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Blood Adv. 2019 Mar 26;3(6):884-896. doi: 10.1182/bloodadvances.2018029629.

Effects of aged stored autologous red blood cells on human plasma metabolome.

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Department of Biochemistry and Molecular Genetics, University of Colorado Denver-Anschutz Medical Campus, Aurora, CO.
Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh and University of Pittsburgh Medical Center, Pittsburgh, PA.
Vitalant Research Institute, Denver, CO.
Pittsburgh Heart, Lung, Blood and Vascular Medicine Institute.
Institute for Transfusion Medicine, and.
Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA.
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver, Denver, CO; and.
Division of Hematology/Oncology, Women and Children's Hospital of Buffalo, Buffalo, NY.


Cold storage of blood for 5 to 6 weeks has been shown to impair endothelial function after transfusion and has been associated with measures of end-organ dysfunction. Although the products of hemolysis, such as cell-free plasma hemoglobin, arginase, heme, and iron, in part mediate these effects, a complete analysis of transfused metabolites that may affect organ function has not been evaluated to date. Blood stored for either 5 or 42 days was collected from 18 healthy autologous volunteers, prior to and after autologous transfusion into the forearm circulation, followed by metabolomics analyses. Significant metabolic changes were observed in the plasma levels of hemolytic markers, oxidized purines, plasticizers, and oxidized lipids in recipients of blood stored for 42 days, compared with 5 days. Notably, transfusion of day 42 red blood cells (RBCs) increased circulating levels of plasticizers (diethylhexyl phthalate and derivatives) by up to 18-fold. Similarly, transfusion of day 42 blood significantly increased circulating levels of proinflammatory oxylipins, including prostaglandins, hydroxyeicosatrienoic acids (HETEs), and dihydroxyoctadecenoic acids. Oxylipins were the most significantly increasing metabolites (for 9-HETE: up to ∼41-fold, P = 3.7e-06) in day 42 supernatants. Measurements of arginine metabolism confirmed an increase in arginase activity at the expense of nitric oxide synthesis capacity in the bloodstream of recipients of day 42 blood, which correlated with measurements of hemodynamics. Metabolic changes in stored RBC supernatants impact the plasma metabolome of healthy transfusion recipients, with observed increases in plasticizers, as well as vasoactive, pro-oxidative, proinflammatory, and immunomodulatory metabolites after 42 days of storage.

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