Abstract: Traumatic brain injury (TBI) is commonly associated with the inability of blood to clot, resulting in secondary or delayed systemic and intracranial bleeding (TBI-induced coagulopathy; TBI-IC). We have recently demonstrated that TBI-IC is consumptive, derived from a hypercoagulable state that is initiated by brain- derived extracellular vesicles (BDEVs) and propagated by extracellular vesicles (EVs) from endothelial cells and platelets. These cells are activated by the synergistic actions of BDEVs and hyperadhesive von Willebrand factor (VWF). TBI is a well-documented risk for long-term neuro-cognitive dysfunction such as Alzheimer’s disease (AD) and related dementia. Previous studies have extensively demonstrated that neuronal injury caused by TBI is the primary factor for predisposing patients to AD. However, recent studies have also implicated hemostatic dysregulation for promoting AD development, especially regarding roles of EVs, fibrinogen and its proteolytic product fibrin, and VWF in the process. These studies led us to hypothesize that TBI-IC poses a distinct long-term risk for AD primarily through hemostatic dysregulation, but its underlying pathway remains poorly defined. It also remains unknown whether and how TBI resuscitation modifies the AD risk. Our research supported by the grant R01HL152200 provides a unique platform through which to fill these key knowledge gaps in linking TBI to AD. Using this platform, we propose to conduct research that will answer two questions: (1) whether TBI-IC contributes to AD independent of or additive to TBI-induced cerebral injury, and (2) whether agents that prevent TBI-IC also mitigate the risk of AD. We propose to expand our current research on acute TBI-IC to monitor mice that survive severe TBI insults for 6-12 months to detect longitudinal changes in neurological function and working memory after they are treated during acute TBI with lactadherin, which enhances EV clearance; ADAMTS-13, which cleaves hyperadhesive VWF to reduce its activity; or a recombinant A2, which blocks the active conformation of hyperadhesive VWF. Longitudinal samples collected from these mice will also be analyzed for VWF reactivity, state of coagulation (fibrinogen and fibrin deposition), levels of circulating EVs from the brain, endothelial cells and platelets, the integrity of the blood-brain barrier, and the formation of neurofibrillary tangles (tau+) and senile plaques (Aβ+). This pilot study will allow us to generate the data needed to develop a properly powered and sufficiently controlled study in the future.