Noninflammatory mechanisms of VT. (A) In healthy veins and physiological blood flow, VWF and TF are not expressed, tPA promotes fibrinolysis, and thrombomodulin blocks the coagulation cascade; NO and PGI2 block platelet aggregation. (B) A schematic overview of noninflammatory mechanisms that contribute to VT. Alterations in blood flow, resulting in local hypoxia of the venous wall, are detected by the mechanosensors such as PIEZO-1, which increases the expression of TF and VWF on EC surfaces, leading to cell recruitment and activation of the coagulation cascade. miR-20a and miR-19b regulate the TF expression, and MPs contribute to thrombus development through VWF release. miR-27a/b regulates the expression of TFPI, which inhibits the initiation of coagulation. PIEZO-1 can further enhance platelet aggregation through blocking NO production. Hyperglycemia represses miR-24, leading to increased VWF expression, and induces shedding and shrinkage of the EG, resulting in endothelial activation. Leptin, a hormone whose levels increase in obesity, increases levels of PAI-1 to inhibit fibrinolysis. The gut microbiota produces TMAO, which enhances the coagulation cascade and platelet aggregation. The gut microbiota also produces LPS that interacts with TLR4 on the endothelial surface and further promotes a hypercoagulable state. The resultant thrombus is erythrocyte and fibrin rich with the presence of certain amounts of platelets. ADP, adenosine diphosphate; eNOS, endothelial nitric oxide synthase; PAI-1, plasminogen activator inhibitor-1; PGI2, prostacyclin; ROS, reactive oxygen species; TFPI, tissue factor pathway inhibitor; TLR4, Toll-like receptor 4; tPA, tissue plasminogen activator.
