ALBERT

Description: Transfusion of red blood cells (RBCs) is associated with excess mortality and morbidity in some anemic patients with critical illness, and no benefit in others, but the underlying mechanisms are poorly understood. Specifically, little is known of how “storage lesions” of the RBC may contribute to adverse outcomes or lack of benefit from a transfusion. The recent discovery of an active role of the human RBC in regulating blood flow – a major determinant of its own function, O2 delivery – prompts a reexamination of storage-induced changes in this and related RBC functions, and motivates specific identification of the relevant mediators. RBCs release the vasodilators S-nitrosothiols (SNOs) and ATP upon physiological exposure to hypoxia, contributing to O2-dependent blood flow regulation. The result is hypoxic vasodilation peripherally and modulation of hypoxic vasoconstriction in the lung. We show that conventionally stored human RBCs become deficient in SNOs within three hours of acquisition and independent of exposure to storage solution or leukofiltration; both hemoglobin-bound SNO and membrane SNO are depressed. Early changes (hours) are also seen in the function of stored RBCs, namely in RBC regulation of vascular tone in vitro and in the lungs of intact mice in vivo, whereas declines in RBC deformability take place more gradually (from days to weeks). We also confirm storage-induced depletion of RBC ATP, a lesion which may contribute to the functional declines in both deformability and in RBC-dependent vasoactivity. Time courses, therefore, vary widely for several storage-induced functional and biochemical defects that may contribute to adverse clinical outcomes following RBC transfusion. Strategies that either prevent the loss of vasoactive mediators during RBC storage, or replete bioactive (S)NO after RBC storage, are reviewed and may inform the rational design of strategies to improve the risk-benefit balance associated with RBC transfusion in critically ill and other anemic patients.