Partial deletion of the αC-domain in the Fibrinogen Perth variant is associated with thrombosis, increased clot strength and delayed fibrinolysis

Thromb Haemost. 2013 Dec;110(6):1135-44. doi: 10.1160/TH13-05-0408. Epub 2013 Sep 19.

Abstract

Genetic fibrinogen (FGN) variants that are associated with bleeding or thrombosis may be informative about fibrin polymerisation, structure and fibrinolysis. We report a four generation family with thrombosis and heritable dysfibrinogenaemia segregating with a c.[1541delC];[=] variation in FGA (FGN-Perth). This deletion predicts a truncated FGN αC-domain with an unpaired terminal Cys at residue 517 of FGN-Aα. In keeping with this, SDS-PAGE of purified FGN-Perth identified a truncated FGN-Aα chain with increased co-purification of albumin, consistent with disulphide bonding to the terminal Cys of the variant FGN-Aα. Clot visco-elastic strength in whole blood containing FGN-Perth was greater than controls and tPA-mediated fibrinolysis was delayed. In FGN-Perth plasma and in purified FGN-Perth, there was markedly reduced final turbidity after thrombin-mediated clot generation. Consistent with this, FGN-Perth formed tighter, thinner fibrin fibres than controls indicating defective lateral aggregation of protofibrils. Clots generated with thrombin in FGN-Perth plasma were resistant to tPA-mediated fibrinolysis. FGN-Perth clot also displayed impaired tPA-mediated plasmin generation but incorporated α2-antiplasmin at a similar rate to control. Impaired fibrinolysis because of defective plasmin generation potentially explains the FGN-Perth clinical phenotype. These findings highlight the importance of the FGN αC-domain in the regulation of clot formation and fibrinolysis.

Keywords: Dysfibrinogenaemia; fibrin polymerisation; fibrinolysis; thrombosis.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Blood Coagulation / genetics*
  • Child
  • DNA Mutational Analysis
  • Female
  • Fibrinogen / genetics*
  • Fibrinogens, Abnormal / genetics
  • Fibrinogens, Abnormal / metabolism*
  • Fibrinogens, Abnormal / ultrastructure
  • Fibrinolysin / metabolism
  • Fibrinolysis / genetics*
  • Genetic Association Studies
  • Humans
  • Male
  • Middle Aged
  • Pedigree
  • Peptide Fragments / genetics*
  • Phenotype
  • Polymorphism, Genetic
  • Protein Structure, Tertiary / genetics
  • Sequence Deletion / genetics
  • Thrombosis / genetics*
  • Young Adult

Substances

  • Fibrinogens, Abnormal
  • Peptide Fragments
  • fibrinogen Perth
  • fibrinogen alphaC
  • Fibrinogen
  • Fibrinolysin