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

老年红细胞单位对镰状细胞病成人患者的影响

基本信息

批准号：
10362450
负责人：
MATTHEW S KARAFIN
金额：
$ 17.82万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10362450
关键词：
Address Adhesions Adult Age Animal Model Antigens Biochemical Biochemical Markers Biochemistry Biology Blood Blood Banks Blood specimen Bolus Infusion Cell membrane Cell surface Cells Cessation of life Chronic Clinical Clinical Trials Coagulation Process Complement Complement Activation Critical Illness Data Development Plans Dose Eating Equipoise Erythrocyte Transfusion Erythrocytes Event Faculty Flow Cytometry Foundations Functional disorder Funding Goals Growth Heme Hemoglobin Hemolysis Hospitalization Hour Immunologics Infection Inflammation Institution Interleukin-10 Iron K-Series Research Career Programs Knowledge Lesion Lipids Macrophage Activation Measures Mentors Nitric Oxide Outcome Patients Phagocytes Phagocytosis Pharmaceutical Preparations Phosphatidylserines Physiological Physiology Plasma Randomized Regimen Reporting Request for Proposals SELL gene Scientist Sepsis Series Sickle Cell Anemia Signal Transduction Stroke prevention Structure Surface Symptoms Testing Tissues Toll-like receptors Transforming Growth Factor beta Transfusion Vascular Endothelial Cell Vascular Endothelium Virulence Vulnerable Populations adverse outcome base career development cytokine diaries immune activation immunoregulation infection rate infection risk laboratory experience macrophage member microbial monocyte mouse model neutrophil pathogenic microbe patient population prevent prospective randomized controlled study randomized trial response risk minimization sickling transfusion medicine

项目摘要

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.

项目概要/摘要当前提案请求支持为马修博士提供指导职业发展奖卡拉芬 (Karafin) 是一名输血医学初级教员。卡拉芬博士的长期目标是成为一名输血医学专家。独立资助的输血医学临床科学家，专注于镰状细胞病 (SCD)。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，补充了解决一个关键问题的三个目标：较旧的红细胞单位是否对患有 SCD 的成年人有害。人们对红细胞长期储存（红细胞储存）如何发生生化变化知之甚少。 “贮积病灶”）对 SCD 患者有影响。1 虽然在其他患者群体中进行的随机试验尚未发现老年单位与不良临床结果相关，2-6 名患有 SCD 的成年人具有独特的病理生理学并且可能容易受到较旧单位改变的生物学的影响，小鼠模型表明，较旧单位的丸剂可能会受到影响。储存的红细胞，其表面磷脂酰乙醇胺（PE）水平增加，磷脂酰丝氨酸 (PS) 和微粒浓度增加，7-10 压倒巨噬细胞并导致炎症和非转铁蛋白结合铁 (NTBI) 显着增加，从而促进微生物病原体的毒力增加和致命的败血症。11-13 为了弥补这一知识差距，我们对患有 SCD 的成人进行了一系列初步研究，结果表明：1）存在平衡血库主管中关于老年单位对 SCD 成人的影响的看法，14 2) 超过 25% 我们机构中患有 SCD 的成人主要输注较旧的红细胞单位（≥33 天）15,16 3) PE和PS的红细胞表面暴露以及微粒浓度增加20倍、6倍和储存7至35天分别为4倍，10 4) 储存≥14天的红细胞单位的输注为与患有 SCD 的成人中巨噬细胞的 CD62L+ 显着激活相关，以及 5) 患有 SCD 的成人中 SCD，接收旧设备会增加感染风险，需要住院治疗 15 由于储存变化（例如 PS 暴露）通过以下方式促进红细胞的吞噬作用：巨噬细胞，17-19 我们努力让较老的红细胞单位触发吞噬作用并激活循环巨噬细胞具有下游免疫调节级联反应并释放过量的 NTBI，从而导致患有 SCD 的成人感染率增加。为了检验这一假设，我们将在目标 1 中进行一项随机前瞻性临床试验。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 SCD 患者输血的生理影响最后，在目标 3 中，我们将。探索 3 个月内接受旧红细胞的临床意义。