The safety of red blood cell transfusions

描述（由申请人提供）：本项目将研究由年老的、储存的红细胞（rbc）输血产生的循环铁对生物膜相关感染的影响。根据FDA的标准，红细胞的最长冷藏保质期为42天。研究表明，输注“较老”的红细胞与输注“较新鲜”的红细胞会显著增加发病和死亡的风险。红细胞在冷藏过程中逐渐受损。输血后，储存受损的红细胞迅速被巨噬细胞从循环中清除。然后，红细胞血红蛋白铁迅速分解代谢并以超过转铁蛋白（生理性铁转运体）吸收铁的速度返回血浆，从而产生循环的非转铁蛋白结合铁。生理上，几乎所有的循环铁都与转铁蛋白结合。相比之下，我们的人体研究表明，即使输入一个单位的储存红细胞，也能在体外输血后血清样品中急性产生循环的非转铁蛋白结合铁，并促进细菌生长。由于铁通过转铁蛋白运输是一种关键的宿主防御策略，可以阻止铁进入感染性病原体，因此我们的创新假设是，在急性巨噬细胞清除储存受损的红细胞后，铁的释放超过了受体安全固铁的能力，从而产生循环的非转铁蛋白结合铁，然后通过增强生物膜的形成作为毒力因子。生物膜是嵌在细胞外聚合物质中的微生物群落生长的聚集体。在许多微生物系统中，分化成生物膜需要高水平的铁。生物膜相关感染是重要的医疗保健相关感染的原因，如中央静脉相关血流感染（CLABSI）。该建议将确定输血红细胞清除产生的循环铁在多大程度上增强微生物病原体的生物膜形成。目的1将使用我院系统中所有儿童和成人CLABSI事件病例，进行一项创新的病例交叉和病例时间对照回顾性研究，以确定输血前红细胞储存时间与CLABSI之间的关联程度。在Aim #2中，我们将使用静态和动态体外生物膜测定来确定非转铁蛋白结合铁对几种相关人类病原体生物膜形成的贡献。目前的项目将填补知识上的关键空白，为输血储存的红细胞和CLABSI之间的关系提供证据，并确定铁对导致这种效应的潜在机制的贡献。这将导致防止循环铁产生的创新方法，从而提高住院患者红细胞输血的安全性。

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.