Thrombophilia Testing Panel
For patients with documented venous thromboembolism, order a comprehensive thrombophilia panel that includes molecular genetic testing for Factor V Leiden and Prothrombin G20210A mutations, functional coagulation assays for antithrombin III, protein C, and protein S, plus plasma homocysteine levels. 1
Core Molecular Genetic Tests
Order these DNA-based tests first:
Factor V Leiden (R506Q) mutation - This is the most common inherited thrombophilia, accounting for 90-95% of activated protein C resistance cases 1. The molecular test is simple, reliable, and can be multiplexed with prothrombin testing 2.
Prothrombin G20210A mutation - The second most common genetic thrombophilia, present in 1-2% of the general population 1. This single nucleotide change in the 3' untranslated region causes elevated prothrombin levels 2. Among Factor V Leiden heterozygotes with VTE, 10% will also carry this mutation 2.
Functional Coagulation Assays
These require functional testing, not molecular analysis, due to genetic heterogeneity:
Antithrombin III functional assay - Multiple different mutations can cause deficiency, making functional testing the standard approach 1, 2.
Protein C functional assay - Similarly requires functional testing rather than molecular analysis 1, 2.
Protein S functional assay - Functional testing is necessary for the same reasons as protein C and antithrombin III 1, 2.
Biochemical Testing
- Plasma homocysteine level - This measurement is more informative than molecular testing for MTHFR variants 1. Hyperhomocysteinemia interacts synergistically with Factor V Leiden to increase venous thrombosis risk 2. Patients with classic homocystinuria are at extremely elevated risk and should be tested for other thrombophilic factors 2.
Additional Tests for Acquired Thrombophilias
Include these in comprehensive risk stratification:
Lupus anticoagulant - Important for recurrent thrombosis evaluation 1.
Anticardiolipin antibody - Should be included alongside hereditary factors 1.
Anti-β2-glycoprotein-1 antibodies - Part of the antiphospholipid antibody syndrome workup 2.
Who Should Be Tested
Testing is indicated for patients with:
- Venous thrombosis under age 50 2
- Recurrent thrombosis 2, 3
- Thrombosis at unusual sites (e.g., cerebral vein, mesenteric vein) 2, 3
- Strong family history of venous thrombosis 2
- Venous thromboembolism during pregnancy or oral contraceptive use 2
- Recurrent late-trimester fetal loss or severe preeclampsia 2
Do not test:
- Asymptomatic individuals for routine screening 2, 1
- Before prescribing oral contraceptives in women without personal or family history of thrombosis 2
- Patients with active malignancy (results won't change management) 2
Critical Timing Considerations
Avoid these common pitfalls:
- Do not test during acute thrombosis while on anticoagulation - protein C, protein S, and antithrombin levels can be falsely low 4
- Wait at least 2-4 weeks after stopping warfarin before testing protein C and S 4
- Factor V Leiden and Prothrombin G20210A can be tested anytime, as they are DNA-based 2
Clinical Rationale
Venous thrombosis is multifactorial, and identifying multiple genetic risk factors is common 1. This comprehensive approach allows proper risk stratification to guide anticoagulation duration decisions 1. The highest diagnostic yield occurs in patients under 50 with unprovoked VTE, where a heritable cause can be identified in a substantial minority of cases 5. Testing results directly impact management decisions regarding duration of anticoagulation therapy and counseling for family members 2.