Jeanne E. Hendrickson

Transfusion of red blood cells after prolonged storage produces harmful effects that are mediated by iron and inflammation

Although red blood cell (RBC) transfusions can be lifesaving, they are not without risk. In critically ill patients, RBC transfusions are associated with increased morbidity and mortality, which may increase with prolonged RBC storage before transfusion. The mechanisms responsible remain unknown. We hypothesized that acute clearance of a subset of damaged, stored RBCs delivers large amounts of iron to the monocyte/macrophage system, inducing inflammation. To test this in a well-controlled setting, we used a murine RBC storage and transfusion model to show that the transfusion of stored RBCs, or washed stored RBCs, increases plasma nontransferrin bound iron (NTBI), produces acute tissue iron deposition, and initiates inflammation. In contrast, the transfusion of fresh RBCs, or the infusion of stored RBC-derived supernatant, ghosts, or stroma-free lysate, does not produce these effects. Furthermore, the insult induced by transfusion of stored RBC synergizes with subclinical endotoxinemia producing clinically overt signs and symptoms. The increased plasma NTBI also enhances bacterial growth in vitro. Taken together, these results suggest that, in a mouse model, the cellular component of leukoreduced, stored RBC units contributes to the harmful effects of RBC transfusion that occur after prolonged storage. Nonetheless, these findings must be confirmed by prospective human studies.

Noninfectious serious hazards of transfusion.

As infectious complications from blood transfusion have decreased because of improved donor questionnaires and sophisticated infectious disease blood screening, noninfectious serious hazards of transfusion (NISHOTs) have emerged as the most common complications of transfusion. The category of NISHOTs is very broad, including everything from well-described and categorized transfusion reactions (hemolytic, febrile, septic, and allergic/urticarial/anaphylactic) to lesser known complications. These include mistransfusion, transfusion-related acute lung injury, transfusion-associated circulatory overload, posttransfusion purpura, transfusion-associated graft versus host disease, microchimerism, transfusion-related immunomodulation, alloimmunization, metabolic derangements, coagulopathic complications of massive transfusion, complications from red cell storage lesions, complications from over or undertransfusion, and iron overload. In recent years, NISHOTs have attracted more attention than ever before, both in the lay press and in the scientific community. As the list of potential complications from blood transfusion grows, investigators have focused on the morbidity and mortality of liberal versus restrictive red blood cell transfusion, as well as the potential dangers of transfusing “older” versus “younger” blood. In this article, we review NISHOTs, focusing on the most recent concerns and literature.

Recipient inflammation affects the frequency and magnitude of immunization to transfused red blood cells.

BACKGROUND: Most alloantigens on transfused red blood cells (RBCs) are weakly immunogenic, with only a 2 to 6 percent overall immunization rate even in patients receiving multiple transfusions. Although recipient genetics may contribute to responder and/or nonresponder status, in most cases HLA type does not predict humoral response to RBC antigens. In contrast, rates of alloimmunization do correspond to the underlying disease status of transfusion recipients, suggesting that acquired host factors may play an important role. In this context, it was hypothesized that the inflammatory status of a transfusion recipient would influence immunization to transfused RBCs.

Initiation and Regulation of Complement during Hemolytic Transfusion Reactions

Hemolytic transfusion reactions represent one of the most common causes of transfusion-related mortality. Although many factors influence hemolytic transfusion reactions, complement activation represents one of the most common features associated with fatality. In this paper we will focus on the role of complement in initiating and regulating hemolytic transfusion reactions and will discuss potential strategies aimed at mitigating or favorably modulating complement during incompatible red blood cell transfusions.

A novel mouse model of red blood cell storage and posttransfusion in vivo survival

BACKGROUND: Storage of red blood cells (RBCs) is necessary for an adequate blood supply. However, reports have identified potential negative sequelae of transfusing stored RBCs. An animal model would be useful to investigate the pathophysiology of transfusing stored RBCs. However, it has been reported that storage of rat RBCs in CPDA‐1 resulted in an unexpected sudden decline in posttransfusion survival. A mouse model of RBC storage and transfusion was developed to assess survival kinetics of mouse RBCs.

Implementation of a pediatric trauma massive transfusion protocol: one institution's experience.

BACKGROUND: Massive transfusion protocols (MTPs) with fixed ratios of blood products may improve outcomes in coagulopathic adult trauma patients. However, there is a paucity of data on transfusion support protocols for pediatric trauma patients, whose mechanisms of injury may differ from those seen in adults. We hypothesized that an MTP would improve outcomes in children, through a balanced blood product resuscitation.

Coagulopathy is prevalent and associated with adverse outcomes in transfused pediatric trauma patients.

OBJECTIVE To evaluate coagulopathy in pediatric trauma patients on presentation to the emergency department, and to quantify the relationship with mortality. STUDY DESIGN Pediatric trauma patients requiring a blood transfusion (red blood cells, fresh frozen plasma, platelets, or cryoprecipitate) within 24 hours of arrival were included. Coagulation values on emergency department arrival were analyzed, as were clinical details and outcome. RESULTS A total of 102 children (mean age, 6 years; mean injury severity score 22, mean Glascow Coma Scale 7, 80% blunt trauma victims) were studied over a 4 year period. An abnormal prothrombin time was found in 72%, partial thromboplastin time in 38%, fibrinogen in 52%, hemoglobin in 58%, and platelet count in 23%. An abnormal prothrombin time, partial thromboplastin time, and platelet count were strongly associated with mortality (P=.005, .001, and <.0001, respectively) and remained significantly associated in multivariate analysis after adjusting for injury severity score. CONCLUSIONS Coagulopathy is prevalent in pediatric trauma patients ill enough to require a transfusion and is strongly associated with mortality. Studies are needed to determine whether early coagulation factor replacement and the institution of massive transfusion protocols may improve outcomes in these patients.

The role of inflammation in alloimmunization to antigens on transfused red blood cells

Purpose of reviewTo discuss how inflammation affects humoral alloimmunization to antigens on transfused red blood cells (RBCs). Recent findingsRecently, three unique murine models of humoral alloimmunization to transfused RBCs have been described. As in humans, RBC alloimmunization rates in recipient mice are variable, with segregation into responder and nonresponder groups. Because the recipient mice are genetically identical, environmental factors may play a role in regulating alloimmunization. These models have further been used to demonstrate that recipient inflammation has a complex regulatory effect upon alloimmunization. Isolated case reports in humans raise the possibility of a similar role of inflammation in regulating alloimmunization to RBCs. SummaryIt is currently unknown why some human transfusion recipients mount strong alloantibody responses, whereas others do not. Human leukocyte antigen immunogenetics likely play a substantial role. However, within groups with the genetic capacity to respond to a given RBC antigen, recipients still segregate into responders and nonresponders. The data reviewed herein indicate that recipient inflammation in mice has the capacity to regulate alloimmunization. Future studies will be required to further understand these effects and to investigate if similar biology regulates alloimmunization to transfused RBCs in humans.

Strain-specific red blood cell storage, metabolism, and eicosanoid generation in a mouse model

Red blood cell (RBC) transfusion is a lifesaving therapy, the logistic implementation of which requires RBC storage. However, stored RBCs exhibit substantial donor variability in multiple characteristics, including hemolysis in vitro and RBC recovery in vivo. The basis of donor variability is poorly understood.

Storage of murine red blood cells enhances alloantibody responses to an erythroid-specific model antigen

BACKGROUND: Red blood cell (RBC) alloimmunization can be a serious complication of blood transfusion, but factors influencing the development of alloantibodies are only partially understood. Within FDA‐approved time limits, RBCs are generally transfused without regard to length of storage. However, recent studies have raised concerns that RBCs stored for more than 14 days have altered biologic properties that may affect medical outcomes. To test the hypothesis that storage time alters RBC immunogenicity, we utilized a murine model of RBC storage and alloimmunization.