Impact of Genetic Predispositions, Diet, and Environment on Storage of Red Blood Cells

It remains controversial whether or not transfusions of human red blood cells (RBCs), which have been refrigerator-stored for extended time intervals, induce or exacerbate clinically-relevant adverse effects in recipients. The described effects include infection, inflammation, renal dysfunction, thrombosis, and even death. It is also controversial whether such effects are seen in particular patient populations predisposed to these types of complications, or whether they are universal. To this end, multiple bench research studies, clinical/translational studies, and prospective randomized controlled trials are currently investigating these issues. What is not controversial is that refrigerated storage produces the "RBC storage lesion" and that this worsens in proportion to increasing storage time, such that, at the FDA-mandated 42-day outdate, on average, only 75% of transfused donor RBCs are still circulating in the recipient at 24-hours post-transfusion. It is also not controversial that RBCs obtained from some healthy volunteer donors do not store well and, at outdate, have a 24-hour post-transfusion recovery (PTR) of significantly less than 75% (i.e., "poor storers"). Analogously, RBCs from some donors store extremely well and may exhibit virtually 100% 24-hour PTR at outdate (i.e., "super storers"). Understanding the underlying mechanisms for these phenomena would allow implementation of various approaches to improve the blood supply, with an ultimate goal of virtually 100% 24-hour PTR and normal long-term circulatory lifespan of transfused RBCs. This goal is especially relevant in the chronic transfusion setting (e.g., patients with sickle cell anemia or beta-thalassemia). Similar observations have been made about hemolysis ex vivo (i.e., "in the bag") during refrigerated storage, which influences the amount of free hemoglobin infused during the transfusion procedure. There is also evidence that these RBC storage characteristics are stable in "poor" and "super" donors, suggesting that genetic, dietary, and/or environmental factors are involved. Indeed, using inbred strains of mice, there is clear evidence that genetic and dietary factors can significantly influence donor RBC storage quality, when measured as 24-hour PTR and/or ex vivo hemolysis. In addition, human genetic polymorphisms, particularly in racial/ethnic groups enriched for malaria-induced traits, result in abnormal expression or abnormal function of various RBC proteins, including hemoglobin and cytosolic enzymes, such as glucose-6-phosphate dehydrogenase. There is increasing evidence that these polymorphisms can influence the ability of human RBCs to tolerate standard conditions of refrigerated storage. Harnessing this information will result in new methods for improving the quality of the blood supply and, consequently, improving patient responses to transfusion therapy.