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内科科学家，一名致力于消除用于支持危重儿童的先进技术的并发症的翻译研究人员。我目前的重点是关注体外循环(CPB)装置对血液成分产生不良影响的病理生理学基础。以患者为导向的导师研究职业发展奖(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、独立的研究人员的必要步骤。在过去的60年里，在体外循环装置(CPB)的支持下，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。尽管泵相关出血可以通过维持血小板水平来减少，但泵依赖的血小板和单核细胞激活可能导致毁灭性的中风。这可以用体外血泵产生的流速来解释，它增加了所施加的剪应力，从而激活了循环中的单核细胞和血小板。这些激活的细胞将释放血小板和单核细胞来源的微粒(PMPs和MoMPs)，即小的(0.1-1微米)细胞来源的膜泡。外加剪应力释放的PMPs和MoMPs可能通过诱导血栓前状态和炎症状态进一步促进血栓栓塞症。我以前的研究记录了PMPs在使用猪全血的体外儿科体外循环循环中的释放。我们假设，儿科体外血泵产生的剪切力增加会促进血栓前微粒的释放。这一奖项将为我提供专门的时间，以获得血栓形成和凝血分析方面的新研究技能，以及进行儿科研究的经验。本研究的目的是从体外循环的儿科模型和CPB支持的儿科患者中确定泵产生的PMPs和MoMPs如何促进血栓形成，以了解其机制和后续治疗方法，以解决体外循环血泵相关的血栓并发症。

 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.