New Insights in the Potential Effect of Transfusing Red Blood Cells that Have Been Stored for Different Periods

Red Blood Cells (RBCs) units which can be stored for up to 42 days in the US undergo biochemical and morphological changes known as the storage lesion. The clinical significance of these changes is unclear. Results from >55 observational studies have produced conflicting results: some are negative while others report associations between transfusion of longer-stored RBCs and mortality, infections, lung injury,  deep vein thrombosis, multiple organ failure, and a decrease in tissue oxygenation. Recent advances are shedding some light on this controversy. While some elements of the RBC storage lesion such as pH and cationic changes and decreases in adenosine triphosphate and 2,3-diphosphoglycerate are well known, the recent application of “omics” technologies is revealing complex changes in metabolites, proteins, and lipids during storage. RBCs storage causes dysregulations in several metabolic (e.g., glycolytic) pathways which vary with unit processing, additive solution, storage period, and blood donor characteristics. Longer-stored RBCs demonstrate decreased antioxidant activity and impaired energy metabolism. Kinases and proteolytic enzymes become activated which affect Band 3 and structural proteins and result in remodeling of the RBCs’ cytoskeleton; leading to increasing osmotic fragility and shedding of microparticles in the supernatant. The timing and extent of these changes need to be further elucidated; some appear to occur immediately (e.g., reduction in S-nitrosohemoglobin) while most appear after 2 weeks.  These changes lead one to question the safety and efficacy profiles of longer-stored RBC transfusions.  Animal models have recently evaluated potential consequences and possible mechanisms that could underlie adverse events in “susceptible” hosts. Two major hypotheses have been corroborated by animal studies. The first relates to the potential inhibition of Nitric Oxide (NO)-mediated vasodilatory effects as a result of NO scavenging by excess cell-free hemoglobin or because of a loss of RBC-mediated hypoxic vasodilation. The second is based on the fact that transfusion of a 42-day old RBC unit provides a large iron bolus to the mononuclear phagocyte system. Such a bolus can result in acute increases in non-transferrin bound iron (NTBI) which can cause oxidative damage and potentiate bacteria proliferation. Both the NO and Iron hypotheses appear at play in a study in septic canines that showed that transfusion of 42-day RBCs resulted in increases in cell free hemoglobin, NTBI, and plasma labile iron resulting in increased shock, lung injury, and mortality. However, two recent clinical trials in 377 premature infants and 2430 intensive care patients, respectively, did not demonstrate differences in outcomes following transfusion of <7 days vs 2-42 days RBCs.  Another trial randomized 1098 complex cardiac surgery patients to ≤10 days or ≥ 21 days RBCs. No significant clinical differences were observed.  These trials are reassuring because shorter-stored RBCs do not appear to have a better safety profile than standard-issue RBCs. Additional clinical trials are underway to test similar hypotheses. However, it is unlikely that these studies will have the power to evaluate transfusions of ≥35 day-old RBCs (when the storage lesion is at its maximum) or the effect of older-stored blood in rarer populations such as highly transfused septic patients. Additional research to minimize the RBC storage lesion and develop biomarkers of RBC transfusion effectiveness is warranted.  Investigations of the impact on blood availability of limiting RBC storage to 35 days should also be considered.