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Fresh blood or old blood? How shall we manage the inventories?

T he morphologic and functional changes that red blood cells (RBCs) undergo as they age, both during in vivo circulation and during refrigerated storage in nutrient anticoagulant solutions, have been recognized for a long time. Studies in the 1940s and 1950s, for example, showed that older cells lose their biconcave disc shape and their enzyme activity, particularly in glycolytic pathways, is reduced. Whether the changes in stored cells persist after transfusion also attracted attention. In this regard, the reduction in enzyme concentrations appears to be reversible, since there is evidence that 2,3-disphosphoglycerate (2,3-DPG) is restored in transfused cells thereby reversing the abnormal shift of the oxygen dissociation curve that is a feature of stored blood. While the return of intraerythrocytic 2,3-DPG levels to normal occurs within hours after transfusion, other changes were shown to take longer. For example, while the decreased performance of the RBC sodium-potassium pump is repaired after transfusion, the return to normal intraerythrocytic electrolyte concentrations takes several days. The possibility that restoration of some features of the RBC internal milieu might influence posttransfusion survival was also raised during the earlier studies. Investigators from the University of Washington Medical School and what was then the King County Central Blood Bank in Seattle studied the in vivo fate of RBCs, which were transfused after a period of refrigerated storage in anticoagulant solutions. They observed that changes during storage, particularly with regard to carbohydrate metabolism and adenosine triphosphate concentration, were not the same as changes during the natural senescence of the RBCs. They coined the term “storage lesion” and went on to show in animal and human studies using blood stored in ACD that metabolic failure in stored RBCs was not permanent. They concluded, “The biochemical storage lesion of the erythrocyte has been shown to be rapidly reversible, once the erythrocyte is introduced into active circulation.” Follow-up studies examining if such a bold conclusion was justified are limited. Subsequently, interest in the in vivo, posttransfusion, performance of RBCs has taken a number of different directions. For example, appreciation for the dissimilarities between older and younger RBCs prompted studies at the National Institutes of Health (NIH) exploring the likelihood that younger cells would survive longer after transfusion, thereby increasing the transfusion interval in chronically transfusion-dependent patients and reducing their risk for iron overload. While clinical benefit proved elusive, the investigators showed that “neocytes,” harvested during continuous flow centrifugation, enjoyed a posttransfusion mean half-life that was significantly longer than that of older cells (which, out of deference to the NIH team’s terminology, this editorialist will in future refer to as “paleocytes”). Posttransfusion survival is also a central licensing issue, since the Food and Drug Administration stipulates RBC recovery standards when the agency evaluates new products in categories such as additive solutions, apheresis equipment, and pathogen reduction processes. The specialized methods available to confidently follow the fate of transfused RBCs are, however, limited to a few laboratories with experience in techniques such as radiolabeling and differential agglutination. It is not surprising, then, given the relative convenience of sampling aliquots of stored RBCs over time, that more attention has been devoted to identifying in vitro changes as a basis from which to predict in vivo survival, rather than following in vivo survival of a small cohort of transfused cells. During the course of the in vitro studies, a broad array of morphologic and biochemical changes has been demonstrated. A recent mini-symposium in TRANSFUSION added to the accumulating evidence for abnormalities in stored RBCs. For example, nitric oxide homeostasis is abnormal, and there is a risk for both complement activation and release of RBC-derived microparticles. Against the background of accumulating awareness of the broad extent of the storage lesion, questions continue to be raised about the functionality of RBCs used for transfusion. In partial answer, many retrospective studies have concluded that blood transfusion, particularly with older units, puts patients at an increased risk for complications. Despite most of the evidence weighing on the side of older units increasing the likelihood of adverse events, some critics have reservations about premature conclusions from observational studies on patients who, despite sharing similar diagnoses, were not consistently compared to untransfused controls. Furthermore, they point out that transfusion policies were not always identical during the periods under review. The limitations to drawing firm conclusions prompted the author of a recent, rigorous meta-analysis to suggest that the issue is at “equipoise.” Opinion is, however, not at equipoise, as evidenced by the emphatic opinion of the authors of another meta-analysis that “older stored blood is associated with significantly increased risk of death.” TRANSFUSION 2013;53:3032-3035.