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.

项目摘要/摘要当前的提案要求为马修博士提供职业发展奖的支持卡拉芬（Karafin），输血医学的初级教职员工。卡拉芬博士的长期目标是成为专注于镰状细胞病（SCD）的独立资助的输血医学临床科学家。该提案是一项结构化的职业发展计划，其中包括专注的教学和实验室经验，完成三个旨在解决一个关键问题：较旧的红细胞单元是否是对患有SCD的成年人有害。关于如何与长时间的红细胞存储相关的生化变化知之甚少（ “储存病变”）影响SCD.1患者，而其他患者人群的随机试验却没有有不良临床结果的相关较旧单位，2-6名SCD成年人具有独特的病理生理学并且可能容易受到较老的生物学改变的影响。鼠模型表明较旧的大推注储存的红细胞，其表面磷酸乙醇胺（PE）的水平增加，磷脂酰丝氨酸（PS）和微粒浓度增加，7-10压倒性巨噬细胞并导致炎症和非转移蛋白结合的铁（NTBI）显着增加，该设施增加了微生物病原体和致命败血症病毒。11-13为了解决这一知识差距，我们有在患有SCD的成年人的成年人中进行了一系列初步研究，证明了：1）在血库导演中，关于旧单位在SCD成年人中的影响，14 2）超过25％我们自己机构中有SCD的成年人主要用较旧的红细胞单位（≥33天）翻译成15,16 3）PE和PS的红细胞表面暴露，以及微粒浓度，增加了20倍，6倍和分别从7天到35天的4倍，10 4）存储≥14天的红细胞单元的输血为与成年人中巨噬细胞的显着CD62L+激活相关，5） SCD，较旧单位的收到与需要医院的感染风险增加有关 15由于存储的变化（例如PS暴露）促进了通过巨噬细胞，17-19我们假设较旧的红细胞单元触发吞噬作用和循环的激活巨噬细胞具有下游免疫调节级联反应和多余NTBI的释放，导致 SCD成人的感染率增加。为了检验这一假设，我们将进行一项随机前瞻性临床试验。在AIM 1中，我们将确定≥30天龄的生化差异与≤10天的单位之间的生化差异。在AIM 2中，我们将确定SCD患者输血血液的生理作用。最后，在AIM 3中，我们将探索在3个月内接收旧红细胞的临床意义。