Donor sex, age and ethnicity impact stored red blood cell antioxidant metabolism through mechanisms in part explained by glucose 6-phosphate dehydrogenase levels and activity

Abstract

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.

Donor‐dependent aging of young and old red blood cell subpopulations: Metabolic and functional heterogeneity

“…Of note, sex-and age-dependent changes in these pathways have been recently reported. 25 In particular, increased purine oxidation or impaired activation of the PPP have been negatively associated with the capacity of stored RBCs to circulate upon transfusion. 46 Here we expand on these observations by describing an impact of the age of RBC subpopulations on these pathways.…”

“…34,[62][63][64] of senescent RBCs within a RCC will presumptively have higher accumulation of side products of aging/lysis that undoubtedly affect the quality of the whole RCC unit. Other studies have discussed the impact of donor age and sex on both the quality characteristics of RCCs during in vitro storage 22,25,28,65 and the transfusion efficacy, [66][67][68][69] with an increased risk of mortality due to sex-mismatched transfusions. [70][71][72][73][74] fRBCs stored in vitro have generally shown superior quality measures, such as less susceptibility to storage-induced hemolysis and mechanical fragility, and better rheologic properties compared to mRBCs 22,75 that can be related to a larger proportion of biologically younger RBCs in female donors.…”

“…10,11 Microvesicle formation is thought to be a main cause of posttransfusion complications due to their role in: (a) the pathogenesis of thrombosis, 12 inflammation, [13][14][15] and responses to pathogens; 16 (b) platelet activation; 17 (c) deformability changes that affect RBC rheology and blood flow; 18 and (d) decreased oxygen delivery due to microvesicle-entrapped Hb, 19 among others. The extent of this storage lesion is highly variable depending on factors including, but not limited to, blood processing methods, [20][21][22][23][24] storage additive solutions, [25][26][27] and donorrelated characteristics. 22,28 At the time of donation, RCCs consist of a population of RBCs with varying biologic ages, from recently matured (young) to senescent (old).…”

Evidence for structural protein damage and membrane lipid remodeling in red blood cells from COVID-19 patients

“…Of note, age and sex significantly affect RBC metabolism in healthy blood donors with respect to energy and redox metabolism. 20 As such, we hypothesized that RBC metabolic differences in COVID-19 patients could contribute to their ability to cope with oxidant stress and hypoxemia and, as such, to the heterogeneity of disease expression. In addition to these considerations, preliminary data were offered by others for peer-review supporting a potential direct structural interaction between SARS-CoV-2 proteins and hemoglobins; 19 if validated, this would provide a direct role for the virus in compromising RBC oxygen transport and delivery.…”

Oxygen in Red Blood Cell Concentrates: Influence of Donors’ Characteristics and Blood Processing

“…The extent of the lesions observed is variable among red cell concentrates (RCCs), which could indicate either a process-or a donor-dependency (Jordan et al, 2016;Tzounakas et al, 2016;Kanias et al, 2017;D'Alessandro et al, 2020). More particularly, it was observed that the initial oxygenation saturation (sO 2 ) levels did widely vary among RCCs.…”