Pro-Thrombotic Microparticles Generated by Pediatric Cardiopulmonary Bypass

My long-term goal is to become a pediatric critical care physician-scientist, a translational researcher committed to eliminate complications from advanced technology used to support critically ill children. My current emphasis is to focus on the pathophysiological basis of the untoward effects of cardiopulmonary bypass (CPB) devices on blood components. The Mentored Patient-Oriented Research Career Development Award (K23) will provide me with time to gather skills and knowledge as a necessary steps toward becoming an established, independent investigator. Over the past sixty years, support by Cardiopulmonary Bypass devices (CPB) has led to significant decreases in the mortality and morbidity of children suffering from life threatening heart or lung diseases. Although pump- related hemorrhage can be attenuated by maintenance of platelet levels, pump-dependent platelet and monocyte activation can lead to devastating stroke. This can be explained by the flow rates generated in extracorporeal blood pumps that increase the applied shear stress, this activates circulating monocytes and platelets. These activated cells will release platelet- and monocyte-derived microparticles (PMPs & MoMPs), small (0.1-1 micron) cell-derived membrane vesicles. PMPs and MoMPs released by applied shear stress may further contribute to thromboembolism by inducing a pro-thrombotic and pro-inflammatory state. My previous studies document the release of PMPs in an in vitro pediatric cardiopulmonary bypass circuit using porcine whole blood. We hypothesize that increased shear stress generated by a pediatric extracorporeal blood pump promotes pro-thrombotic microparticle release. This award will provide me with dedicated time to obtain new research skills in thrombosis and coagulation assays and experience in conducting pediatric studies. The goals of this research is to define how pump-produced PMPs and MoMPs contribute to thrombosis, from a pediatric model of CPB and from pediatric patients supported by CPB, in order to understand the mechanisms and subsequent therapeutics to address extracoporeal blood pump related thrombotic complications. PUBLIC HEALTH RELEVANCE: Understanding the mechanisms behind pump-produced pro-thrombotic microparticles may lead to a decrease in life-threatening thrombotic complications for all patients receiving extracorporeal blood pump support. These studies will start a research program that will positively impact childhood mortality and morbidity by eliminating complications from the treatment of heart and lung diseases.