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Updated: Aug 9, 2026

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms
08:46

Implementation of In Vitro Drug Resistance Assays: Maximizing the Potential for Uncovering Clinically Relevant Resistance Mechanisms

Published on: December 9, 2015

Activated protein C resistance: from phenotype to genotype and clinical practice

A Hillarp1, B Dahlbäck, B Zöller

  • 1Department of Clinical Chemistry, Lund University, Malmö, Sweden.

Blood Reviews
|December 1, 1995
PubMed

Insights

Inherited resistance to activated protein C, a common genetic factor, significantly increases the risk of venous thromboembolism. This resistance, often caused by a factor V gene mutation, leads to lifelong hypercoagulability and more severe thrombosis when combined with other clotting defects.

Area of Science:

  • Hematology
  • Molecular Biology
  • Genetics

Background:

  • The protein C system is crucial for regulating blood coagulation by inactivating factors Va and VIIIa.
  • Genetic deficiencies in protein C, protein S, or antithrombin III are known causes of familial venous thromboembolism.
  • These known deficiencies account for only a small percentage of thrombosis cases.

Purpose of the Study:

  • To investigate the role of inherited resistance to activated protein C as a risk factor for venous thromboembolism.
  • To determine the prevalence and molecular basis of activated protein C resistance.
  • To explore the implications of combined thrombophilic defects.

Main Methods:

  • Phenotypic analysis of activated protein C resistance in patients with venous thrombosis and control populations.
  • Genetic analysis to identify mutations in the factor V gene.
  • Comparison of thrombosis severity in individuals with single versus combined thrombophilic defects.

Main Results:

  • Inherited resistance to activated protein C is a major risk factor for venous thromboembolism, found in 20-60% of patients.
  • The prevalence of this resistance in normal populations ranges from 2-10%.
  • A single point mutation in the factor V gene (Arg506Gln) underlies over 90% of activated protein C resistance cases, leading to impaired inactivation of factor Va and hypercoagulability.
  • Combined defects, such as activated protein C resistance with protein C deficiency, result in more severe and earlier-onset thrombosis.

Conclusions:

  • Inherited resistance to activated protein C is a prevalent and significant risk factor for venous thromboembolism.
  • The factor V Leiden mutation is the primary cause of activated protein C resistance.
  • Thrombophilia may be a multigenetic disorder, with combined defects leading to more severe clinical manifestations.

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