PROJECT SUMMARY Sickle cell disease (SCD) is a multi-system, life-threatening, inherited blood disorder that disproportionally affects low-income vulnerable minorities in the United States. Of the approximately 100,000 individuals living with this condition in the country, people of African descend account for 90% of patients. A hallmark of the disease is the development of vascular-endothelial dysfunction that promotes a chronic prothrombotic state increasing the risk of venous thromboembolism (VTE). Hospitalized pediatric patients with SCD have substantively higher rates of incident and recurrent VTE compared to the hospitalized general pediatric population. However, despite the known association between hypercoagulability and SCD, VTE has remained an underrecognized and understudied complication, particularly in the pediatric SCD population. Specifically, biomarkers and mechanisms for the development of VTE in pediatric SCD have received little attention in research despite such work being urgently needed in order to identify modifiable factors for future investigation in interventional trials. This proposal aims to address this critical gap in knowledge by systematically analyzing VTE data derived from a multicenter mixed prospective-retrospective cohort with parallel biobanking of pediatric patients with SCD with- and without VTE. The Specific Aims are to: 1) Identify clinical risk factors for incident (1a) and recurrent (1b) VTE in pediatric SCD; 2) identify plasma markers of coagulation activation, inflammation, endothelial damage, and unbiased proteomic profiles prognostic of the development of incident (2a) and recurrent (2b) VTE in pediatric SCD; and 3) to develop a novel biomarker-informed clinical prognostic model for VTE in pediatric SCD. The applicant’s long-term goal is to become an independent clinical and translational investigator with expertise in the development of biomarker-informed VTE clinical prognostic models in pediatric SCD. She has designed an individual career development plan with the overarching goal of gaining expertise in biomarker discovery and validation for pediatric VTE, and in the application of biomarkers and clinical risk factors for the development of VTE prognostic models and the design of risk-stratified VTE prevention trials. The specific aims of her career development plan are: 1) to obtain mentored, advanced didactic and experiential education and training in conducting multicenter observational and interventional studies in pediatric VTE and SCD populations; 2) to gain mentored didactic and hands-on expertise on proteomics methods and biomarker discovery, validation and implementation in pediatric hematologic diseases; and 3) to obtain mentored, advanced education and training on the development and application of prognostic models for pediatric hematologic diseases.