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.

Public Health Relevance

This project will examine the effect of red blood cell storage duration on transfusion safety in patients with a heightened risk of infection, such as after trauma, surgery, or intensive care unit admission. We will determine the maximum red cell storage duration that avoids producing circulating non-transferrin-bound iron after transfusion in healthy adult volunteers and critically ill children, and the effect of transfusion-induced non- transferrin-bound iron on the growth in vitro of clinically important pathogens. This new information will help identify ways to improve the safety of red blood cell transfusion in hospitalized patients.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Special Emphasis Panel (ZRG1-VH-F (50))
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Zou, Shimian
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Columbia University (N.Y.)
Schools of Medicine
New York
United States
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Youssef, Lyla A; Rebbaa, Abdelhadi; Pampou, Sergey et al. (2018) Increased erythrophagocytosis induces ferroptosis in red pulp macrophages in a mouse model of transfusion. Blood 131:2581-2593
Nemkov, Travis; Sun, Kaiqi; Reisz, Julie A et al. (2018) Hypoxia modulates the purine salvage pathway and decreases red blood cell and supernatant levels of hypoxanthine during refrigerated storage. Haematologica 103:361-372
Rapido, Francesca; Brittenham, Gary M; Bandyopadhyay, Sheila et al. (2017) Prolonged red cell storage before transfusion increases extravascular hemolysis. J Clin Invest 127:375-382
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L'Acqua, Camilla; Bandyopadhyay, Sheila; Francis, Richard O et al. (2015) Red blood cell transfusion is associated with increased hemolysis and an acute phase response in a subset of critically ill children. Am J Hematol 90:915-20

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