Adverse effects of RBC transfusions: A unifying hypothesis

描述(由申请人提供)： 这是根据RFA-HL-08-005号文件提交的修订申请(优先级分数=191)。最近的证据表明，红细胞(RBC)与内皮细胞协同工作，调节组织的血液流动。红细胞(这是局部氧气需求的微调传感器)和内皮细胞都会释放包括一氧化氮(NO)在内的介质，这些介质控制血管张力，从而控制血流和氧气输送。临床研究表明，输注红细胞与受者的发病率和死亡率有关，这些事件在统计学上与使用“老化的”红细胞单位和增加输血量有关。然而，这些事件的发生及其表现形式多种多样，这给研究它们的努力带来了混乱。我们推测，在FDA批准的血库条件下储存的捐献红细胞减少了合成NO的能力和/或增加了清除NO的活性，两者都导致血管床中NO水平的降低。此外，一系列其他因素(2，3DPG降低；内皮功能障碍；输血后红细胞压积水平升高)可能会进一步降低NO的生物利用度，导致血管收缩、血流量减少和组织氧气供应减少。无生物利用度不足假说(INOBA)将以前未关联的数据结合起来，提出了一种共同的病理生理机制，将红细胞单位和受者特定的因素联系在一起，导致红细胞输血受者的发病率/死亡率的发生。这一假设不仅解释了RBC输注后不良事件的可变性，而且还导致了许多易于检验的预测，这些预测将在AIMS 1-3中使用对人类输血接受者的详细分析进行调查。 公共卫生相关性： 红细胞输注代表了贫血患者的救命疗法。然而，输血也会产生不良反应。这些研究将寻求确定为什么输血后会出现不良后果，并开发改进血液收集和储存的方法，以将这些后果降至最低。

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.