Is diabetic hypercoagulability an acquired annexinopathy? Glycation of annexin II as a putative mechanism for impaired fibrinolysis in diabetic patients.

Diabetics die mainly from thrombotic complications and there is clear evidence that diabetes is a hypercoagulable state. Epidemiological and prospective intervention data link hyperglycemia to vascular complications and glycation of proteins is one favored molecular basis to explain this fact. Cell surface receptors may support fibrinolytic surveillance in both intravascular and extravascular locations by stimulating plasmin generation and by protecting plasmin from its inhibitors. The existing experimental evidence suggests that annexin II in its tetrameric form is the main physiological receptor for plasminogen on the extracellular surface of endothelial cells. We have recently shown that annexin II is an extremely vulnerable target for glycation, quickly responding to restoration of normoglycemia. We hypothesize that glycation of endothelial membrane annexin II impairs the appropriate formation of the plasminogen/tissue plasminogen activator/annexin II complex, disrupting a key regulatory mechanism in fibrinolytic vigilance. This would in turn produce decreased fibrinolytic activity and indirectly promote a thrombophilic state in diabetic patients. We base our hypothesis on our observation and on evidence for the mechanism of action of two major independent risk factors for CV events: lipoprotein (a) and hyperhomocysteinemia. Binding of plasminogen to annexin II is inhibited by Lp (a) and binding of tissue plasminogen activator to annexin II is blocked by homocysteine. If our hypothesis is correct, one of the components of the increased thrombogenicity seen in diabetic patients might then be an acquired annexinopathy.