Red blood cell alloimmunization: lessons from sickle cell disease

Red blood cell (RBC) transfusion is a lifesaving therapy for patients with chronic anemias, including sickle cell disease and myelodysplastic syndrome. However, with multiple intermittent or chronic monthly transfusions, the concern for RBC alloimmunization arises. This issue of TRANSFUSION includes two articles that discuss specific patient groups at increased risk of alloimmunization compared to the general population and most patient groups as well. Although difficult to accurately determine, the baseline incidence of alloimmunization in the general population has been estimated to be approximately 0.5% to 1.5%.1 Some studies have found a higher rate of alloimmunization among hospital patients, but often these studies include clinically insignificant or naturally occurring antibodies.2, 3 Of note, Redman and colleagues4 performed a prospective study of posttransfusion patients who had received a mean of 3 RBC units and they surprisingly found that 8.4% of those patients developed RBC alloantibodies; this higher than expected rate of alloimmunization may be related to their prospective study design or their sensitive serologic methods, which included enzyme or polybrene techniques in addition to indirect antiglobulin tests. In contrast, the incidence of RBC alloantibody formation in patients with sickle cell disease is significantly higher. Before the introduction of prophylactic phenotypic matching, the alloimmunization rate among patients with sickle cell disease ranged from 8% to 36% depending on the study and the specific patient population.5-9 A review of 12 publications found a mean rate of 25%.10 The risks of alloimmunization in this multiply transfused population are real. With the development of alloantibodies, the patient's serologic evaluation may become complex and lead to difficulty obtaining compatible units, resulting in potentially critical delays in blood availability for emergent transfusions. Additionally, alloimmunization is associated with an increased risk of acute and delayed hemolytic transfusion reactions that may be complicated by hyperhemolysis, a life-threatening complication of transfusion which is seen predominantly in patients with sickle cell disease.10-12 The high rate of alloimmunization in patients with sickle cell disease is likely multifactorial. A significant contributory factor is the racial discordance between donor and recipient. The majority of blood donors in the United States are white, while most patients with sickle cell disease are of African descent. This racial discordance results in a disparity in RBC antigen distributions between donors and patients.7, 8 However, there are other contributory factors, as somewhat higher alloimmunization rates are even seen when the donor and recipient are ethnically similar.13 Of note, a study by Natukunda and colleagues13 found that 6.1% of Ugandan patients with sickle cell disease were alloimmunized despite low transfusion exposure and racial homogeneity between donors and recipients. Other influencing factors may include the immune responsiveness of the patient, the number of transfusion exposures, and the patient's age at first transfusion.7, 14 Efforts to prevent alloimmunization in patients with sickle cell disease have focused on prophylactic antigen matching. Several studies have advocated prophylactic matching for C, E, and K antigens for patients with sickle cell disease, whereas some groups use extended phenotypic matching.15-18 These antigen-matching protocols have been associated with a reduction in the rate of alloimmunization and a decrease in hemolytic transfusion reactions. Despite this reported success, studies and surveys have demonstrated no consistent standard of care with significant variability in transfusion practice particularly related to the extent of antigen matching for these patients. In a survey of 1182 North American laboratories, Osby and Shulman19 found that the majority of laboratories only matched for ABO and D in nonalloimmunized patients with sickle cell disease. One-third of laboratories provided RBCs that were prophylatically matched for C, E, and K antigens and one-seventh of the laboratories provided units matched for Jka, Jkb, Fya, and Fyb antigens. Afenyi-Annan and coworkers20 surveyed the transfusion management practices at the participating institutions within the NIH Comprehensive Sickle Cell Centers. Within this focused group of predominantly academic institutions, variability of transfusion practice persists. These institutions showed more consensus regarding matching for Rh and Kell antigens, but differences in matching for additional antigens remained. Some experts do not recommend prophylactic matching for nonalloimmunized patients with sickle cell disease, because the majority of patients do not make antibodies and the provision of phenotypically matched RBCs is costly and may delay care depending upon the extent of prophylactic matching.21, 22 They would argue that when patients initially become alloimmunized, most typically develop a single alloantibody that may be associated with a clinically benign delayed serologic transfusion reaction or a mild delayed hemolytic transfusion reaction. Additionally, RBCs of unusual phenotype are a limited resource and should potentially be reserved for patients who require these antigenic specifications. This situation is further complicated by increasing information related to the occurrence of Rh variant antigens, particularly in patients of African origin. In the presence of some Rh variant antigens, donor RBCs, which appear to be matched to the patient's Rh antigens, may be capable of eliciting an alloantibody due to the presence of an epitope on the donor RBCs that the patient's RBCs lack.14 Consequently, it is becoming progressively more difficult to justify prophylactic matching for Rh antigens with the understanding that the patient's true phenotype including the identification of variant antigens may not be accurately reflected in the serologic phenotype determination. In this issue of TRANSFUSION, Miller and colleagues23 report data on RBC alloimmunization from patients enrolled in the PROACTIVE Feasibility Study. This randomized study evaluated the use of prophylactic transfusion for prevention of acute chest syndrome in patients at increased risk as identified by fever and elevated serum levels of secretory phopholipase A2. Antibody histories and phenotypes were obtained for the 237 enrolled patients; participating institutions were surveyed about their transfusion protocols for patients with sickle cell disease including the provision of prophylactically matched RBCs. Despite routine prophylactic matching for C, E, and K in 83% (19 of 23) of responding centers, antibodies directed against C, E, and K were still identified in these patients and the alloimmunization rate in this study population was 14.4%, comparable to the alloimmunization rate reported by the Cooperative Study of Sickle Cell Disease (CSSCD) published in 1990.7 The authors raise the point that current methods of antibody detection are much more sensitive; it is possible this change in method is reflected in the apparent persistent alloimmunization rate seen in the PROACTIVE patients. Additionally, patients may be receiving transfusions at other institutions that do not provide extended matching. Interestingly, the study by Miller and coworkers also showed that 75.8% of patients had a transfusion history versus only 50% in the CSSCD. This increased rate of transfusion indicates that more patients with SCD are currently receiving transfusions, likely due in part to the findings of the STOP trial.24 It is therefore very likely that transfusion services will continue to be challenged with providing compatible units for these patients. In their conclusion, Miller and colleagues suggest that the standard of care for transfusion of all patients with SCD be the provision of RBCs prophylatically matched for C, E, and K antigens. Also, in this issue of TRANSFUSION, Sanz and colleagues25 report their institution's experience with RBC alloimmunization in patients with myelodysplastic syndrome (MDS). This patient population often requires transfusion support and may ultimately become transfusion dependent. Patients with MDS have been noted to have immunologic abnormalities, including monoclonal gammopathies, polyclonal gammopathies, and RBC autoantibodies. Sokol and coworkers26 reported 46 patients with RBC autoantibodies in the setting of MDS; 15 of those patients had clinically significant autoimmune hemolysis in association with warm, cold, or mixed-type autoantibodies. Although previous publications have reported the frequency of alloimmunization in hematologic disorders, few studies have specifically evaluated patients with MDS.27, 28 Sanz and colleagues studied patients with MDS or chronic myelomonocytic leukemia who received two or more RBC transfusions in a month and were negative for antibodies at first transfusion.25 Fifteen percent (42 of 272) of patients developed a total of 81 alloantibodies and seven autoantibodies. The most frequent antibody specificity was K, with E being the second most common specificity. Additionally, three patients formed autoantibodies without developing an alloantibody. In this study, the rate of alloantibody development increased with increasing number of units transfused. Sanz and colleagues point out that the majority of alloimmunization in their patient population is directed against antigens in the Rh and Kell blood groups, and they observe that other chronically transfused populations have benefited from prophylactic matching of C, E, and K antigens. The authors also note that the majority of patients with MDS do not form antibodies. Much like the studies in sickle cell disease, no distinctive characteristic could be found to predict which patient would develop alloantibodies. Both the article by Miller and colleagues and the article by Sanz and colleagues evaluate alloimmunization and its impact on two groups of chronically transfused patients. Taken together, these two papers indicate the need for a rational approach to the transfusion management for all patient groups at high risk for RBC alloimmunization, including patients with sickle cell disease and those with MDS. Furthermore, there are other groups of patients who warrant inclusion in such a consistent management approach based on their increased risk of alloimmunization, such as patients with autoimmune hemolytic anemia (AIHA). Reports have shown that 12% to 40% of patients with warm autoantibodies also have underlying alloantibodies that could cause an acute or delayed hemolytic transfusion reaction.29 Patients with AIHA may require repeated, possibly emergent, transfusions, and they often present with complex serology precluding timely pretransfusion evaluations, much like patients with sickle cell disease. At Johns Hopkins Hospital, our transfusion management protocol for patients with sickle cell disease includes initial serologic phenotyping with subsequent RBC antigen genotyping.22 It is critical to have documentation of the patient's RBC phenotype because this information will facilitate antibody identification should the patient develop complex serology. RBC antigen genotyping is not only confirmatory, but it provides additional blood group information which is helpful in resolving complex antibody problems, including assessment of the risk of alloimmunization to antigens in the Duffy system. Patients who have not previously developed antibodies are provided leukoreduced, sickle-negative RBCs. After a patient has developed at least one antibody, either alloantibody or autoantibody, we provide RBCs that are matched to the patient's extended RBC phenotype; thus, using the development of a single antibody as an indicator that the patient may be an immune responder with the potential to develop multiple alloantibodies that could be prohibitive for future transfusions. Our approach has been successful in efficiently providing RBCs for our patients with sickle cell disease. Therefore, we advocate a similar approach for patients with AIHA.30, 31 Like the patients with sickle cell disease, these patients have a high incidence of underlying alloantibodies. Additionally, we initially instituted the same protocol for patients with MDS because of their high risk for autoantibody formation and AIHA. The study by Sanz and colleagues25 documenting a high risk for alloimmunization in patients with MDS further strengthens the rationale for maintaining these patients on the same transfusion management protocol as patients with sickle cell disease. The above-mentioned patient groups are complex and require specialized attention from the transfusion medicine service. The specific approach used by individual institutions may be significantly influenced by characteristics of the institution, the specific patient population, and the blood supplier. Thus, the variability in practice related to transfusion support for patients with sickle cell disease may be inevitable to some degree because of these institutional and regional differences. However, despite this variability in transfusion practice, it is clear that patients with sickle cell disease, MDS, and AIHA share a high rate of alloimmunization, which puts them all at risk for delayed availability of compatible RBCs and clinically significant transfusion reactions. Consequently, when transfusion services are formulating their transfusion management protocol for patients with sickle cell disease, a similar approach should be considered for patients with MDS and those with AIHA. Of course, it would be optimal to better understand the mechanism of antibody formation and to better predict which specific patients will make antibodies. Pharmacologic interventions may be possible to reduce or prevent RBC alloimmunization. Until more optimal predictive or preventive measures are available, implementation of relatively broad transfusion protocols is our best approach to prevention of alloimmunization and provision of safe blood in a timely manner for all patients at increased risk. The authors declare no relevant conflicts of interest.