Metabolic pathways that correlate with post-transfusion circulation of stored murine red blood cells

Abstract

T ransfusion of red blood cells is a very common inpatient procedure, with more than 1 in 70 people in the USA receiving a red blood cell transfusion annually. However, stored red blood cells are a non-uniform product, based upon donor-to-donor variation in red blood cell storage biology. While thousands of biological parameters change in red blood cells over storage, it has remained unclear which changes correlate with function of the red blood cells, as opposed to being co-incidental changes. In the current report, a murine model of red blood cell storage/transfusion is applied across 13 genetically distinct mouse strains and combined with high resolution metabolomics to identify metabolic changes that correlated with red blood cell circulation post storage. Oxidation in general, and peroxidation of lipids in particular, emerged as changes that correlated with extreme statistical significance, including generation of dicarboxylic acids and monohydroxy fatty acids. In addition, differences in anti-oxidant pathways known to regulate oxidative stress on lipid membranes were identified. Finally, metabolites were identified that differed at the time the blood was harvested, and predict how the red blood cells perform after storage, allowing the potential to screen donors at time of collection. Together, these findings map out a new landscape in understanding metabolic changes during red blood cell storage as they relate to red blood cell circulation. ABSTRACT

Ethnicity, sex, and age are determinants of red blood cell storage and stress hemolysis: results of the REDS-III RBC-Omics study

“…Although the clinical consequences of such differences have not been established in humans, studies in mice have demonstrated strain-specific susceptibility to RBC injury from cold storage that correlates with posttransfusion RBC recovery and function. 8,9 …”

Biomarkers defining the metabolic age of red blood cells during cold storage

“…35 The data sets used in this work were focused on polar metabolites and some of these metabolites, such as eicosanoids, were not detected. Only 5-oxoproline was identified as a marker associated with oxidative stress or glutathione homeostasis.…”

Metabolic effect of alkaline additives and guanosine/gluconate in storage solutions for red blood cells

“…; extensively described in previous reports) allows the determination of metabolic reprogramming of RBCs stored in different additives. The underlying rationale for this approach is that biochemical constraints of enzymatic reactions result in strong and significant positive/negative correlations across metabolites in the same pathways, unless the activity of one enzyme in the cascade is up/down regulated by modulatory events (e.g., inactivating oxidation of active site cysteine of glyceraldehyde 3‐phosphate dehydrogenase is observed during RBC storage) . Metabolite levels in SAGM RBCs were correlated to each other, prior to repeating a similar correlation analysis across all additives while maintaining the order of metabolites of original elaborations in SAGM (Fig.…”