Platelet-derived disulfide HMGB1 as central mediator of deep venous thrombosis (DVT). Platelets adhere to the vessel wall and present reduced HMGB1 on their surface upon activation. This causes the recruitment of monocytes to the developing thrombus, which upon activation release reactive oxygen species (ROS) resulting in the oxidation of HMGB1, thereby rendering it prothrombotic. In an autocrine/paracrine manner, disulfide HMGB1 promotes further platelet activation and aggregation, potentiating the amount of released HMGB1 within the thrombus. This results in the accumulation of monocytes through RAGE and TLR2, inducing the expression of tissue factor and cytokines, setting in motion a vicious circle of coagulation and inflammation eventually leading to obstructive thrombus formation within the vein. Finally, disulfide HMGB1 induces the formation of prothrombotic neutrophil extracellular traps mediated by RAGE, which in turn expose more HMGB1 on extracellular DNA strands and promote DVT propagation. See supplemental Figure 5 in the article by Stark et al that begins on page 2435.