What is the most accurate description of the inherited condition of Activated Protein C Resistance (APCR)?

Activated Protein C Resistance (APCR): Understanding the Inherited Condition

Activated Protein C Resistance (APCR) may be due to mutations at either of the two APC cleavage sites of factor V. This is the most accurate description of the inherited condition among the options provided, as it correctly identifies that mutations can occur at different cleavage sites in factor V, not just at the single site associated with Factor V Leiden.

Molecular Basis of APCR

APCR is a hemostatic disorder characterized by a poor anticoagulant response to activated protein C (APC). The condition has significant implications for thrombosis risk:

• APC normally functions as a natural anticoagulant by inactivating (via proteolysis) procoagulant factors Va and VIIIa in the presence of protein S 1
• Factor V has three APC cleavage sites: R306, R506, and R679 1
• The most common mutation causing APCR is Factor V Leiden (FVL), which is a single point mutation (G1691A) resulting in substitution of glutamine for arginine at position 506 (R506Q) 1, 2

Why the other options are incorrect:

1. Option C (It is always caused by the factor V Leiden mutation): While Factor V Leiden is the most common cause, accounting for 85-95% of APCR cases depending on the assay used, it is not the only cause 1. Other mutations at different cleavage sites can also cause APCR.

2. Option B (It is due to mutations in the protein S gene): Mutations in protein S gene cause protein S deficiency, which is a separate thrombophilic condition. While protein S is a cofactor for APC, mutations in protein S do not cause APCR 1.

3. Option D (It may be due to mutations in factor V or factor VIII genes): While APC does inactivate both factors Va and VIIIa, inherited APCR is specifically associated with mutations in factor V, not factor VIII 1, 3.

Clinical Significance of APCR

APCR is the most common recognized abnormality of coagulation among patients with venous thromboembolism:

• The Factor V Leiden mutation is carried in heterozygous form by about 5% of the Caucasian population 1
• It produces a relative risk of venous thrombosis of about 7-fold in heterozygous state and about 80-fold in homozygous state 1
• It is found in roughly 11-20% of individuals presenting with their first episode of venous thrombosis 1

Molecular Mechanisms

The FVR506Q mutation affects the protein C anticoagulant system in two ways:

1. It confers partial resistance of FVa to APC-mediated inactivation
2. It impairs the degradation of FVIIIa because APC-mediated cleavage of FV at Arg506 is required for expression of the anticoagulant activity of FV 3

This dual effect creates a hypercoagulable state that increases thrombosis risk.

Laboratory Testing for APCR

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, 4, 2

Predilution assays are recommended because of their high sensitivity and specificity for F5 mutations conferring APC-R 1.

Important Clinical Considerations

APCR is a significant risk factor for venous thrombosis, particularly when combined with other thrombophilic conditions. Individuals with combined genetic defects have a higher risk of thrombosis, supporting the concept that thrombophilia is often a multigenetic disease 3.