Hitchhiker’s guide to the red blood cell storage lesion

Transfusions of red blood cells are therapeutically important in acute and chronic conditions (e.g., trauma and sickle cell disease, respectively). Indeed, they represent the most common therapeutic intervention in hospitalised patients¹. For example, in the United States of America, ~11 million units of RBCs are transfused annually into ~5 million recipients, meaning that one out of every ~65 Americans receives a transfusion every year.

However, to be of practical usefulness, some sort of method is required to store the red blood cells so that they are available when needed. Thus, although some exceptions exist, such as the “walking blood banks” in military settings, the most common approach is to store red blood cell units under refrigerated conditions. For example, in most countries, using modern storage solutions (e.g., AS-3 in the United States and saline-adenine-glucose-mannitol [SAGM] in Europe), refrigerated red blood cell units can now be stored for up to 42 days before use.

Nonetheless, refrigerated storage leads to multiple metabolic, biochemical, and structural alterations of donor red blood cells, which, collectively, are termed the “red blood cell storage lesion.” In addition, it is not completely clear which elements in the long list of these findings are causative, which are consequences, and which are merely coincidental. Because various “trigger trials” suggest that restrictive red blood cell transfusion practices lead to better patient outcomes, as compared to liberal ones², and because the (controversial) suggestion that longer stored red blood cell products may lead to worse patient outcomes³, there has been an explosion of studies of the storage lesion, its causes, the underlying mechanisms, methods to ameliorate it, and its potential clinical consequences. In particular, it remains controversial whether red blood cells that are transfused at or near their outdate lead to adverse patients outcomes; that is, “is old blood bad?” For example, the results of several randomised prospective trials suggest that there are no problems^4,5 and some authors believe that the case is closed⁶; however, some investigators still believe that more work, and more mechanistically-oriented trials, remain to be completed before this issue it put to rest one way or the other^7–9. Nonetheless, it is not controversial that refrigerated storage produces the multiple aspects of the red blood cell storage lesion, and that 24-hour post-transfusion recovery decreases in proportion to the length of the storage interval; thus, as the storage interval lengthens, less and less of a fully functional dose of red blood cells is actually transfused into recipients. Therefore, research focused on continuing to improve storage conditions remains clinically and practically important.

The contribution by Yoshida, Prudent, and D’Alessandro in this issue¹⁰ aims to summarise a vast amount of literature on the red blood cell storage lesion into one, heuristically helpful, figure. One of us (SLS) first glimpsed the initial sketches of this figure, in “samizdat” form, at a National Heart, Lung, and Blood Institute meeting in Bethesda in 2011¹¹, more than 7 years ago. Based on those initial views, the current publication, containing an updated version of that initial figure, along with the accompanying text and references, was eagerly awaited since that time, and it does not disappoint. In addition, the lengthy time interval between then and now actually turned out to be beneficial because so much data and so many publications have accumulated since that time. This research was stimulated, for example, by meetings convened at the National Institutes of Health¹² and other venues, and targeted funding by the National Institutes of Health and others, including the Recipient Epidemiology and Donor Evaluation Study (REDS)-III program, papers from which are now appearing¹³.

The main figure in the paper by Yoshida et al. encapsulates a great deal of data and information in a coherent and visually compelling fashion. As such, it is a useful tool for importing new data and new studies into an existing heuristic context. The central conceit for the ideas described in this figure is the contention that the major causes (i.e., the “prime movers”) of the red blood cell storage lesion include a combination of oxidative stress (primarily derived from haemoglobin autoxidation in the high oxygen environment in the refrigerated storage bag) and metabolic dysfunction (primarily derived from the need to continue to generate ATP by glycolysis). The authors then directly connected this molecular context to cellular effects (focusing on the red blood cells), then connected these to organismal, physiological effects, and then these, in turn, to clinical, disease-related outcomes. Importantly, the figure is lavishly referenced with each topic and each arrow supported by at least one data-driven publication. This approach allows the reader to put the existing knowledge into its appropriate context and gives one a bird’s-eye view of this important topic.

Nonetheless, this central figure, along with the supporting information, can also be “hypothesis generating” in terms of how other factors or interventions could affect the specific processes that are illustrated. For example, this approach has stimulated our own thought processes regarding how and whether specific genetic variations (e.g., G6PD deficiency¹⁴), dietary interventions (e.g., iron deficiency¹⁵ and fish oil supplementation¹⁶), and environmental exposures (e.g., lead intoxication¹⁷, smoking¹⁸), could positively or negatively affect specific elements in this diagram. Not surprisingly, it has also stimulated the thought processes of the three authors (i.e., Drs. Yoshida, Prudent, and D’Alessandro), particularly regarding the role of dissolved oxygen in causing the oxidative stress that initiates and exacerbates the storage lesion and the potential benefits of storing red blood cells under hypoxic conditions¹⁹, and whether particular metabolites are not only mechanistically important, but can also potentially serve as surrogate biomarkers of red blood cell storage quality²⁰.

Taken together, we believe that these authors have done a great service to the field in summarising the existing data, along with pointing the way to future studies that will help develop new approaches to improve the science and practice of transfusion medicine.