Deep vein thrombosis in mice is regulated by platelet HMGB1 through release of neutrophil-extracellular traps and DNA

Venous thromboembolic (VTE) disease, consisting of deep venous thrombosis(DVT) and pulmonary embolism (PE) is a leading cause of morbidity and mortality. Current prophylactic measures are insufficient to prevent all occurrence in part due to an incomplete understanding of the underlying pathophysiology. Mounting evidence describes interplay between activation of the innate immune systemand thrombus development. Recent work has demonstrated that platelet release of HMGB1leads to increased microvascular complications following injury. Additionally, platelet HMGB1was found to enhance DVT and increase the formation of neutrophil extracellular traps(NETs), although the role of HMGB1induced NET release in thrombosis remains unexplored. Utilizing a transgenic mouse lacking HMGB1specifically from platelets and megakaryocyteswe now demonstrate the specific role of platelet-derived HMGB1in acute and subacute/chronic venous thrombosis. Platelets account for the majority of circulating HMGB1and HMGB1deposition within the developing clot. The pro-thrombotic effect of platelet-derived HMGB1is mediated through enhanced neutrophil recruitment, NET formation and specifically release of extracellular DNA during NET formation. Taken together, these data suggest that platelet HMGB1mediated NET release is a primary regulator of DVT formation in mice.