What is the workup for a patient suspected of having thrombophilia?

Workup for Thrombophilia

The workup for thrombophilia should include testing for Factor V Leiden mutation, prothrombin G20210A variant, protein C, protein S, and antithrombin III deficiencies, as well as antiphospholipid antibodies, with testing directed at patients with specific clinical presentations rather than universal screening. 1

Patient Selection for Thrombophilia Testing

Testing for thrombophilia should be targeted to specific patient populations rather than performed universally. Consider testing in:

• Patients with venous thrombosis under age 50
• Venous thrombosis in unusual sites (cerebral, splanchnic, portal veins)
• Recurrent venous thromboembolism (VTE)
• 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 1

Recommended Testing Panel

Inherited Thrombophilias

• Factor V Leiden (R506Q) mutation
• Prothrombin gene (G20210A) mutation
• Protein C deficiency (functional assay)
• Protein S deficiency (functional assay)
• Antithrombin III deficiency (functional assay) 1, 2

Acquired Thrombophilias

• Antiphospholipid antibodies:
  • Lupus anticoagulant
  • Anticardiolipin antibodies
  • Anti-β2 glycoprotein I antibodies 1, 2

Additional Testing

• Plasma homocysteine levels (especially in patients positive for Factor V Leiden)
• Complete blood count with peripheral smear (to evaluate for myeloproliferative disorders)
• JAK2V617F mutation testing (when splanchnic vein thrombosis is present) 2

Timing of Testing

Timing of testing is critical for accurate results:

• Acute thrombosis can cause temporary decreases in protein C, protein S, and antithrombin levels
• Anticoagulation therapy affects multiple test results:
  • Warfarin decreases protein C and S levels
  • Heparin affects antithrombin levels
  • Direct oral anticoagulants interfere with clotting-based assays

For optimal accuracy:

• Perform testing either before anticoagulation is started or at least 2 weeks after discontinuation of anticoagulation
• If testing must be done while on anticoagulation, interpret results with caution and consider repeating after completion of therapy 3

Special Considerations

For Splanchnic Vein Thrombosis

For patients with Budd-Chiari syndrome or portal vein thrombosis:

• Test for both inherited and acquired thrombophilias
• Include JAK2V617F mutation testing to screen for myeloproliferative neoplasms
• In JAK2V617F-negative patients, consider calreticulin mutation screening
• Consider bone marrow histology if both tests are negative 2

For Antiphospholipid Syndrome

• Positive antiphospholipid antibody tests should be repeated after 12 weeks to confirm diagnosis 2

Interpretation and Clinical Implications

Risk Assessment

• Homozygous Factor V Leiden carriers have approximately 18 times higher risk of initial VTE compared to non-carriers
• Multiple thrombophilic factors significantly increase risk (e.g., hyperhomocysteinemia plus Factor V Leiden increases relative risk 20-fold) 1
• The presence of thrombophilia affects decisions regarding:
  • Duration of anticoagulation after unprovoked VTE
  • Prophylaxis during high-risk periods (surgery, pregnancy)
  • Family screening and counseling

Common Pitfalls to Avoid

1. Unnecessary testing: Avoid routine screening in patients with provoked VTE (surgery, immobility, malignancy)
2. Poor timing: Testing during acute thrombosis or while on anticoagulation leads to unreliable results
3. Incomplete testing: Missing important components of the panel can lead to false reassurance
4. Overinterpretation: Finding a mild thrombophilia (heterozygous Factor V Leiden) should not automatically lead to indefinite anticoagulation
5. Underinterpretation: Strong thrombophilias (antithrombin deficiency, homozygous mutations, combined defects) significantly increase recurrence risk and may warrant extended treatment 4, 3

Remember that thrombophilia testing results should be interpreted in the context of the patient's clinical presentation, family history, and other risk factors to guide appropriate management decisions.