During storage, RBCs undergo a series of biological and biochemical changes collectively referred to as "the storage lesion" [57] . This includes intracellular changes (progressive depletion of 2,3-diphosphoglycerate [2,3-DPG] with increased affinity of hemoglobin for oxygen, depletion of ATP), membrane changes (membrane vesiculation, morphological changes eventually leading to irreversibly deformed spheroechinocytes, lipid peroxidation and increased expression of phosphatidylserine, decreased deformability), and changes in the storage medium (decreased pH, increased potassium, release of proinflammatory cytokines). These stored RBCs also have an increased tendency to adhere to endothelium and could promote vasoconstriction; the stored RBCs act as a "sink" for nitric oxide [58] . Some animal studies [13] have shown deleterious effects of old RBCs on the microcirculation (potentially leading to tissue hypoxia and organ dysfunction). A human study found an inverse correlation between the age of transfused RBCs and maximal change in gastric mucosal pH, but these findings were challenged in subsequent studies [59] [60] [61] .