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The prothrombotic phenotypes in familial protein C deficiency are differentiated by computational modeling of

Kathleen E Brummel-Ziedins1, Thomas Orfeo, Peter W Callas

  • 1Department of Biochemistry, University of Vermont, College of Medicine, Burlington, Vermont, United States of America. Kathleen.brummel@uvm.edu

Plos One
|September 18, 2012
PubMed

Insights

Thrombosis risk in a protein C deficient family is multifactorial. Increased thrombin generation, influenced by PC mutation, genetic factors, and gender, contributes to thrombosis risk beyond PC deficiency alone.

Area of Science:

  • Hematology
  • Genetics
  • Biophysics

Background:

  • Protein C (PC) deficiency is a known risk factor for thrombosis, but the underlying causes of thrombosis in affected families are often multifactorial.
  • A large Vermont kindred with protein C deficiency presents an opportunity to investigate the complex interplay of coagulation factors in thrombin generation.

Purpose of the Study:

  • To evaluate the contribution of various coagulation factors to thrombin generation in a protein C deficient kindred using a mathematical model.
  • To examine how protein C mutation, prothrombin G20210A polymorphism, and thrombosis history impact thrombin generation parameters.

Main Methods:

  • Utilized a mathematical model incorporating a mechanistic description of the protein C pathway to simulate thrombin generation profiles.
  • Analyzed thrombin generation parameters (MaxL, MaxR, TMaxL, TMaxR, AUC, CT) in 364 individuals with and without PC mutation, prothrombin G20210A, and thrombosis history.
  • Stratified results by gender to assess gender-specific differences in thrombin generation.

Main Results:

  • The family exhibited higher overall thrombin generation compared to physiologic controls.
  • Protein C mutation carriers showed significantly increased maximum thrombin level (MaxL), rate (MaxR), and area under the curve (AUC) (p<0.001).
  • Individuals with a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) had higher MaxL (p=0.005) and AUC (p<0.001).
  • Women consistently generated more thrombin than men across all categories.

Conclusions:

  • Individuals in this kindred possess an elevated baseline procoagulant potential, characterized by increased thrombin generation, irrespective of protein C deficiency status.
  • Plasma composition variations, particularly gender-associated differences, significantly influence and segregate procoagulant phenotypes within the family.
  • Thrombosis risk in this kindred is multifactorial, involving protein C deficiency, other genetic factors, and gender, leading to an overall increased procoagulant state.

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