Fibrin formation and lysis in hyperglycaemia - molecular and cellular drivers

Clot structure is a well established determinant of thrombosis risk. Hyperglycaemia alters clot architecture and function, producing denser, less permeable fibrin networks with reduced susceptibility to lysis. Although several mechanisms contributing to these effects have been reviewed previously, novel findings and growing evidence of cellular bioenergetics' effect on clot structure have not yet been integrated into this context. This review presents new insights and discusses their relevance for future therapeutic development.

Recent studies have identified novel glycation sites on fibrin(ogen), that contribute to altered microstructures and play important roles in FXIII cross-linking and plasmin cleavage. Increased level of fibrinolysis inhibitor PAI-1 was shown to precede the development of diabetes. Altered platelet and neutrophil bioenergetics in prediabetes and diabetes were shown to contribute to a procoagulant phenotype through increased oxidative stress and NETosis, respectively. Duration of hyperglycaemia and glycaemic control were shown to be key determinants influencing these cellular behaviours.

Considering the interplay between the molecular and cellular drivers of hyperglycaemia-induced alterations in fibrin formation and lysis has important implications for identifying future therapeutic targets. Further research that encompasses hyperglycaemia duration and variations in glycaemic control may support the development of personalised strategies for thrombosis prevention.