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Molecular biology and pathophysiology of APC resistance: current insights and clinical implications
1Department of Biochemistry, Cardiovascular Research Institute Maastricht, Maastricht University, The Netherlands.
Abstract:
APC resistance is often associated with the occurrence of a single point mutation in factor V (factor VLeiden) at a predominant cleavage site for the natural anticoagulant, activated protein C (APC). In this article we will discuss the effects of this mutation (Arg506-->Gln) on the down-regulation of factor Va cofactor activity and on thrombin formation by APC in model systems and in plasma. Our studies on the effects of APC on thrombin formation in plasma resulted in the development of a new method for the screening of APC resistance that is based on measurement of the effect of APC on the endogenous thrombin potential (the time integral of thrombin generated in clotting plasma). It appeared that sensitivities for APC determined via this method were considerably affected by the use of oral contraceptives (OC) and that women who use OC become acquired APC resistant. The fact that acquired APC resistance in women who use third-generation OC was more pronounced than in users of second-generation OC may explain the further increased risk for venous thrombosis associated with the use of third-generation OC.
Insights
Activated protein C (APC) resistance, linked to Factor V Leiden mutation, impacts thrombin generation. Oral contraceptive use causes acquired APC resistance, increasing venous thrombosis risk, especially with third-generation pills.
Area of Science:
- Biochemistry
- Hematology
- Pharmacology
Background:
- Activated protein C (APC) resistance is frequently linked to the Factor V Leiden mutation (Arg506Gln).
- This mutation occurs at a key cleavage site for APC, affecting its anticoagulant function.
- Understanding the mutation's impact on Factor Va cofactor activity and thrombin formation is crucial.
Purpose of the Study:
- To investigate the effects of the Factor V Leiden mutation on APC-mediated down-regulation of Factor Va.
- To analyze the impact of APC on thrombin generation in both model systems and human plasma.
- To develop and validate a novel screening method for APC resistance.
Main Methods:
- Evaluated the Arg506Gln mutation's effect on Factor Va cofactor activity.
- Assessed APC's influence on thrombin formation in plasma using model systems.
- Developed a new APC resistance screening assay based on endogenous thrombin potential measurement.
Main Results:
- The Factor V Leiden mutation significantly alters APC's regulation of Factor Va activity.
- Oral contraceptive (OC) use was found to affect APC sensitivity, inducing acquired APC resistance.
- Third-generation OC users exhibited more pronounced acquired APC resistance than second-generation OC users.
Conclusions:
- The Factor V Leiden mutation impairs APC's anticoagulant activity.
- Oral contraceptive use, particularly third-generation formulations, confers acquired APC resistance.
- Acquired APC resistance associated with OC use may contribute to an elevated venous thrombosis risk.