The influence of type 2 diabetes on fibrin structure and function

Abstract

The precise mechanisms underlying the increased risk of cardiovascular disease (CVD) in type 2 diabetes are unclear. Fibrin clot structure has been related to CVD risk in the general population. We therefore assessed this in type 2 diabetic patients as a potential mechanism whereby diabetes influences CVD risk. Fibrin clots were formed from fibrinogen purified from 150 subjects with type 2 diabetes and varying degrees of glycaemic control (assessed by HbA1c), and from 50 matched control subjects. Clot structure was assessed by turbidity, permeation and confocal microscopy. The specific effect of glucose itself was assessed by analysing the structure of clots formed from purified fibrinogen in the presence of increasing concentrations of the sugar. Clots formed by fibrinogen purified from type 2 diabetic subjects had a denser, less porous structure than those from control subjects. The structural changes found were related to the individual's glycaemic control; HbA1c correlated negatively with permeation coefficient (Ks) values (indicates clot pore size) (r = -0.57, p < 0.0001) and positively with maximum absorbance (indicator of fibre size) (r = 0.33, p < 0.0001), branch point number (r = 0.78, p < 0.0001) and fibre density (r = 0.63, p < 0.0001). The ambient glucose level influenced clot structure; hypo- (< 5 mmol) and hyperglycaemia (> or = 10 mmol/l) were both associated with a reduction in Ks values and maximum absorbance, and with increased fibre density and branch point number within clots. The structural differences found to occur in type 2 diabetes and in association with hypo- and hyperglycaemia may confer increased resistance to fibrinolysis, and in consequence contribute to the increase in CVD risk in diabetic patients.