Red blood cell storage lesion and adverse clinical outcomes: post hoc ergo propter hoc?

Since the beginning of modern transfusion therapy, remarkable efforts have been done to provide a safe and adequate blood supply. Blood banks adopt storage procedures to ensure this blood supply and red blood cell (RBC) units are, nowadays, stored up to 42 days in most of developed nations. Length of storage of red blood cell units is based on the decision that they can be stored as long as the average hemolysis is below 0.8% and the proportion of red blood cells still alive 24 hours post-transfusion is higher than 75%1. Changes in RBC properties during storage have been known for decades, but the exact significance of these changes is still largely uncertain2. Researchers have carefully documented what storage does to red blood cells. It is well established that, when stored, red blood cells undergo several changes referred to as “storage lesion”, the latter being potentially able to irreversibly alter RBC biological functions, including reduced deformability and increased osmotic fragility and a significant decline in adenosine triphosphate and 2,3- diphosphoglycerate3. These changes decrease oxygen transporting capacity and result in more rigid cells impairing the RBC microcirculation1,4,5. Oxidative stress is a common feature of RBC storage lesions. It increases with prolonged storage resulting in lipid peroxidation, protein oxidation and reduced integrity of the erythrocyte membrane, all contributing to the formation of exocytic microvesicles (microparticles) and it has been postulated that these oxidative events occurring in stored RBCs may be correlated with the risk of post-transfusion complication6. It is largely unknown how these storage lesions affect function and survival of RBCs in the circulation after transfusion, but most of these alterations occur in vivo, “allowing one to speculate that storage causes an acceleration of the normal RBC aging process”6. It remains to be determined whether these changes translate into functional perturbations in the transfusion recipient7. Glynn conjectured two mechanisms to explain these potential detrimental outcomes8. One hypothesis proposes that the RBC storage lesions in stored blood components cause immunomodulatory and inflammatory complications in transfusion recipients including changes in vasoregulation. The second hypothesis proposes that susceptibility factors predispose certain patient populations to the clinical-pathologic side effects of older RBC transfusion. Since the publication in 2008 of a retrospective analysis by Koch et al.9 reporting that subjects transfused with red blood cell units stored for longer than 14 days, were more likely to die in the hospital, there has been an intense debate about the topic whether transfusion of older blood is as beneficial as transfusion of fresher blood. Several studies have found suggestive evidence of various adverse consequences after transfusion of older blood such as an increase in length of hospital stay, postoperative infections, prolonged mechanical ventilation, multiple organ failure and mortality10,11. Nevertheless, recently published meta-analyses and reviews indicate that there are many studies that do not report such association between RBC storage age and adverse clinical outcomes11,12,13,14. Yet, it is not currently known if clinical outcomes are affected by the age of transfused blood and uncertainty remains regarding the clinical importance of RBC storage duration and when “new” blood becomes “old” blood. If a causal link exists between duration of RBC storage and morbidity/mortality, it would appear that the most practical solution is younger blood15. But a shortened RBC storage time would have a major impact on the blood stock, thus representing a major public health matter. The shift toward usage of fresher blood would further worsen the precarious balance between the supply from donors and the growing demand, reducing blood inventories and creating significant blood shortages. Blood banks would need to ensure a supply of fresher blood and/or evaluate alternative storage strategies to prevent the development of storage lesions5,8. On the other hand, erroneously concluding that blood storage duration is causally related to increased morbidity and mortality would severely impact blood availability without improving patient care. The editorial by Glynn emphasizes the situation by stating that, despite numerous publications, there is “genuine uncertainty as to whether transfusing fresher blood is more, less, or equally beneficial as transfusion of older blood”8. Indeed, “many of the studies are observational in nature and suffer from lack of adjustment, a small sample size, and/or the inability to generalize results”8 and, as a consequence, it is extremely difficult to interpret existing data. So, current data are inadequate to determine if transfusion of older units of blood is associated with either short- or long-term adverse outcomes. Four large randomized clinical trials related to the age of transfused blood are underway in North America. The Canadian Institutes of Health Research is funding two trials: i) the Age of Blood Evaluation (ABLE) Study16 which has as primary endpoint 90-day all-cause mortality in patients transfused either less than 8-day RBCs or standard RBCs (2–42 days) and ii) the Age of Red Blood Cells in Premature Infants (ARIPI) Study17 with primary endpoint being 90-day measure of all-cause mortality in premature infants randomized to receive either less than 8-day or 2-42-day RBC aliquots. The Cleveland Clinic is conducting the Red Cell Storage and Outcomes in Cardiac Surgery Trial18 in which 18 years old individuals are randomized to receive blood transfusion with storage duration less than 14 days or greater than 20 days. The National Heart, Lung, and Blood Institute (NHLBI) is also sponsoring the Red Cell Storage and Duration Study (RECESS)19 in which individuals 12 years or older undergoing complex cardiac surgery are randomized to receive RBC units that have been stored for 10 days or less or RBC units stored for 21 days or more. These clinical trials are expected to be the key to our understanding of whether the RBC storage lesion produces clinically important consequences or not. Although results will not be available for a few years, a systematic and rigorous approach of randomized controlled trials together with “omics” and biochemical research in transfusion medicine will hopefully lead to a better understanding of the RBC storage lesion as well as to the development of strategies to correct or mitigate storage changes.