title: 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.affiliation: Dr. Sarah Westbury, University of Bristol, Level 7 Bristol Royal Infirmary, Bristol, BS2 8HW, United Kingdom, Tel +44 117 3423152; Fax +44 117 3424036, E-mail sarah.westbury@bristol.ac.uk.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Westbury
authors.forename: Cédric
authors.initials: C
authors.lastname: Duval
authors.forename: Helen
authors.initials: H
authors.lastname: Philippou
authors.forename: Rebecca
authors.initials: R
authors.lastname: Brown
authors.forename: Kurtis R
authors.initials: KR
authors.lastname: Lee
authors.forename: Sherina L
authors.initials: SL
authors.lastname: Murden
authors.forename: Emma
authors.initials: E
authors.lastname: Phillips
authors.forename: Christopher
authors.initials: C
authors.lastname: Reilly-Stitt
authors.forename: Daniel
authors.initials: D
authors.lastname: Whalley
authors.forename: Robert A
authors.initials: RA
authors.lastname: Ariëns
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Mumford
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001777:Blood Coagulation / Q000235:genetics*; D002648:Child; D004252:DNA Mutational Analysis; D005260:Female; D005340:Fibrinogen / Q000235:genetics*; D015241:Fibrinogens, Abnormal / Q000235:genetics / Q000378:metabolism* / Q000648:ultrastructure; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis / Q000235:genetics*; D056726:Genetic Association Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010446:Peptide Fragments / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D017434:Protein Structure, Tertiary / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D013927:Thrombosis / Q000235:genetics*; D055815:Young Adult
chemical_list: D015241:Fibrinogens, Abnormal; D010446:Peptide Fragments; C483329:fibrinogen Perth; C098000:fibrinogen alphaC; D005340:Fibrinogen; D005341:Fibrinolysin
keywords: Dysfibrinogenaemia; fibrin polymerisation; fibrinolysis; thrombosis