Transfusion-related red blood cell alloantibodies: induction and consequences.

Blood transfusion is the most common procedure completed during a given hospitalization in the United States. Although often life-saving, transfusions are not risk-free. One sequela that occurs in a subset of red blood cell (RBC) transfusion recipients is the development of alloantibodies. It is estimated that only 30% of induced RBC alloantibodies are detected, given alloantibody induction and evanescence patterns, missed opportunities for alloantibody detection, and record fragmentation. Alloantibodies may be clinically significant in future transfusion scenarios, potentially resulting in acute or delayed hemolytic transfusion reactions or in difficulty locating compatible RBC units for future transfusion. Alloantibodies can also be clinically significant in future pregnancies, potentially resulting in hemolytic disease of the fetus and newborn. A better understanding of factors that impact RBC alloantibody formation may allow general or targeted preventative strategies to be developed. Animal and human studies suggest that blood donor, blood product, and transfusion recipient variables potentially influence which transfusion recipients will become alloimmunized, with genetic as well as innate/adaptive immune factors also playing a role. At present, judicious transfusion of RBCs is the primary strategy invoked in alloimmunization prevention. Other mitigation strategies include matching RBC antigens of blood donors to those of transfusion recipients or providing immunomodulatory therapies prior to blood product exposure in select recipients with a history of life-threatening alloimmunization. Multidisciplinary collaborations between providers with expertise in transfusion medicine, hematology, oncology, transplantation, obstetrics, and immunology, among other areas, are needed to better understand RBC alloimmunization and refine preventative strategies.

Noninfectious transfusion-associated adverse events and their mitigation strategies.

Blood transfusions are life-saving therapies; however, they can result in adverse events that can be infectious or, more commonly, noninfectious. The most common noninfectious reactions include febrile nonhemolytic transfusion reactions, allergic transfusion reactions, transfusion-associated circulatory overload, transfusion-related acute lung injury, and acute and delayed hemolytic transfusion reactions. These reactions can be asymptomatic, mild, or potentially fatal. There are several new methodologies to diagnose, treat, and prevent these reactions. Hemovigilance systems for monitoring transfusion events have been developed and demonstrated decreases in some adverse events, such as hemolytic transfusion reactions. Now vein-to-vein databases are being created to study the interactions of the donor, product, and patient factors in the role of adverse outcomes. This article reviews the definition, pathophysiology, management, and mitigation strategies, including the role of the donor, product, and patient, of the most common noninfectious transfusion-associated adverse events. Prevention strategies, such as leukoreduction, plasma reduction, additive solutions, and patient blood management programs, are actively being used to enhance transfusion safety. Understanding the incidence, pathophysiology, and current management strategies will help to create innovative products and continually hone in on best transfusion practices that suit individualized patient needs.

Role of complement in alloimmunization and hyperhemolysis.

PURPOSE OF REVIEW: The purpose of this review is to summarize the role of complement in regulating the removal of a target alloantigen following an incompatible red blood cell (RBC) transfusion, the formation of alloantibodies following RBC alloantigen exposure, and the development of hyperhemolysis in patients with sickle cell disease (SCD). RECENT FINDINGS: Recent studies demonstrate that complement can accelerate alloantibody-mediated removal of target alloantigens from the RBC surface following incompatible transfusion. Complement also influences alloantigen availability during developing alloimmune responses and serves as a unique mediator of CD4 T-cell-independent alloantibody formation following RBC alloantigen exposure. Finally, alternative complement pathway activation appears to play a key role in the development of acute hemolytic episodes in patients with SCD, providing a potential druggable target to prevent acute complications in patients with this disease. SUMMARY: Recent studies suggest that complement can regulate a wide variety of processes germane to hematology, from transfusion complications to baseline hemolysis in patients with SCD. As the role of complement in various disease processes becomes more fully understood, the ability to leverage recently developed complement modulating drugs will only continue to enhance providers' ability to favorably intervene in many hematological diseases.

Fatal acute hemolytic transfusion reaction due to anti-B from a platelet apheresis unit stored in platelet additive solution.

BACKGROUND: Hemolytic transfusion reactions from out-of-group plasma in platelet (PLT) transfusions are uncommon, with most involving passive transfer of anti-A. Only rare reactions have ever been reported due to anti-B. STUDY DESIGN AND METHODS: An apheresis PLT product was donated by a blood group O male, processed using PLT additive solution, and pathogen reduced. Postreaction recipient testing included an antibody screen using gel technology, a direct antiglobulin test (DAT) using immunoglobulin G and C3, and an eluate against group O and B cells. Postreaction donor testing included measuring anti-B titers in saline, with and without anti-human globulin. RESULTS: A 60-year-old blood group B patient with relapsed acute myeloid leukemia developed confusion, fever, and hypotension within hours after a blood group O PLT transfusion. The posttransfusion reaction evaluation was remarkable for a positive DAT 3+ for C3; the eluate showed anti-B. Rapid extravascular hemolysis occurred, with a 50% decline in hemoglobin, a high lactate dehydrogenase, and a high bilirubin. She was resuscitated with fluids, blood products, pressors, and oxygen and died of asystole 60 hours later. The donor's anti-B titers were 128 by tube testing at immediate spin and 512 at the anti-human globulin phase. Notably, a group B patient at a different hospital received a split of the same apheresis unit, with no reaction. CONCLUSION: To our knowledge, this is the first fatality reported from passively transfused anti-B. The fact that one transfusion recipient died whereas another did not have any reported reaction highlights the potential importance of recipient variables in isohemagglutinin-mediated hemolysis.

Red blood cell alloimmunization and minor red blood cell antigen phenotypes in transfused Ghanaian patients with sickle cell disease.

BACKGROUND: The routine pretransfusion investigations in Southern Ghana involve only ABO-D blood group typing and ABO compatibility testing without screening for irregular red blood cell (RBC) antibodies. The prevalence and specificities of RBC antibodies and frequencies of most minor blood group antigens in transfused patients with sickle cell disease (SCD) in Ghana are not known and are the objectives of this study. STUDY DESIGN AND METHODS: This was a cross-sectional study that investigated transfused patients with SCD for the presence of irregular RBC antibodies and Rhesus, Kell, Duffy, Kidd, and Ss antigens. RESULTS: From a total of 154 patients (median age, 9 years), 10 patients (6.5%) possessed 13 antibodies, predominantly against D, C, and E antigens. In three patients, the antibodies (anti-D, anti-D + C, and anti-C + e) were against antigens they possessed by serology. Genotyping showed that two of these patients had variant RHCE genes that encode for weak and partial e antigens and one patient had a partial RHC gene. Frequencies of most RBC antigens were comparable with frequencies established among the African American population; however, K-k- and Jk(a-b-) phenotypes were more frequent and were present in 21% and 17% of patients, respectively. CONCLUSION: The prevalence of RBC alloimmunization in transfused Ghanaian patients with SCD was 6.5% and the majority of antibodies were against antigens of the Rh system. Our findings stress the need to include pretransfusion testing for RBC antibodies in patients with SCD, to improve transfusion safety.

Antibodies to human neutrophil antigen HNA-3b implicated in cases of neonatal alloimmune neutropenia.

BACKGROUND: Neonatal alloimmune neutropenia results from maternal alloimmunization to human neutrophil antigens. The alloantibodies involved in neonatal alloimmune neutropenia are against human neutrophil antigens HNA-1a, HNA-1b, HNA-1c, HNA-1d, HNA-2, HNA-3a, HNA-4a, HNA-4b, and HNA-5a; however, to date, antibodies specific to HNA-3b have not been reported. STUDY DESIGN AND METHODS: Blood samples from 10,000 unselected neonates were analyzed, resulting in the selection of 88 neutropenic newborns (neutrophil count <1.5 × 109 /L) from 83 mothers (three pairs of twins and one triplet). HNA-3 genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism to identify the cases of maternal-fetal HNA-3 incompatibility. Serologic studies for detecting maternal HNA-3 alloantibodies were performed with the granulocyte agglutination test, the white blood cell immunofluorescence test, and a LABScreen Multi-HNA Kit. RESULTS: Genotyping studies identified 13 of 88 (14.8%) instances of maternal-fetal HNA-3 incompatibility, with all mothers typed as HNA-3a/a and neonates typed as HNA-3a/b. Serologic studies revealed that five of 13 (38.5%) mothers carried anti-HNA-3b plus human leukocyte antigen antibodies and that three of 13 (23.1%) mothers had anti-HNA-3b without human leukocyte antigen antibodies. CONCLUSION: Here, we report the first three cases of neonatal alloimmune neutropenia associated with HNA-3b antibodies resulting in a neonatal alloimmune neutropenia incidence of one in 3333 live births.

Risks of red blood cell alloimmunization in transfusion-dependent ß-thalassemia in Oman: a 25-year experience of a university tertiary care reference center and a literature review.

BACKGROUND: ß-Thalassemia is a common hemoglobinopathy in the Arabian Peninsula. Red blood cell (RBC) transfusion is a cornerstone for its management, but can create significant challenges including RBC alloimmunization. Herein, we examine alloimmunization risk factors in Omani patients with transfusion-dependent ß-thalassemia. Existing literature is summarized. STUDY DESIGN AND METHODS: A retrospective review of all patients attending our center over 25 years was performed. Clinical and transfusion records were examined. Chi-square test was used to assess the association between the categorical variables. Nonparametric Mann-Whitney test was used to assess the association between transfusion and risk of alloimmunization. RESULTS: A total of 268 patients were identified (168 adults and 100 pediatrics), of whom 226 are alive (84.3%). Males accounted for 53.4%. The cohort had a median age of 22 years (range, 2-43 years). The most common blood group was O+ (39%). The prevalence of alloimmunization was 9.3% with anti-E (24%) and anti-K (24%) being the commonest antibodies identified. There was a significant association between age and alloimmunization, with 68% of alloimmunized patients in the age group of 19 to 30 years (p < 0.01). Among adults, there was a significant association between alloimmunization and number of units transfused (p = 0.001). There was no association between alloimmunization and sex or history of splenectomy. CONCLUSION: Our study shows an association between alloimmunization and the age of the patients and number of units transfused. Transfusion support of this group of patients necessitates the availability of needed expertise and blood bank facilities.

Transient loss of A1 phenotype in a patient with passenger lymphocyte syndrome after ABO minor incompatible liver transplantation: The first case report.

Passenger lymphocyte syndrome (PLS) is a well-known cause of antibody mediated hemolysis after minor ABO mismatched transplantations. In most cases, PLS is mild and self-limited and easily recovered through transfusion. We report an unusual case of transient loss of A1 phenotype in AB blood type patient with PLS after ABO minor incompatible liver transplantation from B blood type deceased donor.

Transfusion Therapy in Children With Sickle Cell Disease.

Hydroxyurea, blood transfusions, and hematopoietic stem cell transplantation represent the 3 disease-modifying therapies in children with sickle cell disease (SCD). Blood transfusions play an increasingly important role in both prevention and management of SCD complications in this age group. This review will focus on the indications of blood transfusion in children with SCD and modalities of its administration. It will also highlight the complications of this life-saving therapy and ways of optimizing transfusion to minimize its associated risks.

Hemolytic transfusion reaction attributable to anti-Dia.

CONCLUSIONS: In situations when a patient's antibody detection test is negative, many institutions have moved from an indirect antiglobulin test (IAT) crossmatch to an electronic crossmatch system. Here we report a case of an acute hemolytic transfusion reaction attributable to anti-Dia in a patient with a negative antibody detection test. A 22-year-old female patient with a diagnosis of ß thalassemia and sickle cell anemia commenced a routine exchange transfusion of 5 units of red blood cells (RBCs) in the apheresis unit as part of her regular treatment. When the patient started receiving the implicated unit, she reported back pain, chest pain, and a feeling of anxiety, suggestive of an acute transfusion reaction. The transfusion was ceased and an investigation of an adverse event was commenced. This case illustrates that the presence of antibodies to low-prevalence antigens remains a significant issue for transfusion-dependent individuals. To prevent other transfusion reactions by anti-Dia, the addition of Di(a+) cells to the reagent RBCs used for the antibody detection test along with IAT-crossmatching of donor units for all patients with sickle cell disease is recommended.

Wrong blood in tube - potential for serious outcomes: can it be prevented?

'Wrong blood in tube' (WBIT) errors, where the blood in the tube is not that of the patient identified on the label, may lead to catastrophic outcomes, such as death from ABO-incompatible red cell transfusion. Transfusion is a multistep, multidisciplinary process in which the human error rate has remained unchanged despite multiple interventions (education, training, competency testing and guidelines). The most effective interventions are probably the introduction of end-to-end electronic systems and a group-check sample for patients about to receive their first transfusion, but neither of these eradicates all errors. Further longer term studies are required with assessment before and after introduction of the intervention. Although most focus has been on WBIT in relation to blood transfusion, all pathology samples should be identified and linked to the correct patient with the same degree of care. Human factors education and training could help to increase awareness of human vulnerability to error, particularly in the medical setting where there are many risk factors.

Low frequency of anti-D alloimmunization following D+ platelet transfusion: the Anti-D Alloimmunization after D-incompatible Platelet Transfusions (ADAPT) study.

The reported frequency of D alloimmunization in D- recipients after transfusion of D+ platelets varies. This study was designed to determine the frequency of D alloimmunization, previously reported to be an average of 5 ± 2%. A primary anti-D immune response was defined as the detection of anti-D ≥ 28 d following the first D+ platelet transfusion. Data were collected on 485 D- recipients of D+ platelets in 11 centres between 2010 and 2012. Their median age was 60 (range 2-100) years. Diagnoses included: haematological (203/485, 42%), oncological (64/485, 13%) and other diseases (218/485, 45%). Only 7/485 (1·44%; 95% CI 0·58-2·97%) recipients had a primary anti-D response after a median serological follow-up of 77 d (range: 28-2111). There were no statistically significant differences between the primary anti-D formers and the other patients, in terms of gender, age, receipt of immunosuppressive therapy, proportion of patients with haematological/oncological diseases, transfusion of whole blood-derived or apheresis platelets or both, and total number of transfused platelet products. This is the largest study with the longest follow-up of D alloimmunization following D+ platelet transfusion. The low frequency of D alloimmunization should be considered when deciding whether to administer Rh Immune Globulin to D- males and D- females without childbearing potential after transfusion of D+ platelets.

Female sex of older patients is an independent risk factor for red blood cell alloimmunization after transfusion.

BACKGROUND: More women than men are encountered with red blood cell (RBC) antibodies. It is not clear whether this difference is explained by more immunizing events in women or by a different acting immune system. To assess whether there is a difference in the posttransfusion RBC alloimmunization rate between women and men, a study on RBC alloimmunization during a 5-year period was conducted in patients with at least one antibody follow-up more than 14 days after transfusion. STUDY DESIGN AND METHODS: Data on transfusion and antibody follow-up characteristics in female and male transfusion recipients from the Leiden University Medical Center laboratory database were collected. Hazard ratios of alloimmunization, according to sex of the transfusion recipient, were estimated using Cox proportional hazards regression models taking possible confounders into account. RESULTS: From a total of 1699 women and 1969 men who were eligible, 4.2% of women and 3.4% of men (relative risk, 1.3; 95% confidence interval [CI], 0.9-1.8) developed posttransfusion antibodies. Adjustment for confounders resulted in a relative 80% higher risk in women older than 45 years of age. CONCLUSION: Elder women beyond childbearing age have a higher risk of posttransfusion antibody formation compared to men.

Anti-K formation is not associated with the storage time of transfused red blood cells.

BACKGROUND: The formation of red blood cell (RBC) antibodies could be enhanced by the presence of inflammation caused by prolonged RBC storage, as was shown in animal studies. The low occurrence (<10%) of K-antigen in most populations often enables identification of the K+ RBC unit that triggered anti-K formation and determination of its storage time. This study aims to quantify the association of anti-K formation with RBC storage time. STUDY DESIGN AND METHODS: K- patients who had not been previously transfused and received at least 1 K+ unit between January 2004 and August 2013 were identified. First, the influence of storage time of the K+ units was assessed as mean, maximum, and minimum storage times within one transfusion interval and at various cutoff points for old versus young blood (14, 18, and 21 days). Second, concomitantly transfused K- units were studied within different periods surrounding the K+ unit(s). RESULTS: Twenty-three patients formed anti-K, while 274 patients did not. The adjusted relative risks of anti-K formation for mean, maximum, and minimum storage time (days) ranged from 1.01 to 1.03 (95% confidence interval, 0.96-1.08). When analyzing the association between only "younger" and only "older" K+ units at various cutoff points, no association was found. Similarly, no association was found between storage time of the concomitantly transfused K- units and anti-K formation. CONCLUSION: Within the range of storage times used in normal clinical practice in the Netherlands, no association could be found between RBC storage time and anti-K formation.

Easier said than done: ABO compatibility and D matching in apheresis platelet transfusions.

BACKGROUND: Many hospital transfusion services prioritize ABO plasma compatibility in platelet (PLT) transfusion to minimize risk for acute hemolytic transfusion reactions. In spite of the low risk of D alloimmunization associated with apheresis PLT transfusion, attempts may also be made to provide D- PLTs to D- patients. This study was undertaken to assess how often ABO compatibility and/or D matching occurs at our institution and how the ABO and D mix of our PLT supply impacts PLT selection. STUDY DESIGN AND METHODS: We retrospectively reviewed the ABO and D type of all PLTs transfused plus the age, sex, and ABO and D type of all PLT recipients between January 2010 and March 2014 (51 months). RESULTS: We provided ABO-identical PLTs for 5281 (54.6%), ABO plasma-compatible and cellular-incompatible for 3136 (32.4%), ABO low-titer plasma-incompatible and cellular-compatible for 1150 (11.9%), ABO plasma-incompatible and cellular-compatible for 30 (0.3%), and ABO plasma-incompatible and cellular-incompatible for 72 (0.7%). PLT supply did not match PLT demand based on patient ABO type, primarily due to a lower than expected supply of group O PLTs and higher than expected supply of group A and AB. D- patients were less likely to receive ABO-identical PLT transfusions (p = 0.0008), but were more likely to receive D- PLT transfusions (p < 0.0001). CONCLUSION: At our hospital, available inventory and PLT selection practices resulted in the majority of group O patients receiving cellular-incompatible PLT transfusions. Efforts to provide D- PLTs to D- patients also resulted in fewer D- patients receiving ABO-identical PLT transfusions.

Transfusion reactions in pediatric compared with adult patients: a look at rate, reaction type, and associated products.

BACKGROUND: The majority of reports on transfusion reactions address adult patients. Less is known about the types, incidence, and other clinical details of transfusion reactions in pediatric populations. Furthermore, to our knowledge, there have been no previous reports directly comparing these aspects between adults and pediatric patient populations to assess if there are differences. STUDY DESIGN AND METHODS: Between the period of January 1, 2011, and February 1, 2013, all reported adult and pediatric transfusion reactions at Vanderbilt University Medical Center (VUMC) were evaluated by transfusion medicine clinical service. The information was subsequently shared with the hemovigilance database. Data provided to hemovigilance included age, sex, blood product associated with the reaction, severity of the reaction, and the type of transfusion reactions. These were collated with hospital and blood bank information system-acquired data on overall admission and product transfusion. RESULTS: A total of 133,671 transfusions were performed at VUMC during the study period including 20,179 platelet (PLT) transfusions, 31,605 plasma transfusions, 79,933 red blood cell (RBC) transfusions, and 2154 cryoprecipitate transfusions. Over the same period, 108 pediatric and 277 adult transfusion reactions were recorded. This corresponds to an incidence of 6.2 reactions per 1000 transfusions within the pediatric (age < 21) population and an incidence of 2.4 reactions per 1000 transfusions within the adult population. In both adult and pediatric populations, transfusion reactions were most commonly associated with PLT, followed by RBC, and then plasma transfusions. Within the pediatric population, subset analysis identified multiple differences when compared to the adult population, including an increased incidence of allergic transfusion reactions (2.7/1000 vs. 1.1/1000, p < 0.001), febrile nonhemolytic transfusion reactions (1.9/1000 vs. 0.47/1000, p < 0.001), and hypotensive transfusion reactions (0.29/1000 vs. 0.078/1000, p < 0.05). Interestingly, while the reaction incidence was the same between sexes in adults, in pediatric patients, reactions were more common in male patients (7.9/1000 pediatric males vs. 4.3/1000 pediatric females, p < 0.01). CONCLUSION: To our knowledge this is the first study to provide detailed comparisons of acute transfusion reactions to all blood products between pediatric and adult populations at a single institution and supported by a single transfusion service and culture. Collectively these data provide insight into pediatric transfusion reactions and demonstrate a general increase in the incidence of transfusion reactions within the pediatric compared to adult population.

Severe hemolytic transfusion reaction due to anti-D in a D+ patient with sickle cell disease.

A 5-year-old male with sickle cell disease presented with pain, dark urine, and fatigue 10 days after a red blood cell (RBC) transfusion. Laboratory evaluation demonstrated severe anemia, blood type O+, and anti-D in the serum. Anti-D in a D+ patient led to RH genotyping, which revealed homozygosity for RHD*DAU4 that encodes partial D antigen. Anti-D in this patient whose RBCs exclusively express partial D caused a delayed hemolytic transfusion reaction after exposure to D+ RBCs. The finding of anti-D in a D+patient should be investigated by molecular methods to help distinguish an alloantibody from an autoantibody.

Effects of universal vs bedside leukoreductions on the alloimmunization to platelets and the platelet transfusion refractoriness.

BACKGROUND: Multiple platelet exposure induces anti-HLA and/or anti-HPA antibody production, which may cause platelet transfusion refractoriness (PTR). In Japan, the universal pre-storage leukocyte reduction (ULR) was fully implemented since 2006, but prior to ULR, in our institution, leukocyte reduction filters were routinely used at the bedside (bedside leukoreduction, BSLR) for all onco-hematological patients receiving multiple platelet transfusions. OBJECTIVE: We retrospectively compared patients receiving platelet transfusions in the era of ULR with those of BSLR era. MATERIALS AND METHODS: Patients of the BSLR group (409 cases) and the ULR group (586 cases) were compared in terms of alloimmunization and immunological PTR. The clinico-pathological features, including gender, history of pregnancy, number of exposed transfusion donors, periods of transfusion, and prior stem cell transplantation were compared, and the risk factors of alloimmunization were determined. RESULTS: The antibody detection rate was significantly higher in the ULR compared to BSLR group (8.7% vs. 5.4%), as well as the immunological PTR rate (7.3% vs. 3.2%). By the multivariate analysis, female gender and the number of platelet donor exposure, but not universal leukoreduction or transfusion period, were found to be the risk factors strongly associated with alloantibody formation. CONCLUSION: Although ULR may be superior to BSLR in terms of preventing non-hemolytic transfusion reactions, BSLR was found to be as effective as ULR in terms of preventing platelet alloimmunization and refractoriness. Thus, BSLR should be actively indicated as a realistic alternative in developing countries, before the universal leukoreduction is fully implemented.

Red cell alloimmunisation in regularly transfused beta thalassemia patients in Pakistan.

BACKGROUND: In Pakistan routine blood group typing of thalassemia patients identifies ABO and Rh(D) antigens only. Therefore, other antigen incompatibilities between blood donor and blood recipient may cause alloimmunisation. OBJECTIVE: The aim of this study was to estimate the frequency of alloimmunisation and to evaluate the risk factors associated with its development in beta (ß)-thalassemia patients receiving regular blood transfusions. MATERIALS AND METHODS: In total 162 ß thalassemia patients were included in this study. An extended red cell antigen panel was performed to detect antibodies. Patients received red cell concentrates, which were matched for ABO and Rh(D) antigens. Clinical and laboratory data were collected and analysed to estimate the frequency of alloantibodies and the factors influencing immunisation in patients on regular blood transfusion. RESULTS: The median age of patients was 6·7 (range: 0·5-25) years. A total of 14 (8·6%) patients developed alloantibodies against red cell antigens. The most frequently occurring alloantibodies was anti-E (2·5%), anti-K (1·8%), anti-e (1·2%) and anti-D (0·6%). Five (3·1%) patients developed more than one red blood cell (RBC) alloantibody. Age at first transfusion in alloimmunised patients was 1·22 ± 0·87 years. The frequency of blood transfusion in alloimmunised patients was 23 ± 8·81 days and in those without alloimmunisation was 31·8 ± 16 days (p = 0·02). Logistic regression analysis showed no independent risk factor associated with alloimmunisation. CONCLUSION: The frequency of transfusion was increased in patients who developed alloantibodies. Typing patients and donors to match for Rh and Kell antigens would prevent more than 90% of RBC alloantibodies and reduce the frequency of transfusion in thalassemia patients.

Red cell transfusion and the immune system.

Understanding the complex immunological consequences of red cell transfusion is essential if we are to use this valuable resource wisely and safely. The decision to transfuse red cells should be made after serious considerations of the associated risks and benefits. Immunological risks of transfusion include major incompatibility reactions and transfusion-related acute lung injury, while other immunological insults such as transfusion-related immunomodulation are relatively underappreciated. Red cell transfusions should be acknowledged as immunological exposures, with consequences weighed against expected benefits. This article reviews immunological consequences and the emerging evidence that may inform risk-benefit considerations in clinical practice.