Hereditary Thrombophilia - Hypercoagulability

Indications for Testing

Although routine testing for hereditary thrombophilia is generally discouraged, testing may be appropriate when results could impact clinical management and decision-making in patients with one or more of the following    ^,  :

• Unprovoked thrombosis at a young age (≤50 years)
• Recurrent thrombosis
• Thromboses at unusual sites
• First-degree relatives with a strong history of early VTE

These criteria are not exhaustive; precise indications for testing may vary by medical organization and clinical situation.

Laboratory Testing

Overview of Testing in Hereditary Thrombophilia

Although experts propose a variety of testing strategies for hereditary thrombophilias, a helpful approach may be to test for disorders likely to impact patient care in the specific clinical circumstance (eg, protein C or S deficiency in infants with purpura fulminans).

Methods of testing for inherited thrombophilia include functional, antigenic, and genetic assays, which may be ordered individually or as a panel. Individual tests can be useful when a strong family history points to a specific disorder, whereas panel tests may be beneficial when no previous information exists.  Some experts recommend a focused approach using individual tests rather than panel tests, particularly in circumstances in which inaccurate results (eg, due to anticoagulant interference in testing) may occur. 

Preanalytic Factors That May Lead to Clinically Inaccurate Results

Many factors can contribute to inaccurate or discrepant test results, including medications, transient conditions (eg, pregnancy), specific test components, and biologic variability.   Functional testing is not recommended during acute thrombotic episodes because results may be inaccurate (due to consumption, acute phase responses, etc.) and will not affect acute care.   Clinical guidelines recommend appropriate confirmatory or repeat testing to verify any abnormal functional or antigenic test result before making a definitive thrombophilia diagnosis. 

Anticoagulant medications are among the most common sources of coagulation testing interference. Avoid testing for at least 2-3 days after direct oral anticoagulant use , and for a minimum of 2-4 weeks after vitamin K antagonist use (eg, warfarin).    For more information on anticoagulant medication interference, see Impacts of Common Anticoagulants on Coagulation Testing.

Testing for Hereditary Causes of Thrombophilia

Factor V Leiden Thrombophilia

The FVL variant of the F5 gene, also known as c.1601G>A (p.Arg534Gln) or R506Q, is a common inherited cause of activated protein C (APC) resistance. Because APC resistance is a typical feature of FVL thrombophilia, plasma-based functional assays that measure the APC resistance ratio can be used as an initial test for this disorder. An abnormal APC result that is suggestive of FVL should be confirmed with genetic testing.  Genetic assays can also be useful to distinguish heterozygotes from homozygotes and inform a risk assessment for VTE. 

Although APC resistance tests are inexpensive and highly specific for FVL thrombophilia, genetic testing may be preferable as a first step in certain situations, such as when the patient is receiving anticoagulant therapy  or has a first-degree family member with a previously identified familial variant.

Factor II c.*97G>A Thrombophilia

The factor II c.*97G>A variant, also known as prothrombin G20210A, causes hypercoagulability due to increased prothrombin.  Genetic testing for the c.*97G>A variant is the only reliable means to diagnose this condition; factor II activity is not an appropriate test for diagnosis.  Testing for this variant can include targeted polymerase chain reaction (PCR) assays or broader panels that assess individuals for multiple prothrombotic variants, such as FVL. 

Protein C Deficiency

Protein C deficiency, a prothrombotic state that can be either acquired or inherited (in association with the PROC gene), involves a qualitative or quantitative lack of protein C that hinders normal anticoagulant activity in the blood. Functional assays, such as clot-based assays and chromogenic assays, can be used as initial tests to assess protein C activity.  Chromogenic assays are considered less prone to interference and are thus typically preferred for initial testing.  Immunoassays (antigenic tests) can be used to measure total protein C levels and subtype the deficiency.  Genetic testing is not widely available or required for diagnosis of protein C deficiency in most cases.

Protein S Deficiency

Protein S deficiency is a prothrombic condition, either acquired or inherited (in association with the PROS1 gene), in which a quantitative or qualitative lack of protein S hinders normal anticoagulant activity in the blood.  Antigenic tests (typically immunoassays) that measure free protein S are considered a reliable means of detecting a deficiency.  Clot-based functional assays can also be used to evaluate protein S activity, but these tests may be prone to interference ; if selected, clot-based assays should be ordered concurrently with immunoassays that measure free protein S.  Genetic testing is not widely available or required for diagnosis of protein S deficiency in most cases.

Antithrombin Deficiency

Antithrombin deficiency can be inherited (SERPINC1 gene) or acquired and may be qualitative or quantitative. Testing for antithrombin deficiency can involve both functional and antigenic assays. The former, which are typically chromogenic assays, evaluate antithrombin’s capacity to neutralize specific clotting factors IIa and Xa, whereas the latter assess the total quantities of antithrombin available in the blood.  Functional tests are recommended as the initial tests. Antigenic testing can be used to confirm and subtype the deficiency but will not detect qualitative abnormalities.  Genetic testing is not widely available or required for diagnosis of antithrombin deficiency in most cases.