1
• Increases risk of venous thromboembolism (VTE) 3-6 times compared to the general population 2
• Annual incidence of thromboembolism in carriers is approximately 0.34-0.56% 2

Testing Methods

Two primary methods are used to detect Factor V Leiden:

1. Functional Assay (APC Resistance Test):

   • Initial screening test that measures clotting time in presence and absence of activated protein C
   • High sensitivity but suboptimal specificity for Factor V Leiden 1
   • Russell viper venom time-based assays show improved sensitivity 3

2. DNA Analysis (Genetic Test):

   • Gold standard for diagnosis
   • Detects the specific R506Q mutation in the F5 gene
   • Methods include PCR with restriction enzyme analysis, heteroduplex technology, or other validated molecular techniques 1, 4
   • Can distinguish between heterozygotes (one copy) and homozygotes (two copies) 1

Who Should Be Tested?

Testing is recommended for:

• Patients with venous thrombosis under age 50 2
• Venous thrombosis in unusual sites 2
• Recurrent venous thromboembolism 2
• Strong family history of thrombotic disease 2
• Venous thrombosis in pregnant women or women taking oral contraceptives 2
• Women with recurrent pregnancy loss, unexplained severe preeclampsia, placental abruption, intrauterine growth restriction, or stillbirth 2
• First-degree relatives of individuals with venous thrombosis under age 50 2

Testing is NOT recommended for:

• Random screening of the general population 2
• Routine testing for patients with arterial thrombotic disorders (except young female smokers with myocardial infarction) 2
• Prenatal testing or routine newborn screening 2
• Routine screening of asymptomatic women contemplating or using oral contraceptives (except those with a personal history of thromboembolism) 2

Clinical Significance of Test Results

• Heterozygotes (one copy):

  • 3-7 fold increased risk of venous thrombosis 1, 5
  • Annual incidence of thromboembolism approximately 0.45% 6
  • Risk increases with age from 0.25% in 15-30 year olds to 1.1% in those over 60 6

• Homozygotes (two copies):

  • Approximately 18 times higher risk of initial VTE compared to non-carriers 2
  • Lifetime risk for venous thrombosis >80% 1
  • Should be considered for lifelong anticoagulation after a thrombotic event 1

• Combined with other risk factors:

  • Presence of multiple thrombophilic factors significantly increases risk
  • Factor V Leiden with hyperhomocysteinemia increases relative risk 20-fold 2
  • Heterozygosity for both Factor V Leiden and prothrombin 20210A mutation has high recurrence risk 1

Additional Testing Considerations

When Factor V Leiden testing is positive, additional testing should be considered for:

• Prothrombin 20210A variant 1, 2
• Plasma homocysteine levels 1, 2
• Functional coagulation assays for protein C, protein S, and antithrombin III deficiencies 1, 2
• Antiphospholipid antibodies in appropriate clinical settings 2

Important Patient Information

• Specific informed consent is not required for Factor V Leiden testing 1
• Patients should be informed that:
  • This is a genetic test with implications for family members 1
  • Results may have issues related to confidentiality and possible insurance discrimination 1
  • The presence of Factor V Leiden affects decisions regarding duration of anticoagulation, prophylaxis during high-risk periods, and family screening 2

Testing Timing

• Testing should be performed either before anticoagulation is started or at least 2 weeks after discontinuation of anticoagulation 2
• Acute thrombosis and anticoagulation therapy can affect functional test results 2

Factor V Leiden testing is a valuable tool for assessing thrombotic risk and guiding clinical management in appropriate patient populations, though decisions regarding anticoagulation should be based on individualized assessment of thrombosis recurrence risk versus bleeding risk.