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The presence of gamma' chain impairs fibrin polymerization

Kathryn C Gersh1, Chandrasekaran Nagaswami, John W Weisel

  • 1Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA.

Thrombosis Research
|January 14, 2009
PubMed

Insights

The presence of fibrinogen gamma' chains alters clot structure by slowing fiber aggregation and creating thinner, non-uniform networks. This impacts fibrin polymerization and may influence cardiovascular risk.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cardiovascular Science

Background:

  • A subset of fibrinogen molecules includes an alternatively spliced variant chain, gamma'.
  • Elevated plasma levels of fibrinogen gamma' have been linked to myocardial infarction and venous thrombosis.
  • Fibrin clot structure is a known factor in cardiovascular risk.

Purpose of the Study:

  • To investigate the impact of the fibrinogen gamma' chain on fibrin clot structure.
  • To understand how gamma' chain incorporation affects fibrin polymerization dynamics and resulting clot morphology.

Main Methods:

  • Expression of three distinct fibrinogen variants (gamma/gamma, gamma/gamma', gamma'/gamma') in Chinese hamster ovary (CHO) cells.
  • Analysis of thrombin-mediated fibrinopeptide release using High-Performance Liquid Chromatography (HPLC).
  • Assessment of fibrin polymerization kinetics via turbidity measurements and clot structure visualization using scanning electron microscopy (SEM).
  • Characterization of post-translational modifications on the gamma' chain using mass spectrometry.

Main Results:

  • Fibrinopeptide A release rates were consistent across all fibrinogen variants.
  • Fibrinopeptide B release was accelerated in the gamma'/gamma' homodimer.
  • Fibrin polymerization exhibited slower turbidity increases and lower final absorbance with gamma'-containing fibrinogens.
  • SEM revealed that gamma'/gamma' fibrin clots comprised very thin fibers, while gamma/gamma' fibers resembled gamma/gamma fibers.
  • Non-uniform fiber networks were observed in gamma'-containing fibrin samples.
  • Mass spectrometry identified heterogeneous N-glycan addition and tyrosine sulfation on the gamma' chain.

Conclusions:

  • The incorporation of gamma' chains into fibrinogen significantly alters fibrin clot structure by impeding lateral aggregation.
  • Gamma'-containing fibrin clots display thinner and less uniform fiber networks compared to those without gamma' chains.
  • These structural modifications, potentially driven by charge-charge repulsion from post-translational modifications on the gamma' chain, may influence the polymerization process and contribute to altered cardiovascular risk.
Abstract

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