Who should be tested for factor V Leiden (factor V) mutation?

Factor V Leiden Testing Recommendations

Factor V Leiden testing should be performed in patients with venous thrombosis under age 50, thrombosis in unusual sites, recurrent venous thrombosis, venous thrombosis with strong family history, venous thrombosis during pregnancy or oral contraceptive use, and in relatives of individuals with venous thrombosis under age 50. 1, 2

Primary Indications for Testing

Testing is strongly recommended in the following circumstances:

• Venous thrombosis in patients under age 50
• Thrombosis in unusual sites (hepatic, mesenteric, cerebral veins)
• Recurrent venous thrombosis
• Venous thrombosis with strong family history of thrombotic disease
• Venous thrombosis in pregnant women or women taking oral contraceptives
• Relatives of individuals with venous thrombosis under age 50
• Myocardial infarction in female smokers under age 50

Secondary Indications for Testing

Testing may also be considered in:

• Venous thrombosis in patients over age 50, except when active malignancy is present
• Relatives of individuals known to have factor V Leiden (to guide pregnancy management and oral contraceptive use decisions)
• Women with:
  • Recurrent pregnancy loss
  • Unexplained severe preeclampsia
  • Placental abruption
  • Intrauterine fetal growth retardation
  • Stillbirth

Testing Methodology

When testing is indicated, clinicians should:

1. Use either direct DNA-based genotyping or a factor V Leiden-specific functional assay (activated protein C resistance assay) 1, 2
2. Confirm positive functional assay results with DNA testing to distinguish heterozygotes from homozygotes
3. Use direct DNA testing for patients on heparin therapy or with known lupus anticoagulant
4. Use direct DNA testing when testing relatives of known factor V Leiden carriers

When Testing is NOT Recommended

• Random screening of the general population 1, 2
• Routine testing for patients with arterial thrombotic disorders (except for myocardial infarction in young female smokers)
• Routine screening of asymptomatic women contemplating or using oral contraceptives (except those with personal history of thromboembolism)
• Screening of asymptomatic individuals with environmental risk factors (surgery, trauma, paralysis, malignancy) as they should receive appropriate thromboprophylaxis regardless of carrier status

Additional Testing Considerations

When factor V Leiden testing is positive, consider additional testing for:

• Prothrombin 20210A variant (most common co-occurring thrombophilia)
• Hyperhomocysteinemia
• Protein S, protein C, and antithrombin III deficiencies (especially with strong family history)

Clinical Context

The incidence of venous thromboembolism in carriers of factor V Leiden is approximately 0.34-0.56% per year, which is 3-6 times higher than the general population 3, 4. This risk increases with age, from 0.25% per year in 15-30 year olds to 1.1% per year in those over 60 5.

Important Caveats

• The R506Q mutation is currently the only molecular analysis of the factor V gene indicated in routine thrombotic risk workup 1
• Testing should be performed using validated technical approaches adhering to quality assurance guidelines
• Patients should be counseled about the genetic implications of testing and potential impact on family members
• The thrombotic risk in unselected relatives with factor V Leiden is considerably lower than in carriers from thrombophilic families (0.34% vs 1.7% per year) 4, highlighting the importance of family history in risk assessment