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

项目摘要/摘要 目前的提案要求为马修博士的指导职业发展奖提供支持 卡拉芬说，他是输血医学的初级教员。卡拉芬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……里面 这项建议是一项有组织的职业发展计划，包括重点讲授和实验室 经验，补充了三个旨在解决一个关键问题的目标：较老的红细胞单位是否 对患有SCD的成年人有害。 鲜为人知的是，与红细胞长期储存有关的生化变化( 影响SCD.1的患者，而在其他患者群体中的随机试验没有影响 与较老的单位相关的不良临床结果，2-6名患有SCD的成年人有独特的病理生理学 而且可能容易受到较老单位的生物变化的影响。小鼠模型表明，一批年龄较大的 储存的红细胞，它增加了表面磷酸乙醇胺(PE)的水平， 磷脂酰丝氨酸(PS)和浓度增加的微粒，7-10压倒巨噬细胞 并导致炎症和非转铁蛋白结合铁(NTBI)的显著增加，这有助于 微生物病原体和致命败血症的毒力增加。11-13为了解决这一知识鸿沟，我们有 对患有SCD的成年人进行了一系列初步研究，证明：1)存在平衡 在血库主管中，年龄较大的单位对患有SCD的成年人的影响，142)超过25% 在我们自己的机构中患有SCD的成年人主要是输注较老的红细胞单位(≥33天)，15，16 3)红细胞表面暴露PE和PS，以及微粒浓度，分别增加20倍、6倍和 4)分别从保存7天到35天，输注10个红细胞单位保存14天是≥ 与成人SCD患者巨噬细胞CD62L+显著激活有关，以及5)成人SCD患者 SCD，接受较旧的设备会增加感染的风险，需要住院 15由于储存变化，如PS暴露，通过以下方式促进红细胞的吞噬 巨噬细胞，17-19我们假设较老的红细胞单位触发吞噬和激活循环 具有下游免疫调节级联和释放过量NTBI的巨噬细胞导致 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，我们将 确定≥30日龄单位与≤10日龄单位之间的生化差异。在目标2中，我们将 确定SCD患者输血的生理效应。最后，在目标3中，我们将 探讨在3个月内接受较老的红细胞的临床意义。

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.