Stroke is one of the most devastating clinical events that occurs in children with sickle cell anemia (SCA) , occurring in 5 to 10% of children, with the highest incidence below age 10 years. The stroke typically is thrombotic (interactive) and often causes permanent damage and long-term disability including motor weakness, neuropsychological deficits, seizures, and learning difficulties. Unfortunately, no single laboratory or clinical parameter can accurately predict which children with SCA will develop stroke. Transcranial Doppler (TCD) ultrasonography of intracranial vessels was recently reported to identify children at increased risk for stroke. The overall goal of my research proposal is to investigate the etiology of stroke in children with SCA, by investigating the mechanism by which an abnormal TCD flow velocity predicts stroke risk. My hypothesis is that a subset of children with SCA have inherited DNA mutations that predispose them to thrombosis and cerebrovascular disease. These hypbercoagulable genetic mutations lead to thrombus formation within an intracranial artery, stenosis of the vessel lumen, abnormal TCD flow velocity, and ultimately to vaso- occlusion and clinical stroke. The specific aims of my proposal include screening children with SCA for the presence of specific inherited thrombotic mutations, including mutations in the genes for Factor V, Factor VII, MTHFR, GPIIa, prothrombin and fibrinogen, using DNA analysis. Children will also be screened for abnormal arterial flow velocities using TCD. By statistical analysis I will test the relationships between thrombotic DNA mutations, abnormal TCD values, and clinical stroke. Tjo accomplish this project, which is an important step toward my goal of becoming an independent clinical investigator, I will receive formal training in the principles of clinical research. I will be directly involved in all aspects of protocol management and will have a supervised period of investigation with a mentor who has experience in research and ongoing involvement in my career development plans. Based on this fact-finding study, I will design a hypothesis-driven therapeutic clinical trial for children at highest risk of developing stroke.