The Effects of Older Red Cell Units in Adults with Sickle Cell Disease

项目总结/摘要 目前的提案要求支持马修博士的指导职业发展奖 Karafin是输血医学系的一名初级教员。Karafin博士的长期目标是成为 独立资助的输血医学临床科学家，专注于镰状细胞病（SCD）。在 该提案是一个结构化的职业发展计划，其中包括重点教学和实验室 经验，补充了三个目标，以解决一个关键问题：老年红细胞单位是否 对成年SCD患者有害。 关于红细胞长期储存相关的生化变化（ “储存性病变”）影响SCD患者。 与具有不良临床结局的老年单位相关，2-6名SCD成人具有独特的病理生理学 可能会受到旧单位生物学改变的影响小鼠模型表明， 储存的红细胞，其具有增加的表面磷脂酰乙醇胺（PE）水平， 磷脂酰丝氨酸（PS）和微粒浓度增加，7-10 μ m巨噬细胞 并导致炎症和非转铁蛋白结合铁（NTBI）的显著增加， 微生物病原体的毒力增加和致命的败血症。11 -13为了解决这一知识缺口，我们 对成人SCD患者进行了一系列初步研究，结果表明：1） 在血库主管中，关于老年病房对成人SCD患者的影响，14 2）超过25%的 在我们自己的机构中，SCD成人主要输注老年红细胞单位（≥33天），15，16 3)PE和PS的红细胞表面暴露以及微粒浓度分别增加20倍、6倍和 4-储存≥14天的红细胞单位的输注 与SCD成人中巨噬细胞的显著CD 62 L+活化相关，和5）在SCD成人中， SCD，接收较旧的单位与需要住院的感染风险增加有关 15由于储存变化，如PS暴露，促进红细胞的吞噬作用， 巨噬细胞，17-19，我们假设老年红细胞单位触发吞噬作用和激活循环 巨噬细胞与下游免疫调节级联和释放过量的NTBI，导致 成人SCD感染率增加。 为了验证这一假设，我们将进行一项随机前瞻性临床试验。在目标1中， 确定≥30日龄与≤10日龄单位之间的生化差异。在目标2中，我们将 确定输注血液对SCD患者的生理影响。在目标3中，我们将 探索在3个月内接受老化红细胞的临床意义。

Project Summary/Abstract The current proposal requests support for a mentored career development award for Dr. Matthew Karafin, a junior faculty member in transfusion medicine. Dr. Karafin's long-term goal is to be an independently-funded clinical scientist in transfusion medicine with a focus on sickle cell disease (SCD). In this proposal, a structured career development plan, which includes focused didactic and laboratory experiences, complements three aims to address a critical question: whether older red cell units are harmful to an adult with SCD. Little is known about how the biochemical changes associated with prolonged red cell storage (the “storage lesion”) impact patients with SCD.1 While randomized trials in other patient populations have not associated older units with adverse clinical outcomes,2-6 adults with SCD have a unique pathophysiology and may be susceptible to an older unit's altered biology. Murine models suggest that a bolus of older stored red cells, which have increased levels of surface phosphotidlyethanolamine (PE), phosphatidylserine (PS), and increased concentrations of microparticles,7-10 overwhelms macrophages and results in marked increases in inflammation and non-transferrin bound iron (NTBI), which facilitates increased virulence of microbial pathogens and fatal sepsis.11-13 To address this knowledge gap, we have conducted a series of preliminary studies in adults with SCD that demonstrated: 1) there is equipoise among blood bank directors about the effects of older units in adults with SCD,14 2) greater than 25% of adults with SCD at our own institution are predominantly transfused with older red cell units (≥33 days),15,16 3) red cell surface exposure of PE and PS, and microparticle concentration, increases 20-fold, 6-fold and 4-fold from 7 to 35 days of storage, respectively,10 4) transfusion of red cell units stored ≥14 days is associated with significant CD62L+ activation of macrophages in adults with SCD, and 5) in adults with SCD, receipt of older units is associated with an increased risk for infection that requires a hospital admission.15 Since storage changes, such as PS exposure, promote phagocytosis of red cells by macrophages,17-19 we hypothesize that older red cell units trigger phagocytosis and activation of circulating macrophages with a downstream immunomodulatory cascade and release of excess NTBI that leads to increased rates of infection in adults with SCD. To test this hypothesis, we will perform a randomized prospective clinical trial. In aim 1, we will determine the biochemical differences between ≥30 day-old versus ≤10 day-old units. In aim 2, we will determine the physiologic effects of the transfused blood in a patient with SCD. Lastly, in aim 3, we will explore the clinical implications of receiving older red cells over a 3 month period.