How does Activated Protein C Resistance (APCR) contribute to a thrombophilic tendency?

Activated Protein C Resistance and Thrombophilia

Activated Protein C Resistance (APCR) contributes to a thrombophilic tendency primarily through decreased destruction of factor Va by activated protein C. 1, 2

Mechanism of APCR

Activated Protein C (APC) normally functions as a natural anticoagulant by:

• Inactivating (via proteolysis) procoagulant factors Va and VIIIa in the presence of protein S 1
• Limiting thrombin generation and preventing excessive clot formation

In APCR, this anticoagulant function is impaired, specifically:

1. Factor V has three APC cleavage sites: R306, R506, and R679 1, 2
2. The most common cause of APCR is Factor V Leiden (FVL) - a point mutation (G1691A) resulting in substitution of glutamine for arginine at position 506 (R506Q) 1, 2
3. This mutation prevents normal inactivation of activated factor V by APC 3
4. Initial APC cleavage at the R506 position is required for optimal exposure and subsequent rapid inactivation of factor V by APC cleavage at positions R306 and R679 1

Why Factor Va Resistance is Key

While APC inactivates both factors Va and VIIIa, the primary mechanism of APCR's thrombophilic effect is through factor Va resistance because:

• The Factor V Leiden mutation directly affects factor V/Va structure 1, 2
• This makes factor Va resistant to proteolytic inactivation by APC 1
• Factor VIIIa inactivation is affected secondarily, but the primary defect is in factor Va inactivation 2

Clinical Significance

• APCR is the most common recognized abnormality of coagulation among patients with venous thromboembolism 1
• The Factor V Leiden mutation produces a relative risk of venous thrombosis of about 7-fold in heterozygous state and about 80-fold in homozygous state 1, 3
• It is found in roughly 11-20% of individuals presenting with their first episode of venous thrombosis 1, 2

Diagnostic Considerations

Several methods are available for detecting APCR:

• APTT-based assays with or without predilution in FV-deficient plasma
• Russell Viper Venom-based clotting assays
• Direct molecular genetic testing for the R506Q mutation 1, 2

Common Pitfalls

• Not all APCR is due to Factor V Leiden - other rare mutations in factor V can also cause APCR 1
• Acquired causes of APCR can occur in the absence of F5 mutations (pregnancy, oral contraceptives, elevated FVIII) 1
• APCR testing can be affected by various factors including lupus anticoagulants, protein S deficiency, and anticoagulant medications 1

The answer is C: decreased destruction of factor Va by activated protein C.