BβArg448Lys polymorphism is associated with altered fibrin clot structure and fibrinolysis in type 2 diabetes

Both type 2 diabetes (T2DM) and B beta 448Lys variant of fibrinogen are associated with dense fibrin clots, impaired fibrinolysis and increased cardiovascular risk. It was our objective to investigate whether B beta Arg448Lys adds to vascular risk by modulating fibrin network structure and/or fibrinolysis in diabetes. The primary aim was to study effects of B beta Arg448Lys on fibrin network characteristics in T2DM. Secondary aims investigated interactions between gender and B beta Arg448Lys substitution in relation to fibrin clot properties and vascular disease. Genotyping for B beta Arg448Lys and dynamic clot studies were carried out on 822 T2DM patients enrolled in the Edinburgh Type 2 Diabetes Study. Turbidimetric assays of individual plasma samples analysed fibrin clot characteristics with additional experiments conducted on clots made from purified fibrinogen, further examined by confocal and electron microscopy. Plasma clot lysis time in B beta 448Lys was longer than B beta 448Arg variant (mean +/- SD; 763 +/- 322 and 719 +/- 351 seconds [s], respectively; p<0.05). Clots made from plasma-purified fibrinogen of individuals with Arg/Arg, Arg/Lys and Lys/Lys genotypes showed differences in fibre thickness (46.75 +/- 8.07, 38.40 +/- 6.04 and 25 +/- 4.99 nm, respectively; p<0.001) and clot lysis time (419 +/- 64, 442 +/- 87 and 517 +/- 65 s, respectively; p=0.02), directly implicating the polymorphism in the observed changes. Women with B beta 448Lys genotype had increased risk of cerebrovascular events and were younger compared with B beta 448Arg variant (67.2 +/- 4.0 and 68.2 +/- 4.4 years, respectively; p=0.035). In conclusion, fibrinogen B beta 448Lys variant is associated with thrombotic fibrin clots in diabetes independently of traditional risk factors. Prospective studies are warranted to fully understand the role of B beta Arg448Lys in predisposition to vascular ischaemia in T2DM with the potential to develop individualised anti thrombotic management strategies.