The safety of red blood cell transfusions

描述(由申请人提供)：该项目将研究输注较老的储存的红细胞(RBC)产生的循环铁对生物膜相关感染的影响。根据FDA的标准，红血球的冷藏保质期最长为42天。研究表明，输注“较旧的”与“较新鲜的”储存的红细胞单位与显著增加发病率和死亡率有关。红细胞在冰箱储存过程中会逐渐受损。输血后，储存受损的红细胞会被巨噬细胞迅速从循环中清除。然后，这些红细胞血红蛋白铁被迅速分解并返回到血浆中，其速度可以超过生理铁转运体转铁蛋白对铁的吸收速度，从而产生循环中的非转铁蛋白结合铁。从生理上讲，几乎所有循环中的铁都与转铁蛋白结合。相反，我们的人体研究表明，即使输注一单位储存的红细胞，也可以在体外尖锐地产生循环中的非转铁蛋白结合铁，并促进输血后血清样本中的细菌生长。由于转铁蛋白转运铁是阻止铁感染病原体的关键宿主防御策略，我们的创新假设是，储存受损的红细胞在急性巨噬细胞清除后释放的铁超过了接受者安全固铁的能力，从而产生循环中的非转铁蛋白结合的铁，然后通过促进生物膜的形成而起到毒力因子的作用。生物膜是在嵌入胞外聚合物的群落中生长的微生物的聚集体。在许多微生物系统中，生物膜的分化需要高水平的铁。与生物膜相关的感染是与医疗保健相关的重要感染，如中心线相关血流感染(CLABSI)。这项建议将确定通过清除输注的红细胞产生的循环铁在多大程度上促进微生物病原体的生物被膜形成。目的#1将使用我们医院系统中所有的儿童和成人CLABSI病例进行创新性的病例交叉和病例-时间对照的回顾性研究，以确定输血前红细胞储存时间与CLABSI之间的关联程度。在目标2中，我们将使用静态和动态的体外生物膜试验来确定非转铁蛋白结合的铁对几种相关的人类病原体生物膜形成的贡献。目前的项目将通过为输注储存的红细胞和CLABSI之间的关系提供证据，并确定铁对导致这一效应的潜在机制的贡献(S)来填补知识的关键空白。这将导致防止循环铁产生的创新方法，从而提高住院患者的红细胞输注安全性。

DESCRIPTION (provided by applicant): This project will examine the effect of circulating iron produced from transfusions of older, stored red blood cells (RBCs) on biofilm-related infections. By FDA criteria, RBCs have a maximum refrigerated shelf life of 42 days. Studies suggest that transfusion of "older" versus "fresher" stored RBC units is associated with significantly increased risk of morbidity and mortality. RBCs are damaged progressively during refrigerator storage. After transfusion, storage-damaged RBCs are rapidly cleared from the circulation by macrophages. This RBC hemoglobin iron is then rapidly catabolized and returned to plasma at a pace that can exceed the rate of iron uptake by transferrin, the physiologic iron transporter, and thereby producing circulating non-transferrin- bound iron. Physiologically, virtually all circulating iron is transferrin-bound. In contrast, our human studies show that transfusion of even one unit of stored RBCs can acutely produce circulating non-transferrin-bound iron and enhance bacterial growth in post-transfusion serum samples in vitro. Because iron transport by transferrin is a critical host defense strategy that withholds iron from infectious pathogens, our innovative hypothesis is that release of iron after acute macrophage clearance of storage-damaged RBCs overwhelms the recipient's capacity for safe iron sequestration, thereby producing circulating non- transferrin-bound iron that then acts as a virulence factor by enhancing biofilm formation. Biofilms are aggregates of microorganisms growing in a community embedded in an extracellular polymeric substance. In many microbial systems, differentiation into a biofilm requires high levels of iron. Biofilm-related infections are responsible for importat healthcare-associated infections, such as central line-associated blood stream infections (CLABSI). This proposal will determine the extent to which circulating iron produced by clearance of transfused RBCs enhances biofilm formation of microbial pathogens. Aim #1 will use all pediatric and adult incident cases of CLABSI in our hospital system to conduct an innovative case-crossover and case- time-control retrospective study to determine the extent of the association between the duration of RBC storage prior to transfusion and CLABSI. In Aim #2, we will use static and dynamic in vitro biofilm assays to determine the contribution of non-transferrin-bound iron to biofilm formation of several relevant human pathogens. The current project will fill critical gaps in knowledge by providing evidence for a relationship between transfusions of stored RBCs and CLABSI, and determining the contribution of iron to the underlying mechanism(s) responsible for this effect. This will lead to innovative approaches for preventing production of circulating iron, thereby improving RBC transfusion safety in hospitalized patients.