Pro-thrombotic Microparticles Generated by Pediatric Cardiopulmonary Bypass

 描述（由申请人提供）：我的长期目标是成为一名儿科重症监护医生-科学家，一名致力于消除用于支持重症儿童的先进技术并发症的转化研究人员。我目前的重点是集中在心肺转流（CPB）设备对血液成分的不良影响的病理生理学基础。指导以患者为导向的研究职业发展奖（K23）将为我提供时间来收集技能和知识，作为成为一名成熟的独立研究者的必要步骤。在过去的六十年里，心脏搭桥设备（CPB）的支持已经导致患有危及生命的心脏或肺部疾病的儿童的死亡率和发病率显著下降。虽然泵相关出血可以通过维持血小板水平来减轻，但泵依赖性血小板和单核细胞活化可导致毁灭性卒中。这可以通过体外血液泵中产生的流速来解释，该流速增加了所施加的剪切应力，这激活了循环单核细胞和血小板。这些活化的细胞将释放血小板和单核细胞衍生的微粒（PMP和MoMP），小的（0.1-1微米）细胞衍生的膜囊泡。通过施加剪切应力释放的PMP和MoMP可能通过诱导促血栓形成和促炎状态而进一步促成血栓栓塞。我以前的研究记录了使用猪全血的体外小儿心肺转流回路中PMP的释放。我们假设儿科体外血泵产生的剪切应力增加会促进促血栓形成微粒的释放。该奖项将为我提供专门的时间，以获得血栓形成和凝血试验的新的研究技能和进行儿科研究的经验。本研究的目的是从CPB的儿科模型和CPB支持的儿科患者中确定泵产生的PMP和MoMP如何促成血栓形成，以了解解决体外血泵相关血栓形成并发症的机制和后续治疗方法。

 DESCRIPTION (provided by applicant): 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.