Donor glucose-6-phosphate dehydrogenase deficiency decreases blood quality for transfusion

Abstract

METHODS. Male volunteers were screened for G6PD deficiency; 27 control and 10 G6PD-deficient volunteers each donated 1 RBC unit. After 42 days of refrigerated storage, autologous 51-chromium 24-hour posttransfusion RBC recovery (PTR) studies were performed. Metabolomics analyses of these RBC units were also performed. RESULTS. The mean 24-hour PTR for G6PD-deficient subjects was 78.5% ± 8.4% (mean ± SD), which was significantly lower than that for G6PD-normal RBCs (85.3% ± 3.2%; P = 0.0009). None of the G6PD-normal volunteers (0/27) and 3 G6PD-deficient volunteers (3/10) had PTR results below 75%, a key FDA acceptability criterion for stored donor RBCs. As expected, fresh G6PD-deficient RBCs demonstrated defects in the oxidative phase of the pentose phosphate pathway. During refrigerated storage, G6PD-deficient RBCs demonstrated increased glycolysis, impaired glutathione homeostasis, and increased purine oxidation, as compared with G6PD-normal RBCs. In addition, there were significant correlations between PTR and specific metabolites in these pathways. CONCLUSION. Based on current FDA criteria, RBCs from G6PD-deficient donors would not meet the requirements for storage quality. Metabolomics assessment identified markers of PTR and G6PD deficiency (e.g., pyruvate/lactate ratios), along with potential compensatory pathways that could be leveraged to ameliorate the metabolic needs of G6PD-deficient RBCs. TRIAL REGISTRATION. ClinicalTrials.gov NCT04081272.

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

“…Although relative levels may not reflect enzymatic activity, one may speculate that the effects of COVID-19 on RBC biology may be exacerbated when the stability and activity of G6PD are modified by natural mutations. Thus, G6PD deficiency 20,39 is the most common human enzymopathy, affecting ~400 million people world-wide; it also disproportionally affects particular ethnic groups, including African Americans, who are more susceptible to developing severe COVID-19. Because G6PD is also an X-linked gene, it may also partially explain the sex-dependent component of COVID-19 severity, with worse outcomes in male patients.…”

Protein-L-isoaspartate O-methyltransferase is required for <i>in vivo</i> control of oxidative damage in red blood cells

“…Thus, this counts as importance evidence against the lipid oxidation hypothesis of RBC clearance after storage. On the other hand, it is worth noting that PCMT1 KO RBCs have a compensatory activation of the PPP, which is relevant in the light of the recently reported decreases in PTR in blood donors with G6PD deficiency, 29,32 the most common enzymopathy in humans and thus clinically relevant for ~400 million individuals worldwide. It remains to be assessed whether ablated PIMT activity may result in poor post-transfusion performances of the stored RBC in the context of G6PD deficiency or other genetic factors that have been shown to negatively impact post-transfusion recoveries in mice (e.g., STEAP3 16 ).…”

The interactome of the N-terminus of band 3 regulates red blood cell metabolism and storage quality

“…32,36,37 Methylene blue treatments RBCs from WT and band 3 KO mice were incubated with methylene blue (100 uM, Sigma Aldrich) at 37°C for 1h, as described. 31 Storage under blood bank conditions RBCs from the four main strains investigated in this study, along with 13 different mouse strains described before 38 were collected, processed, stored, transfused and post-transfusion recovery was determined as previously described. 38…”

“…MB is metabolized into leukomethylene blue in a reaction that consumes NADPH and thus promotes PPP activation by law of mass action. 31 Determination of lactate isotopologues 2,3-13 C 2 and 1,2,3-13 C 3and their ratios -are indicative of the activation of the PPP and glycolysis, respectively, since the first carbon atom of 1,2,3-13 C 3 -glucose is lost in the form of 13…”

“…Notably, activation of the PPP and post-transfusion recoveries were normalized in band 3 KO RBCs lacking AE residues 1-11 (HA Del) upon incubation with a cell-penetrating AE1 1-56 peptide. To this end, it is worth stressing that the band 3 KO mice phenocopied G6PD deficient RBCs31,32 with respect to the decreased capacity to activate the PPP and ultimately poor post-transfusion recovery. These data were here accompanied by preliminary evidence of the possibility to rescue altered RBC metabolic phenotypes upon AE1 genetic ablation/storage-induced damage by means of a cell membrane permeable version of a peptide coding for AE1 amino acids 1-56.…”