Red blood cell storage in the blood bank promotes the progressive accumulation of metabolic alterations that may ultimately impact the erythrocyte capacity to cope with
oxidant stressors. However, the metabolic underpinnings of the capacity of RBCs to resist
oxidant stress and the potential impact of donor biology on this phenotype are not known. Within the framework of the REDS-III RBC-Omics study, RBCs from 8,502 healthy blood donors were stored for 42 days and tested for their propensity to hemolyze following
oxidant stress. A subset of extreme hemolyzers donated a second unit of blood, which was stored for 10, 23, and 42 days and profiled again for oxidative
hemolysis and metabolomics (599 samples). Alterations of RBC energy and redox homeostasis were noted in donors with high oxidative
hemolysis. RBCs from females, donors over 60 years old, donors of Asian/South Asian race-ethnicity, and RBCs stored in additive solution-3 were each independently characterized by improved
antioxidant metabolism compared to, respectively, males, donors under 30 years old, Hispanic and African American race ethnicity donors, and RBCs stored in additive solution-1. Merging metabolomics data with results from an independent GWAS study on the same cohort, we identified metabolic markers of
hemolysis and G6PD-deficiency, which were associated with extremes in oxidative
hemolysis and dysregulation in
NADPH and
glutathione-dependent detoxification pathways of oxidized
lipids. Donor sex, age, ethnicity, additive
solution and G6PD status impact the metabolism of the stored erythrocyte and its susceptibility to
hemolysis following oxidative insults.