Genetic Thrombophilia Workup

Core Genetic Tests

A comprehensive thrombophilia panel should include molecular genetic testing for Factor V Leiden and Prothrombin G20210A mutations, as well as functional coagulation assays for antithrombin III, protein C, and protein S, along with plasma homocysteine levels, as recommended by the American College of Medical Genetics 1, 2, 3
Factor V Leiden mutation is the most common inherited thrombophilia, accounting for 90-95% of activated protein C resistance cases, according to the American College of Medical Genetics 2
Prothrombin G20210A mutation is the second most common genetic thrombophilia, present in 1-2% of the general population, as stated by the American College of Medical Genetics 4, 5

Antithrombin III functional assay is the standard approach due to genetic heterogeneity, as recommended by the American College of Medical Genetics 1, 3, 6
Protein C functional assay requires functional testing rather than molecular analysis due to genetic heterogeneity, according to the American College of Medical Genetics 1, 3, 6
Protein S functional assay similarly requires functional testing for the same reasons as protein C and antithrombin III, as stated by the American College of Medical Genetics 1, 3, 6

Plasma homocysteine level measurement is more informative than molecular testing for MTHFR variants, as it interacts synergistically with Factor V Leiden to increase venous thrombosis risk, according to the American College of Medical Genetics 6, 7

Lupus anticoagulant should be included in comprehensive risk stratification for recurrent thrombosis, as recommended by the American College of Medical Genetics 1, 3
Anticardiolipin antibody should be included in panel testing alongside hereditary factors, according to the American College of Medical Genetics 1, 3

The American College of Medical Genetics emphasizes that venous thrombosis is multifactorial, and identifying multiple genetic risk factors is common, which allows for proper risk stratification to target anticoagulation therapy 3, 7
Testing should be reserved for patients with documented venous thromboembolism, not for general population screening or routine pre-oral contraceptive screening, as recommended by the American College of Medical Genetics, with the highest yield in patients under age 50 with venous thrombosis, those with thrombosis in unusual sites, recurrent thrombosis, strong family history, or pregnancy/oral contraceptive-associated thrombosis 8