The safety of red blood cell transfusions

描述（由申请人提供）：本项目将检查输注较老的储存红细胞（RBC）产生的循环铁对生物膜相关感染的影响。根据FDA标准，RBC的最大冷藏保质期为42天。研究表明，输注“较旧”与“较新”储存的RBC单位与发病率和死亡率风险显著增加相关。红细胞在冰箱储存过程中逐渐受损。输血后，储存受损的RBC被巨噬细胞迅速从循环中清除。然后，这种RBC血红蛋白铁被快速分解代谢，并以超过转铁蛋白（生理铁转运蛋白）吸收铁的速率的速度返回血浆，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是转铁蛋白结合的。相比之下，我们的人体研究表明，即使输注一个单位的储存红细胞也可以在体外迅速产生循环非转铁蛋白结合铁并增强输血后血清样品中的细菌生长。因为通过转铁蛋白的铁转运是阻止铁来自传染性病原体的关键宿主防御策略，所以我们的创新假设是在急性巨噬细胞清除储存受损的RBC后释放铁破坏了受体安全铁螯合的能力，从而产生循环的非转铁蛋白结合的铁，其然后通过增强生物膜形成而充当毒力因子。生物膜是在包埋于细胞外聚合物物质中的群落中生长的微生物的聚集体。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，如中心静脉导管相关血流感染（CLABSI）。该提案将确定通过清除输注的RBC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。目标#1将使用我们医院系统中的所有儿童和成人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RBC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的生物膜形成的贡献。目前的项目将填补知识的关键空白，提供证据证明输血储存的红细胞和CLABSI之间的关系，并确定铁对这种影响的潜在机制的贡献。这将导致创新的方法来防止循环铁的产生，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.