Harmful effects of red blood cell transfusions are mediated by iron

红细胞输注的有害影响是由铁介导的

• 批准号: 8450960
• 负责人: STEVEN L SPITALNIK
• 金额: $ 54.78万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-15 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8450960
• 关键词: Acute; Admission activity; Adult; Allogenic; Appearance; Autologous; Bacteremia; Binding; Biochemical; Biomechanics; Blood; Blood Circulation; Blood Transfusion; Bolus Infusion; Child; Childhood; Clinical; Critical Illness; Critically ill children; Erythrocyte Transfusion; Erythrocytes; Erythroid; Growth; Hemoglobin; Hospitalized Child; Host Defense; Hour; Human Volunteers; In Vitro; Infant; Infection; Intensive Care Units; Iron; Knowledge; Laboratories; Lead; Life; Longevity; Marrow; Measures; Mediating; Methods; Morbidity - disease rate; Natural Immunity; Observational Study; Operative Surgical Procedures; Patients; Pediatric Intensive Care Units; Physiological; Plasma; Production; Prospective Studies; Publishing; Recovery; Research; Risk; Safety; Sampling; Sepsis; Serum; Tissues; Transferrin; Transfusion; Trauma; United States; healthy volunteer; improved; in vivo; macrophage; meetings; microbial; mortality; novel; pathogen; prospective; public health relevance; senescence; uptake; volunteer

DESCRIPTION (provided by applicant): This project will examine the effect of the duration of red blood cell (RBC) storage on the safety of transfusion in patients with a heightened risk of infectious complications, such as after trauma, surgery, or admission to an intensive care unit. Accumulating evidence suggests that transfusion of blood stored for 14 days or longer is associated with increased rates of infection, morbidity, and mortality in hospitalized patients. During storage in vitro, RBCs undergo cumulative biochemical and biomechanical changes that reduce their survival in vivo. After transfusion, storage damaged RBCs are quickly cleared from the circulation by reticuloendothelial macrophages, usually within the first hour. This RBC hemoglobin iron is then rapidly catabolized and returned to plasma at a pace that can exceed the rate of uptake by transferrin, the physiologic iron transporter, thereby producing plasma non-transferrin-bound iron, which can stimulate microbial growth. Our overarching hypothesis is that transfusions of RBCs after prolonged storage produce acute elevations of circulating non- transferrin-bound iron, which increase the risk of infectious complications by enhancing the growth of microbial pathogens. To this end, we propose carefully controlled, prospective studies of healthy volunteers and critically ill pediatric patients. In Aim 1, we will determine the relationship between the duration of RBC storage, RBC clearance, and production of circulating non-transferrin-bound iron after autologous transfusion in healthy adult volunteers. In Aim 2, we will determine the magnitude and course of circulating non-transferrin-bound iron after allogeneic RBC transfusions in critically ill infants and children in the Pediatric ICU. Finally, i Aim #3 we will determine whether circulating non-transferrin-bound iron enhances growth in vitro of clinically important pathogens responsible for bacteremia and sepsis in the Pediatric ICU. This project will fill critical gaps in knowledge by (i) defining a safe RBC storage interval that avoids production of circulating non-transferrin- bound iron, (ii) quantifying concentrations f circulating non-transferrin-bound iron in critically ill pediatric patients after allogeneic transfsion, and (iii) determining the effects of circulating non-transferrin-bound iron on the growth of clinically important pathogens isolated from pediatric patients. This new information will help identify ways to improve the safety of RBC transfusions in hospitalized patients.

描述（由申请人提供）：该项目将研究红细胞 (RBC) 储存时间对感染并发症风险较高的患者（例如创伤、手术或入住重症监护室后）输血安全性的影响。越来越多的证据表明，输注储存 14 天或更长时间的血液与住院患者的感染率、发病率和死亡率增加有关。在体外储存期间，红细胞会经历累积的生化和生物力学变化，从而降低其在体内的存活率。输血后，储存受损的红细胞通常会在第一个小时内被网状内皮巨噬细胞从循环中迅速清除。然后，红细胞血红蛋白铁被快速分解代谢并以超过转铁蛋白（生理性铁转运蛋白）的摄取速度的速度返回血浆，从而产生血浆非转铁蛋白结合的铁，从而刺激微生物生长。我们的总体假设是，长期储存后输注红细胞会导致循环中非转铁蛋白结合铁急剧升高，从而通过促进微生物病原体的生长而增加感染并发症的风险。为此，我们建议对健康志愿者和危重儿科患者进行仔细对照的前瞻性研究。在目标 1 中，我们将确定健康成年志愿者自体输血后红细胞储存时间、红细胞清除率和循环非转铁蛋白结合铁的产生之间的关系。在目标 2 中，我们将确定儿科 ICU 危重婴儿和儿童同种异体红细胞输注后循环非转铁蛋白结合铁的量级和过程。最后，目标#3，我们将确定循环的非转铁蛋白结合铁是否会增强儿科 ICU 中导致菌血症和败血症的临床重要病原体的体外生长。该项目将通过以下方式填补关键知识空白：(i) 确定安全的红细胞储存间隔，避免产生循环非转铁蛋白结合铁；(ii) 量化同种异体移植后危重儿科患者中循环非转铁蛋白结合铁的浓度；(iii) 确定循环非转铁蛋白结合铁对临床重要病原体生长的影响 与儿科患者隔离。这一新信息将有助于确定提高住院患者红细胞输注安全性的方法。