Recent studies highlight HMGB1 as a key mediator of the crosstalk between NETosis and thrombosis: during the acute phase of cerebral ischemia, HMGB1 expression on platelets is significantly upregulated, mediating platelet aggregation, activation, and thrombosis via the TLR4/MyD88 and cGMP/PKG pathways.74, 75Activated platelets release HMGB1, it subsequently attaches to neutrophils' TLR4 and receptor for advanced glycation end products (RAGE), causing NETosis and encouraging thrombus development.67, 75, 76, 77. This evidence concerns the gene TLR4 and brain ischemia.