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Partial deletion of the αC-domain in the Fibrinogen Perth variant is associated with thrombosis, increased clot strength and delayed fibrinolysis.
- Source :
-
Thrombosis and haemostasis [Thromb Haemost] 2013 Dec; Vol. 110 (6), pp. 1135-44. Date of Electronic Publication: 2013 Sep 19. - Publication Year :
- 2013
-
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.
- Subjects :
- Adolescent
Adult
Aged
Child
DNA Mutational Analysis
Female
Fibrinogens, Abnormal genetics
Fibrinogens, Abnormal ultrastructure
Fibrinolysin metabolism
Genetic Association Studies
Humans
Male
Middle Aged
Pedigree
Phenotype
Polymorphism, Genetic
Protein Structure, Tertiary genetics
Sequence Deletion genetics
Young Adult
Blood Coagulation genetics
Fibrinogen genetics
Fibrinogens, Abnormal metabolism
Fibrinolysis genetics
Peptide Fragments genetics
Thrombosis genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2567-689X
- Volume :
- 110
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Thrombosis and haemostasis
- Publication Type :
- Academic Journal
- Accession number :
- 24048413
- Full Text :
- https://doi.org/10.1160/TH13-05-0408