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

Giuseppe Paglia, Angelo D'Alessandro, Óttar Rolfsson, Ólafur E. Sigurjónsson, Aarash Bordbar, Sirus Palsson, Travis Nemkov, Kirk C. Hansen, Sveinn Gudmundsson and Bernhard O. Palsson

Key points

  • Eight extracellular biomarkers define the metabolic age of stored red blood cells.

  • Metabolomics defines a universal signature of red blood cell storage lesion.


Metabolomic investigations of packed red blood cells (RBCs) stored under refrigerated conditions in saline adenine glucose mannitol (SAGM) additives have revealed the presence of three distinct metabolic phases, occurring on days 0-10, 10-18, and after day 18 of storage. Here we used receiving operating characteristics curve analysis to identify biomarkers that can differentiate between the three metabolic states. We first recruited 24 donors and we analyzed 308 samples coming from RBC concentrates stored in SAGM and additive solution 3 (AS3). We found that eight extra-cellular compounds (lactic acid, nicotinamide, 5-oxoproline, xanthine, hypoxanthine, glucose, malic acid, and adenine) form the basis for an accurate classification/regression model and are able to differentiate among the metabolic phases. This model was then validated by analyzing additional 49 samples obtained by preparing 7 new RBC concentrates in SAGM. Despite the technical variability associated with RBC processing strategies, verification of these markers was independently confirmed in two separate laboratories with different analytical setups and different sample sets. The eight compounds proposed here highly correlate with the metabolic age of packed RBCs, and can be prospectively validated as biomarkers of the RBC metabolic lesion.

  • Submitted June 9, 2016.
  • Accepted August 12, 2016.