What genetic tests are recommended for patients with a history of blood clots or a family history of clotting disorders?

Genetic Testing for Blood Clots

For patients with a history of blood clots or a family history of clotting disorders, genetic testing should include Factor V Leiden (R506Q), prothrombin G20210A variant, and functional assays for protein C, protein S, and antithrombin III deficiencies. 1

Indications for Genetic Thrombophilia Testing

Recommended for:

• Patients under 50 years with venous thrombosis
• Venous thrombosis in unusual sites
• Recurrent venous thrombosis
• 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
• Women with recurrent pregnancy loss, unexplained severe preeclampsia, placental abruption, intrauterine growth restriction, or stillbirth 2, 1

Not Recommended for:

• Random screening of the general population
• Routine testing for patients with arterial thrombotic disorders (except young female smokers with myocardial infarction)
• Prenatal testing or routine newborn screening
• Routine screening of asymptomatic women contemplating or using oral contraceptives (except those with a personal history of thromboembolism) 2, 1

Specific Genetic Tests to Order

First-Line Testing:

• Factor V Leiden mutation (R506Q) - The most common inherited risk factor for thrombosis 2, 1
• Prothrombin G20210A variant - The second most common inherited risk factor 2, 1

Additional Testing:

• Functional assays for:
  • Protein C deficiency
  • Protein S deficiency
  • Antithrombin III deficiency 2, 1
• Plasma homocysteine levels - Especially important in patients who test positive for Factor V Leiden 2, 1

Testing Methods

• Direct DNA-based genotyping is recommended for Factor V Leiden and prothrombin G20210A 1
• Initial screening test for Factor V Leiden is the activated protein C (APC) resistance assay, with DNA analysis for confirmation 1
• Functional coagulation assays should be used for protein C, protein S, and antithrombin III deficiencies 2, 1

Clinical Significance and Management Implications

• The clinical penetrance of thrombophilia genes varies:

  • Lower risk: Heterozygous carriers of Factor V Leiden and prothrombin G20210A (mild thrombophilia)
  • Higher risk: Carriers of deficiencies of antithrombin, protein C or S, and those with multiple or homozygous abnormalities 3

• Incidence of venous thromboembolism in carriers of Factor V Leiden is approximately 0.34-0.56% per year (3-6 times higher than the general population) 1

• Homozygous Factor V Leiden carriers have approximately 18 times higher risk of initial VTE compared to non-carriers 2

• The presence of multiple thrombophilic factors significantly increases risk - hyperhomocysteinemia with Factor V Leiden increases relative risk of venous thrombosis 20-fold compared to individuals without either risk factor 2

Important Caveats and Pitfalls

• Testing timing matters: Testing during an acute thrombotic event or while on anticoagulation may affect results of functional assays (protein C, protein S, antithrombin III) 1

• Limited utility for treatment decisions: Genetic thrombophilia testing has limited clinical utility for patients already on anticoagulation for DVT/PE. The decision to continue anticoagulation should be based primarily on clinical risk factors for recurrence, whether the event was provoked or unprovoked, and bleeding risk 1

• Declining yield of testing: There has been a trend toward annual reduction in detection of Factor V Leiden mutation from over 25% in 1996 to approximately 10% in recent years, suggesting poorer patient selection 4

• Gender differences in testing yield: Studies show proportionally more males than females are identified with Factor V Leiden (15.4% vs. 6.6%) or prothrombin gene mutation (10.4% vs. 4.3%) despite more testing being performed in females 4

• Rare disorders consideration: Inherited disorders of the fibrinolytic pathway are extremely rare and primarily have hemorrhagic phenotypes. These require specialized testing at dedicated centers 5

Patient Counseling

• Patients should be informed that genetic testing has implications for family members 2, 1
• When Factor V Leiden testing is positive, consider additional testing for other thrombophilias 2
• Formal informed consent is not required for Factor V Leiden testing, but patients should be made aware of potential implications for family members and possible insurance discrimination 2

By following these evidence-based recommendations for genetic testing in patients with a history of blood clots or family history of clotting disorders, clinicians can appropriately identify inherited thrombophilias and guide management decisions to reduce morbidity and mortality from thrombotic events.