Functional Fibrinolysis, Thromboinflammation and VTE Risk for Ventilated Children

PROJECT SUMMARY Critically ill children undergoing invasive mechanical ventilation (IMV) experience elevated rates of hospital- acquired venous thromboembolism (HA-VTE) but are also at increased bleeding risk. The absence of trial- derived safety data for thromboprophylaxis and prospectively validated pediatric HA-VTE risk models precludes the application of universal thromboprophylaxis in critically ill children. Therefore, the development of risk stratification and predictive models to identify children with the greatest risk of HA-VTE balanced by bleeding risk is vital to inform risk-stratified thromboprophylaxis trials. This proposal is based on a conceptual model that greater IMV exposure intensity impairs functional fibrinolysis and results in a thromboinflammatory each of which confers an increased risk of HA-VTE. Accordingly, the scientific objectives are to determine the impact of IMV intensity on functional fibrinolysis (Aim 1); identify plasma biomarkers of HA-VTE risk (including select thrombo- inflammatory cytokines [Aims 2a] and plasma proteomic phenotypes [Aim 2b]); and derive an enhanced risk prediction model for HA-VTE for children undergoing acute IMV combining fibrinolytic and coagulative function, IMV parameters, thromboinflammatory cytokines, and prothrombotic clinical features (Aim 3). The three independent aims will inform risk-stratified thromboprophylaxis trial design and identify pathophysiological mechanisms that will lead to alternative/adjunctive interventions for this vulnerable population. The K23 training aims are directly aligned with the complementary expertise of the mentors and the scientific objectives, and include: achieving a deeper understanding of the role of the coagulative and fibrinolytic system in acquired prothrombotic states and thrombogenesis (Training Aim 1); acquiring proficiency in the evaluation of thromboinflammatory pathways and biomarker discovery and validation (Training Aim 2); and obtaining certificate and practical training in clinical trials to gather the essential skills and knowledge in risk prediction modeling and the design, conduct and analysis of risk-stratified, biomarker-informed multicenter randomized clinical trials in children (Training Aim 3). The candidate, Dr. Anthony Sochet, Assistant Professor of Anesthesiology and Critical Care Medicine at the Johns Hopkins University (JHU) based on the Johns Hopkins All Children’s Hospital (JHACH) campus, has assembled a team of mentors with internationally recognized clinical and research expertise in thrombosis, biomarker discovery, advanced risk prediction modeling, and clinical trials. His career development will include a Certificate in Clinical Trials through JHU and thrombosis curriculum through the International Society on Thrombosis and Haemostasis. He will be supported by the extensive resources of the Institutes for Clinical and Translational Research at JHACH and JHU. Through this K23 mentored career development award, Dr. Sochet will become an independent physician scientist with expertise in pediatric thrombosis and fibrinolysis, prepared to design, conduct, and analyze multicenter clinical trials focused on risk-stratified HA-VTE prevention strategies in critically ill children.