What is inherited thrombophilia?

Inherited Thrombophilia

Inherited thrombophilia refers to genetically determined conditions that increase the risk of developing venous thrombosis due to a hypercoagulable state. 1 These hereditary conditions predispose individuals to abnormal blood clotting by disrupting the delicate balance between the natural procoagulant and anticoagulant systems.

Major Types of Inherited Thrombophilias

Common Inherited Thrombophilias

• Factor V Leiden (R506Q) mutation:

  • Most common inherited thrombophilia 2
  • Present in approximately 5% of Caucasian Americans 2
  • Causes resistance to activated protein C (APC-R) 2
  • Increases relative risk of venous thrombosis 7-fold in heterozygotes and 80-fold in homozygotes 2, 1
  • Found in 20% of idiopathic first venous thrombosis cases 2

• Prothrombin G20210A mutation:

  • Second most common inherited thrombophilia 1
  • Population prevalence of ~2% 1
  • Relative risk of 2-3 for venous thrombosis 1

Rare Inherited Thrombophilias

• Antithrombin deficiency:

  • Population prevalence of 0.04% 1
  • Relative risk of 15-20 for venous thrombosis 1

• Protein C deficiency:

  • Population prevalence of 0.3% 1
  • Relative risk of 15-20 for venous thrombosis 1

• Protein S deficiency:

  • Population prevalence of 0.3% 1
  • Relative risk of 15-20 for venous thrombosis 1

Pathophysiology

Inherited thrombophilias disrupt normal hemostasis by:

1. Reducing natural anticoagulant function (protein C, protein S, antithrombin deficiencies)
2. Increasing procoagulant activity (Factor V Leiden, prothrombin mutation)
3. Altering fibrinolysis

Factor V Leiden specifically causes resistance to APC by substituting glutamine for arginine at residue 506 (R506Q), which is one of three APC cleavage sites. This mutation prevents normal inactivation of factor V by APC, leading to increased thrombin generation and a hypercoagulable state 2.

Clinical Significance

The clinical importance of inherited thrombophilias varies based on:

1. Type of thrombophilia: Antithrombin deficiency carries higher risk than Factor V Leiden heterozygosity 1

2. Homozygosity vs. heterozygosity: Homozygous mutations generally confer higher risk 2

3. Multiple thrombophilic factors: Coexistence of multiple thrombophilias significantly increases thrombosis risk 1

4. Interaction with acquired risk factors: Pregnancy, oral contraceptive use, surgery, immobility, and other acquired conditions can dramatically increase thrombosis risk in those with inherited thrombophilias 2, 1

Known genetic causes are present in approximately 25% of unselected venous thrombosis cases and up to 63% of familial cases 2.

Testing Considerations

Testing for inherited thrombophilias should be considered in:

• Patients with venous thrombosis before age 50
• Patients with recurrent venous thrombosis
• Patients with thrombosis at unusual sites (cerebral veins, splanchnic veins)
• Patients with strong family history of thrombosis
• Women with pregnancy-related thrombosis

Important testing principles:

• Testing for a single thrombophilic factor is insufficient 1
• For patients with positive Factor V Leiden, testing for other thrombophilias (particularly prothrombin 20210A) is recommended 1
• Proper sample handling is essential for accurate results 1

Clinical Management Implications

1. Risk assessment: Understanding a patient's thrombophilia status helps stratify their risk for initial and recurrent thrombosis

2. Family screening: When a child with stroke is found to have thrombophilia, other family members may harbor the same condition and be at risk 2

3. Pregnancy and contraception decisions: Female carriers of thrombophilias may need special consideration regarding oral contraceptive use and pregnancy management 2

4. Thromboprophylaxis decisions: Knowledge of thrombophilia status may influence decisions about prophylaxis during high-risk situations (surgery, pregnancy, prolonged immobility)

Pitfalls and Caveats

• The usefulness of genetic screening to detect inherited hypercoagulable states for prevention of first stroke is not well established 2
• Testing should not be performed during acute thrombosis or while on anticoagulation therapy, as it may affect results
• Direct oral anticoagulants (DOACs) can interfere with thrombophilia testing, potentially causing false-negative results 3
• Inherited thrombophilia is just one component of the multifactorial pathogenesis of venous thromboembolism 4
• Not all individuals with inherited thrombophilias will develop thrombosis; approximately 50% of carriers develop VTE 4

Inherited thrombophilia testing should be approached systematically with careful consideration of how the results will impact clinical management decisions.