Adverse effects of RBC transfusions: A unifying hypothesis

描述（由申请人提供）： 这是为响应RFA-HL-08-005（优先级评分= 191）而提交的修订申请。最近的证据表明，红细胞（RBC）与内皮细胞协同工作，以调节组织血流。红细胞（是局部O2需求的微调传感器）和内皮细胞都释放包括一氧化氮（NO）在内的介质，这些介质控制血管张力，从而控制血流和O2输送。临床研究表明，红细胞输注与受者的发病率和死亡率相关，这些事件在统计学上与使用“老化”红细胞单位和输血量增加相关。然而，这些事件的发生及其表现形式各不相同，这使研究这些事件的努力受到干扰。我们假设，在FDA批准的血库条件下储存的捐献的RBC具有降低的NO合成能力和/或增加的NO清除活性，这两者都导致血管床中NO水平降低。此外，一系列其他因素（2，3 DPG降低;内皮功能障碍;输血后血细胞比容水平升高）可能进一步降低NO生物利用度，导致血管收缩、血流量减少和组织O2输送减少。这种NO生物利用度不足（INOBA）的假设汇集了以前不相关的数据，表明在RBC输注受者的发病率/死亡率中，RBC单位特异性因素和毒性特异性因素之间存在共同的病理生理机制。这一假设不仅解释了红细胞输注后不良事件的变异性，还导致了许多易于检验的预测，将在目标1-3中使用对人输血受者的详细分析进行研究。 公共卫生相关性： 红细胞输注是贫血患者的救命疗法。然而，输血与不良反应有关。这些研究将试图确定输血后发生不良后果的原因，并开发改善血液采集和储存的方法，以尽量减少这些后果。

DESCRIPTION (provided by applicant): This is a revised application submitted in response to RFA-HL-08-005 (Priority score = 191). Recent evidence suggests that red blood cells (RBCs) work in concert with endothelial cells to regulate tissue blood flow. Both RBCs (which are finely-tuned sensors of local O2 demand) and endothelial cells release mediators including nitric oxide (NO) that control vascular tone and thus blood flow and O2 delivery. Clinical studies suggest that RBC transfusions are associated with morbidity and mortality in recipients, and that these events are statistically associated with the use of "aged" RBC units and increased transfusion volumes. However, the occurrence of these events and their manifestations are variable, which has confounded efforts to study them. We hypothesize that donated RBCs stored under FDA-approved blood bank conditions have reduced capacity for NO synthesis and/or increased NO scavenging activity, both leading to reduced NO levels in vascular beds. Furthermore, a collection of other factors (reduced 2,3 DPG; endothelial dysfunction; elevated post-transfusion hematocrit levels) may further reduce NO bioavailability, leading to vasoconstriction, decreased blood flow, and reduced tissue O2 delivery. This hypothesis of insufficient NO bioavailability (INOBA) brings together previously unconnected data to suggest a common pathophysiologic mechanism linking RBC unit- and recipient-specific factors in the occurrence of morbidity/mortality in RBC transfusion recipients. This hypothesis not only accounts for the variability of adverse events following RBC transfusion, but also leads to a number of readily testable predictions that will be investigated in Aims 1-3 using detailed analyses of human transfusion recipients. PUBLIC HEALTH RELEVANCE: Red blood cell transfusions represent lifesaving therapies for anemic patients. However, transfusions are associated with adverse effects. These studies will seek to determine why adverse outcomes happen after transfusion, and develop ways to improve blood collection and storage to minimize these outcomes.