Figure 1.

Diabetes enhances the risk of thrombosis. Diabetes induces endothelial dysfunction with subsequent decline in the expression/release of molecules that can reduce platelet activation and associated thrombus formation. At a platelet level, there are several mechanisms by which diabetes could enhance platelet susceptibility to activation including: (i) a higher abundance of advanced glycation end-products (AGEs) which induces insulin resistance and alters membrane fluidity; (ii) an enhanced oxidative stress which leads to the formation of isoprostanes which in turn induce platelet activation by interacting with the thromboxane receptor (TP); (iii) a higher production of thromboxane (TXA₂); and (iv) an increased expression of multiple platelet activation receptors and a higher reactivity to several platelet agonists. As for coagulation, diabetes is associated with a higher amount of tissue factor (TF), thrombin (factor II), and fibrinogen production, which, in concurrence with lower anticoagulant proteins [protein C-antithrombin III complex (PC/ATIII)], favours the formation of the fibrin mesh, which undergoes glycation and oxidative modifications, becoming more dense and resistant to fibrinolysis. Diabetes is also associated with a hypofibrinolytic state characterized by higher abundance of inhibitors of tissue plasminogen activator (tPA) such as plasminogen activator inhibitor-1 (PAI-1) and thrombin-activatable fibrinolysis inhibitor (TAFI), and increased incorporation of antifibrinolytic proteins into the clot [plasmin inhibitor (PI) and complement 3 (C3)] which collectively reduce the efficiency of fibrinolysis. AA: arachidonic acid; ADP: adenosine diphosphate; Cox: cyclooxygenase; GP: glycoprotein; IRc: insulin receptors; miR: microRNAs; NO: nitric oxide; PAR: protease-activated receptor; PGI₂: prostacyclin; ROS: reactive oxygen species; TM: thrombomodulin; VLDL: very-low-density lipoprotein; vWF: von Willebrand factor.