Stroke is the leading cause of disability in the US. The majority of these events are ischemic strokes, subdivided into non-lacunar (large-vessel, 80% of all ischemic strokes) and lacunar (small- vessel, 20% of all ischemic strokes) subtypes. The ability to predict recurrence and prognosis is crucial for developing novel treatment and prevention strategies. Current guidelines have identified diagnostic criteria for stroke diagnosis that include clinical and imaging data. However, no biomarker is currently available to the clinician that can reliably predict recurrence and prognosis. Lack of such knowledge limits medical management and impairs our ability to modify the sequence of events leading to ischemic stroke. Coated-platelets are a subset of platelets observed after co-activation with collagen and thrombin that express high levels of several procoagulant proteins on their surface. We demonstrated that production of coated-platelets is significantly different between patients with lacunar versus non- lacunar ischemic stroke, with elevated levels of coated-platelets occurring in non-lacunar stroke compared to controls and lacunar stroke. In addition, we have shown that patients with spontaneous intracerebral hemorrhage have significantly lower coated-platelet levels as compared to normal controls and these levels correlate with the bleed volume. In preliminary studies in non-lacunar ischemic stroke patients, higher coated-platelet levels were associated with an increased likelihood for recurrent ischemic stroke, whereas lower coated-platelet levels were related to an increased likelihood for early hemorrhagic transformation. These findings raise the possibility that coated- platelets will serve as a risk stratification tool for recurrence and prognosis. The research hypotheses for the current proposal are: 1) Coated-platelet levels in non-lacunar stroke patients are markers for prognosis and recurrence: higher levels indicate increased likelihood of recurrent ischemic stroke while lower levels indicate an increased likelihood of hemorrhagic complications, and 2) An increased inflammatory response contributes to the elevated coated-platelet levels observed in non-lacunar stroke patients. The objective of the current application is to determine the relationship of coated-platelets to ischemic stroke. We plan to test our hypotheses through the following specific objectives: 1) Determine the relationship between coated-platelets levels and recurrence/prognosis in non-lacunar stroke patients, and 2) Examine inflammatory markers in non-lacunar stroke patients to determine if measures of systemic inflammation are associated with high coated-platelet levels. We plan to test coated-platelet production in 2 population groups: stroke patients (n = 900), and controls (n = 100) in order to achieve our objectives and test our hypotheses. The rationale for the proposed research is that once we understand the relationship between coated-platelets and stroke we will be better able to characterize changes leading to stroke and to identify groups at risk for developing recurrent stroke or complications related to stroke. Ultimately, the development of improved pharmacological treatments and novel risk assessment tools may be feasible. PUBLIC HEALTH RELEVANCE: Stroke represents the third most common cause of death in adults after heart disease and cancer and is the leading cause of disability in the United States. Future demographic changes due to the aging of "baby boomers" in the US and the burgeoning number of elderly across the world will make stroke an even greater public concern than it already represents. Given the age distribution of the veterans, stroke represents a significant problem in the VA Medical System that follows the trend seen across the nation. The possibility of improved treatment and adequate assessment of risks and benefits associated with medical therapy for veterans with stroke will facilitate delivery of care and will lead in turn to improved quality of life, better medical care and a decreased financial burden for the VA and for society as a whole.