What is the Leiden mutation and what other blood clotting factor abnormalities can occur with it?

Factor V Leiden Mutation: Summary and Associated Coagulation Abnormalities

What is Factor V Leiden?

Factor V Leiden is a single point mutation (G to A at nucleotide 1691) in the factor V gene that results in substitution of glutamine for arginine at position 506 (R506Q), making factor Va resistant to inactivation by activated protein C (APC) and creating a hypercoagulable state. 1

Molecular Mechanism

• The mutation prevents normal APC cleavage at the R506 position, which is required for optimal exposure and subsequent rapid inactivation of factor V at positions R306 and R679 1
• This resistance to APC degradation allows factor Va to remain active longer, perpetuating thrombin generation and increasing thrombotic risk 1
• Factor V Leiden accounts for 85-95% of patients with APC resistance, depending on the functional assay used 1

Epidemiology and Clinical Significance

• Approximately 5% of Caucasians carry the heterozygous mutation, with lower prevalence in Hispanic-Americans and African-Americans, and virtual absence in Africans and Asians 1
• It is the most common hereditary thrombophilia, found in 11-20% of individuals presenting with their first episode of venous thrombosis 1
• In selected populations (age <50 years and/or recurrent thrombosis), up to 40% carry the Factor V Leiden genotype 1

Thrombotic Risk

• Heterozygotes have a 4- to 7-fold increased risk for venous thromboembolism (VTE) 2, 3
• Homozygotes have an 80-fold increased risk for VTE 1
• The lifetime risk of VTE is approximately 10% for heterozygotes and exceeds 80% for homozygotes 2
• Deep venous thrombosis and pulmonary embolism are the most common manifestations 3

Other Blood Clotting Factor Abnormalities That Can Occur with Factor V Leiden

The recognized coagulation abnormalities that can coexist with Factor V Leiden include deficiencies in antithrombin III, protein C, and protein S—these familial thrombophilias collectively account for 5-20% of venous thromboembolism patients. 1

Natural Anticoagulant Deficiencies

Antithrombin III deficiency:

• Antithrombin III is a serine protease inhibitor that irreversibly inhibits thrombin by covalently binding its active site 1
• Familial reductions in antithrombin III activity (either reduced protein levels or dysfunctional protein) are strongly associated with deep vein thrombosis and pulmonary embolism 1

Protein C deficiency:

• Protein C is a vitamin K-dependent zymogen activated to APC by the thrombin-thrombomodulin complex 1
• APC functions as a natural anticoagulant by inactivating procoagulant factors Va and VIIIa in the presence of protein S 1
• Familial protein C deficiency significantly increases thrombotic risk 1

Protein S deficiency:

• Protein S serves as a cofactor for APC in the inactivation of factors Va and VIIIa 1
• Familial reductions in protein S activity are strongly associated with venous thromboembolism 1

Combined Thrombophilias

• The clinical expression of Factor V Leiden is influenced by coexisting genetic and acquired thrombophilic disorders 3
• When Factor V Leiden occurs with other thrombophilias, the thrombotic risk is multiplicatively increased rather than simply additive 3
• The prevalence of these previously recognized familial thrombophilias (antithrombin III, protein C, protein S deficiencies) among venous thromboembolism patients ranges from 5-20%, depending on cohort selection 1

Other Considerations

• APC resistance can occur even without the Factor V Leiden mutation and represents an independent risk factor for venous thrombosis (odds ratio 1.7) 4
• Elevated antiphospholipid antibodies have been reported in combination with Factor V Leiden in arterial thrombotic events 5
• The mutation follows an autosomal dominant inheritance pattern, meaning each child of a heterozygous parent has a 50% chance of inheriting it 6

Clinical Implications

• Testing for Factor V Leiden should prompt consideration of comprehensive thrombophilia screening, particularly when there is strong family history or recurrent thrombosis 6
• Patients testing positive should understand that results have implications for other family members 6
• The combination of multiple thrombophilias significantly alters risk stratification and may influence decisions regarding prophylactic anticoagulation in high-risk clinical settings 3