Stored red blood cell transfusions: Iron, inflammation, immunity, and infection
The potential adverse effects of transfusion of red blood cells after prolonged storage have been hotly debated. During refrigerated storage, red blood cells are damaged, a process known as the red blood cell "storage lesion." We hypothesized that the delivery of a bolus of iron derived from these rapidly cleared, damaged, red blood cells is responsible for some of the adverse effects of transfusion. Iron may play a role in producing a pro-inflammatory response to transfused red blood cells, potentially through the effects of reactive oxygen species on stress pathways and inflammasome activation. Furthermore, the excess iron may impair the host's ability to combat infection by its innate iron-withholding pathways. This symposium paper summarizes the background for the "iron hypothesis" as it relates to transfusion of red blood cells after prolonged refrigerated storage. It also includes a summary of the data from recent murine and human studies, and concludes with a discussion of several unresolved questions arising from these published studies.
[Show abstract] [Hide abstract] ABSTRACT: Background: Sepsis is a major health care problem, with a significant mortality rate in intensive care units. We evaluated biochemical and inflammatory markers in patients with severe sepsis and septic shock and its association of with mortality rates. Methods: Critically ill patients with diagnoses of sepsis - severe sepsis group (n=23) and septic shock group (n=25), and a control group (n=17) were recruited within 24h of entry into the ICU. Serum levels of inflammatory mediators were measured (IL-1β, IL-6, IL-8, IL-10, TNF-α, IL-18 and nitric oxide). We have also collected clinical parameters and laboratorial tests to estimate severity and organ dysfunction (APACHE II, SOFA, lactate). These results were compared between survivors and no survivors. Results: IL-18 was directly related to mortality independently of other inflammatory mediators, especially IL-1β, although the inflammatory pathway is closely linked to inflammassome activation and both have simultaneous release in the infectious process. Mortality was directly proportional to IL-18 plasma levels, which did not occur with other inflammatory mediators. Conclusions: IL-18 is an important predictor of mortality in humans with both severe sepsis and septic shock, independent of IL-1β.
- "The sepsis/septic shock diagnosis was performed according to the American College of Chest Physicians/Society for Critical Care Medicine Consensus Conference definitions . We have excluded patients with hyperuricemia, confirmed or under investigation of cancer, ongoing chemotherapy or submitted to treatment in the last year, receiving blood transfusion in the last 5 days, presence of acute coronary events such as acute myocardial infarction in the last year, catheterization in the last 6 months, heart surgery in the last year and with a HIV positive test   . "
[Show abstract] [Hide abstract] ABSTRACT: Numerous retrospective clinical studies suggest that transfusion of longer-stored red blood cells (RBCs) is associated with an independent risk for poorer outcomes for certain groups of patients, including trauma, intensive care and cardiac surgery patients. Large multi-center randomized controlled trials (RCTs) are currently underway to address the concern about RBC storage duration. However, none of these RCTs focus specifically on trauma patients with hemorrhage. Major trauma, particularly due to road accidents, is the leading cause of critical injury in the under 40 year-old age group. Severe bleeding associated with major trauma induces hemodynamic dysregulation that increases the risk of hypoxia, coagulopathy and potentially multi-organ failure, which can be fatal. In major trauma, a multitude of stress-associated changes occur to the patient’s RBCs, including morphological changes that increase cell rigidity and thereby alter blood flow hemodynamics, particularly in the microvascular vessels, and reduce RBC survival. Initial inflammatory responses induce deleterious cellular interactions, including endothelial activation, RBC adhesion and erythrophagocytosis that are quickly followed by profound immunosuppressive responses. Stored RBCs exhibit similar biophysical characteristics to those of trauma-stressed RBCs. Whether or not transfusion of RBCs that exhibit storage lesion changes exacerbates the hemodynamic perturbations already active in the trauma patient is not known. This paper reviews findings from several recent non-randomized studies examining RBC storage duration and clinical outcomes in trauma patients. The rationale for further research on RBC storage duration in the trauma setting is provided.
- "Phagocytosis of large numbers of damaged RBCs is conjectured to result in immunological disturbance due to an inflammatory response provoked by iron‐hemoglobin. The proposed immune disturbance is initially inflammatory followed by a predominantly immunosuppressive response  . Furthermore, laboratory and animal studies suggest that damage signals displayed by RBCs in combination with activation of the endothelium lead to RBC‐ endothelial adhesion along with altered leukocyte and platelet interac- tions697071727374. "
[Show abstract] [Hide abstract] ABSTRACT: Alloimmunization is an undesirable iatrogenic effect of transfusion and transplantation. In fact, recipients can be considered as responders or not responders, in a continuum from tolerance, including organ transplantation and transfusion, to polyimmunized and refractory patients. New models and large studies have enabled a better understanding of the mechanisms that induce specific alloantibody (alloAb) generation. Here, we focus on risk factors of alloimmunization. We review the alloantibody characteristics, summarize the different leukocytes involved in their induction, and suggest some hypotheses.
- "The role of iron in creating inflammatory conditions in stored RBCCs is still disputed. Iron-mediated inflammatory conditions have been proven , and iron is released during storage, but aged (versus fresh) RBCCs do not seem to enhance alloimmunization in large-scale studies . Recently it has been suggested that the collection and preparation mode of RBCCs could affect the proinflammatory status of the RBCC or the single donor apheresis platelet component in ex vivo experiments. "