Hereditary Thrombophilia - Hypercoagulability

Hereditary thrombophilias are prothrombotic conditions, including factor V Leiden (FVL), factor II c.*97G>A (also known as prothrombin G20210A), and anticoagulant protein deficiencies, that vary in severity and increase the risk of first-time and recurrent venous thromboembolism (VTE).

Given that thrombotic risk is multifactorial and that a genetic predisposition to hypercoagulation does not guarantee VTE occurrence or recurrence, the decision to test for hereditary thrombophilia can be complicated. In most circumstances, treatment and prevention of VTE are guided more by clinical factors than by laboratory tests. If laboratory testing is performed, functional, antigenic, and/or genetic assays may be used.

This topic discusses laboratory testing for hereditary thrombophilia. For detailed information on antiphospholipid syndrome, an acquired thrombophilia, see the ARUP Consult Antiphospholipid Syndrome topic.

Quick Answers for Clinicians

What is the role of hereditary thrombophilia testing in patient care?

Current data suggest that establishing a diagnosis of hereditary thrombophilia does not lead to a reduction in venous thromboembolism (VTE) recurrence rates or to improved outcomes.   Although inherited thrombophilia may be included in some thrombotic risk calculators, clinical factors such as personal and family history of VTE are more important in risk stratification and VTE management for most patients. Testing for hereditary thrombophilia may be useful in patients with a personal or family history of unprovoked VTE when test results would affect clinical management. 

What are the potential negative effects of testing for hereditary thrombophilia?

In addition to concerns about the excessive cost, emotional impact, and potential for inaccurate results (eg, in functional assays) associated with testing for hereditary thrombophilia, the Anticoagulation Forum suggests that conflating thrombophilia status (positive or negative) with overall thrombotic risk could lead to significant over- or undertreatment. 

Because of these potential effects and a lack of demonstrated benefit in most circumstances, medical associations and experts broadly recommend against testing for hereditary thrombophilia in a range of settings, including the following:

  • Pregnancy complications  
  • Infertility 
  • Arterial thrombosis  
  • VTE with obvious provoking factors  
  • VTE occurring in the context of cancer  or major transient risk factors  

Additionally, nongenetic testing should be avoided in the context of acute thrombotic events, pregnancy, and current or recent anticoagulant use.   

Do anticoagulant medications interfere with testing for inherited and acquired thrombophilia?

Yes, frequent interferences occur in functional testing due to current or recent anticoagulant use. These vary depending on drug, dose, and test methodology. For additional information about known sources of coagulation testing interference, see Impacts of Common Anticoagulants on Coagulation Testing.

When is genetic testing preferred over functional testing for factor V Leiden thrombophilia?

Because activated protein C (APC) resistance testing is inexpensive and has a high negative predictive value for factor V Leiden (FVL) thrombophilia, this functional assay is often used as an initial method of detection.  Additionally, genetic testing for FVL may not detect all variants that cause the disorder. However, there are certain situations in which genetic testing is preferable, such as when the patient: 

  • Is taking anticoagulants that interfere with APC resistance testing
  • Has other clinical circumstances, such as the presence of a lupus anticoagulant, that result in an abnormal clotting time and interfere with the test
  • Has a first-degree family member in whom FVL has been previously identified

Genetic testing should be used to confirm FVL following an abnormal APC result and to differentiate between homozygotes and heterozygotes for the purposes of risk assessment.

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.

ARUP Laboratory Tests

Comprehensive Panel Testing

Panel to evaluate for inherited and acquired thrombophilias

Method

Chromogenic Assay/Electromagnetic Mechanical Clot Detection/Quantitative Enzymatic/Semi-Quantitative Enzyme-Linked Immunosorbent Assay/Polymerase Chain Reaction/Fluorescence Monitoring/Microlatex Particle Mediated Immunoassay

Other Panel Testing

Acceptable panel to screen for common inherited thrombophilias

Acceptable panel to screen for uncommon inherited thrombophilias

Use to detect and subtype deficiencies of proteins C and S

Use to detect deficiencies of proteins C and S

Use to detect and subtype antithrombin deficiency

Factor V Leiden Testing

Preferred test to detect APC resistance and confirm the presence of an FVL variant

Acceptable initial test to detect APC resistance due to an FVL variant

Used to detect FVL (c.1601G>A; p.Arg534Gln; also referred to as R506Q)

Preferred initial test for individuals with abnormal clotting times (eg, due to anticoagulant use) or with a family member who has the FVL variant

For additional test information, refer to the Factor V Leiden (F5) R506Q Variant Test Fact Sheet

Prothrombin G20210A Mutation Testing

Use to detect the prothrombin c.*97G>A (G20210A) pathogenic variant

For additional test information, refer to the Prothrombin (F2) c.*97G>A (G20210A) Pathogenic Variant Test Fact Sheet

Protein C Deficiency Testing

Preferred test to detect protein C deficiency

Use to subtype deficiency in individuals known to be protein C deficient

Use to detect and subtype protein C deficiency

Protein S Deficiency Testing

Preferred test to detect protein S deficiency

Acceptable test to detect protein S deficiency

Use to subtype deficiency in individuals known to be protein S deficient

Use to detect and subtype protein S deficiency

Antithrombin Deficiency Testing

Preferred test to detect antithrombin deficiency

Use to subtype deficiency in individuals known to be antithrombin deficient

Medical Experts

Contributor

Moser

Karen A. Moser, MD
Associate Professor of Pathology (Clinical), University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories
Contributor

Smock

Kristi J. Smock, MD
Professor of Pathology (Clinical), University of Utah
Medical Director, Hemostasis/Thrombosis, ARUP Laboratories
Contributor

References