PROJECT SUMMARY: Intracerebral hemorrhage (ICH) carries the highest morbidity and mortality of all stroke subtypes due to the initial injury and the ongoing bleeding, otherwise known as hematoma expansion (HE), which can occur afterwards. HE occurs acutely within 24 hours in up to 30% of patients with ICH and is the strongest driver of worse outcomes in this patient population. Consequently, acute ICH treatment paradigms largely focus on preventing HE utilizing rapid transfusion based approaches in efforts to improve outcome. However, recent trials using generalized, rapid transfusion based treatment approaches with coagulation factors or platelet transfusions to prevent HE have not yielded improved outcomes. This emphasizes a critical knowledge gap in approaches and treatment targets of HE. Lower red blood cell (RBC) levels have been associated with bleeding with proposed mechanisms being due to suboptimal radial displacement of platelets and endothelial binding. While evidence in ICH has consistently revealed an association of low RBC levels with worse outcomes, this has largely been attributed to impaired cerebral oxygenation rather than coagulopathy. This extrapolates the associations of low RBC levels with impaired cerebral oxygenation and poor clinical outcomes from subarachnoid hemorrhage and traumatic brain injury patient populations as no such studies have yet been performed in ICH. However, there is evidence of larger baseline hematoma volumes and more recently, increased HE in ICH patients with lower baseline RBC levels to suggest a role of coagulopathy related to RBC levels in these patients. The role of RBCs on functional coagulation and cerebral oxygenation after ICH will be investigated via a) reductionist murine models of anemia, ICH and RBC transfusions and b) a prospective observational human ICH study evaluating the relationship of RBC levels and RBC transfusions on independent changes in functional coagulation and cerebral oxygenation. This project will fill an important gap in ICH treatment paradigms by establishing novel tools to investigate mechanisms of RBC levels on ICH outcomes in order to ultimately inform future clinical transfusion based treatment approaches in patients with ICH to improve their outcomes.