Targeting hypercoagulability in ischemic stroke modulates fibrin-driven microglial polarization via JAK-STAT pathway

Ischemic stroke is a leading cause of mortality and disability worldwide, yet its pathophysiological mechanisms remain poorly understood. In this study, we analyzed the coagulation function in 60 patients with acute ischemic stroke and found that their blood was in a hypercoagulable state. We confirmed this hematological change using a middle cerebral artery occlusion/reperfusion (MCAO/r) mouse model and improved the hypercoagulable state with the synthetic peptide Arg-Gly-Asp-Cys (RGDC), which inhibits platelet aggregation and fibrinogen binding. Interestingly, in MCAO/r mice, RGDC treatment led to enhanced neurological function, reduced blood-brain barrier (BBB) disruption, and alleviated neuroinflammation. Further analysis revealed that fibrin, the end product of coagulation, binds to ITGB2 on primary microglia and activates the JAK-STAT signaling pathway, influencing microglial polarization. These results establish a novel link between the hypercoagulable state and microglial function, offering a promising therapeutic approach to reduce neuroinflammation, improve neurological function and enhance outcomes in ischemic stroke by targeting coagulation pathways.