Journal
THROMBOSIS AND HAEMOSTASIS
Volume 110, Issue 6, Pages 1135-1144Publisher
GEORG THIEME VERLAG KG
DOI: 10.1160/TH13-05-0408
Keywords
Dysfibrinogenaemia; thrombosis; fibrin polymerisation; fibrinolysis
Categories
Funding
- British Heart Foundation [RG/13/3/30104] Funding Source: Medline
- Medical Research Council [G0901546] Funding Source: Medline
- Department of Health Funding Source: Medline
- MRC [G0901546] Funding Source: UKRI
- British Heart Foundation [RG/13/3/30104] Funding Source: researchfish
- Medical Research Council [G0901546] Funding Source: researchfish
- National Institute for Health Research [ACF-2011-25-007] Funding Source: researchfish
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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 alpha C-domain with an unpaired terminal Cys at residue 517 of FGN-A alpha. In keeping with this, SDS-PAGE of purified FGN-Perth identified a truncated FGN-Aa chain with increased co-purification of albumin, consistent with disulphide bonding to the terminal Cys of the variant FGN-Aa. 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 alpha 2-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 aC-domain in the regulation of clot formation and fibrinolysis.
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