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

Sarah K Westbury, Cédric Duval, Helen Philippou, Rebecca Brown, Kurtis R Lee, Sherina L Murden, Emma Phillips, Christopher Reilly-Stitt, Daniel Whalley, Robert A Ariëns, Andrew D Mumford

Research output: Contribution to journalArticle (Academic Journal)peer-review

8 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1135-44
Number of pages10
JournalThrombosis & Haemostasis
Volume110
Issue number6
DOIs
Publication statusPublished - Dec 2013

Keywords

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

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