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

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.

• Authors: 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
• Journal: Thrombosis and haemostasis (Thromb Haemost) Vol. 110 Issue 6 Pg. 1135-44 (Dec 2013) ISSN: 2567-689X [Electronic] Germany
• PMID: 24048413 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Adolescent
• Adult
• Aged
• Blood Coagulation (genetics)
• Child
• DNA Mutational Analysis
• Female
• Fibrinogen (genetics)
• Fibrinogens, Abnormal (genetics, metabolism, 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