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I M M U N O H E M AT O L O G Y Extended red blood cell antigen matching for transfusions in sickle cell disease: a review of a 14-year experience from a single center _3045 1732..1739 Michele LaSalle-Williams, Rachelle Nuss, Tuan Le, Laura Cole, Kathy Hassell, James R. Murphy, and Daniel R. Ambruso BACKGROUND: Alloimmunization to red blood cell (RBC) blood group antigens is a major complication for patients with sickle cell disease (SCD), which limits the usefulness of RBC transfusion. Here, we report our experiences with extended RBC antigen matching for SCD patients. STUDY DESIGN AND METHODS: Records for 99 SCD patients transfused only with the extended matching protocol between 1993 and 2006 were reviewed. Patients and donors were phenotyped for 20 blood group antigens and RBC units that were negative for antigens not expressed by the recipient were provided. When necessary, mismatches were allowed at Lea, Leb, Fyb, and MNSs to meet requirements for antigens regarded as the most clinically significant. Matched RBC units (6946) were provided to 99 patients (mean, 70 units/patient; range, 1-519 units/patient). Eliminating mismatches, 90% of the transfusions matched all other negative antigens. RESULTS: Seven alloantibodies were detected in seven patients resulting in 7% alloimmunized at a rate of 0.1 antibodies per 100 units transfused. Three recipients who developed antibodies were D mosaic and would have been mistyped with serologic techniques. Alloimmunization was decreased compared to ABO and/or D matching at our institution and others. Twelve autoantibodies and no severe hemolytic transfusion reactions were reported. CONCLUSION: Exact matching for ABO, Rhesus, Kell, Kidd, and Fya and extending this match whenever possible is an effective strategy to reduce alloimmunization to RBC antigens. Consideration should be given to exploring this conclusion further with a controlled, multiinstitutional trial to determine efficacy, cost-benefit analysis, and reproducibility of this approach. 1732 TRANSFUSION Volume 51, August 2011 W orldwide, sickle cell disease (SCD) affects individuals of many different racial and ethnic groups, but in the United States, most patients are African American.1,2 Although hydroxyurea administration has improved outcomes for some patients with SCD, transfusion therapy remains a mainstay for the treatment of severe, acute complications and a critical strategy to reduce the chronic morbidity and mortality associated with the disease. Associated with transfusion therapy is the risk of alloimmunization to minor red blood cell (RBC) blood group antigens, which increases with repeated transfusions. The mechanism for alloimmunization with SCD patients is, for the most part, related to the lack of compatibility of RBC antigens between the donors of largely European background and the African American recipients;3-7 the alloimmunization rate in the SCD patient population ranges between 18 and 46%.3-12 The presence of RBC alloantibodies creates the potential for serologic incompatibility, makes the selection of appropriate units for future transfusions more ABBREVIATION: SCD = sickle cell disease. From the Bonfils Blood Center, Denver, Colorado; the Departments of Pediatrics and Medicine, The University of Colorado at Denver and Health Sciences Center, The Children’s Hospital, and the Colorado Sickle Cell Treatment and Research Center, Aurora, Colorado; and the Division of Biostatistics and Informatics, National Jewish Health, Denver, Colorado. Address correspondence to: Daniel R. Ambruso, MD, Bonfils Blood Center, 717 Yosemite Street, Denver, CO 80230; e-mail: [email protected]. Supported by The Bonfils Blood Center, The Colorado Sickle Cell Treatment and Research Center, and The Stacey Marie True Memorial Trust. Received for publication October 8, 2010; revision received December 14, 2010, and accepted December 15, 2010. doi: 10.1111/j.1537-2995.2010.03045.x TRANSFUSION 2011;51:1732-1739. MINOR ANTIGEN MATCHING FOR SICKLE CELL DISEASE difficult, delays the use of a potentially life-saving therapy, and presents a risk for hemolytic transfusion reactions, some potentially life-threatening.4,7,13,14 RBC autoantibody formation is higher when alloimmunization has occurred.4,9,11,15-20 Currently, there is no consensus for matching RBC antigens when transfusing patients who are not yet alloimmunized.2,21 A review by the College of American Pathologists completed several years ago concludes that most laboratories surveyed do not routinely perform phenotyping of RBC antigens for SCD patients beyond A, B, and D, and those that did, most commonly limited the extended matching to C, E, and K.21 Recent technological advances in completing RBC antigen typing by molecular rather than serologic techniques may change this approach. Many centers caring for SCD patients allow for the initial development of alloantibodies before organizing matching beyond ABO and D.21 Some providers advocate additional but limited matching for C, E, and K since 50% of alloantibodies demonstrated in SCD patients are against these antigens.10,11,13 Castro and colleagues10 have suggested a protocol for extended matching for additional antigens such as Fya and Jkb to C, E, and K could further reduce the rate of alloimmunization. In this article, we describe our experience with an extended antigen-matched RBC transfusion protocol for SCD patients receiving care through a regional, universitybased comprehensive SCD program. The program was initiated in 1978, and reports for SCD patients on chronic transfusion therapy demonstrated a significant decrease in the rate of alloimmunization in patients with SCD.4,22 Results for extended RBC antigen matching in a larger number of patients for a wider variety of indications since 1993 are presented here. MATERIALS AND METHODS Patient population Patients were identified either through a neonatal screening program or when they sought care at the Colorado Sickle Cell Treatment and Research Center at a later age and received transfusions at The Children’s Hospital Denver, University of Colorado Hospital (Denver), and Memorial Hospital (Colorado Springs). Chart review was completed under a protocol approved by the Colorado Multiple Institutional Review Board (The Children’s Hospital, University of Colorado Hospital) and Memorial Hospital Institutional Review Board. Clinical records from patients with homozygous HbSS, HbSC, HbS b-thalassemia (b+ or b°) were reviewed from January 1, 1993, to December 31, 2006. Only those patients who received transfusions under the extended matching protocol as described were included in the analysis (n = 99) and none had antibodies documented before their first transfusion. For each patient, age, sex, SCD categories, RBC phenotype, and indications for transfusion were recorded. The extent of phenotype match was analyzed by a computer program structured to evaluate each unit of RBCs transfused to each patient enrolled. Adverse events associated with any transfusion were noted. Reactions were reported and documented by the clinical transfusing service caring for the patients and evaluated by the transfusion service at the transfusing hospital. Event characteristics were defined using descriptions in the Technical Manual.23 Finally, the presence and characteristics of any allo- or autoantibody detected during the matching protocol were documented as described below. Control data for SCD patients receiving transfusions matched for ABO and D only were obtained from records before our extended matching and previously reported.4 Laboratory testing and extended matching Patients’ RBCs were phenotyped for multiple blood group systems and antigens including ABO; Rh (C, c, D, E, e); Kell (K, k); Duffy (Fya, Fyb); Kidd (Jka, Jkb); Lewis (Lea, Leb); and MNS (M, N, S, s) with commercial reagents by standard serologic techniques.4,23 To assure accuracy of typing, tests were repeated twice as previously described.4 Antibody screening was completed at visits to the comprehensive clinic, before each transfusion, or 3 to 4 weeks after each transfusion in the case of chronically transfused patients in preparation for the next transfusion. Phenotyping and antibody testing were performed in the AABB-accredited Immunohematology Reference Laboratory at Bonfils Blood Center. Antibody detection during the period of study involved a three-cell antibody screen on patient serum or plasma using low-ionic-strength-saline or polyethylene glycol to enhance antibody-antigen interactions with standard tube technique.4,23 Reactivity was documented with standard agglutination grading or hemolysis. A screen was positive if agglutination of reagent screening cells occurred after immediate spin, after incubation at 37°C, or at AHG phase. If the screening test was positive, antibody identification was completed using at least a 10-cell panel testing at immediate spin, 37°C, and AHG phase. For autoantibody evaluation, DAT with polyspecific and monospecific reagents were used. Specificities for autoantibodies were completed with panels as noted above with comparison to the patient’s RBC phenotype. Cold autoantibodies were evaluated with cold antibody screen at 4°C, thermal amplitude studies, reactivity with cord blood cells, or more recently, a pathologic cold antibody test at 30°C. Since 1978, donors for this program have been tested for the RBC antigens noted above by standard serologic techniques.4,23 Phenotypes were confirmed on a second occasion, and more than 120,000 donors have been studied and used as a source for transfusion products since 1978. Volume 51, August 2011 TRANSFUSION 1733 LASALLE-WILLIAMS ET AL. For each transfusion request, attempts were made to match each negative antigen in the recipient with a negative antigen in the donor.4 Mismatches were allowed when necessary for MNSs, Fyb, and Lea or Leb because of lower immunogenicity and risk for sensitization or the infrequent incidence of hemolytic transfusion reactions. During the course of the study, eight patients received 13 units of RBCs matched only for ABO and D. The urgency of the complications precluded waiting for extended matching (see Results). Compatibility testing for each unit was completed with patient’s serum by standard techniques. When alloantibodies occurred, units negative for the requisite antigen were provided. A clinically significant antibody was defined as one that is frequently associated with a hemolytic transfusion reaction, a notable decrease in survival of RBCs, or hemolytic disease of the newborn and would include antibodies to C, D, E, c, e, K, k, Kpa, Fya, Fyb, Jka, Jkb, S, or s. Initially, washed or frozen, deglycerolized RBCs were provided for the transfusions in this program, and subsequently, leukoreduced units were used. When possible, especially for chronic transfusions, products negative for sickle trait were provided for transfusion. For statistical comparison of extended matching with other matching strategies, the exact likelihood ratio test was used, adjusting for multiple comparisons by Bonferroni employing a computer program (Stat Exact, Cytel, Inc., Cambridge, MA). For multiple comparisons, each test must be a p value of 0.0023 or less. RESULTS Ninety-nine patients managed exclusively under the extended-match protocol met the inclusion criteria for this study. The characteristics of the study population data are displayed in Table 1. First transfusions were provided from infancy to adult years with a mean age of 7.4 years. Slightly more than half of the patients were males. Most patients had homozygous sickle cell anemia (HbSS); a small number (14%) had HbSC or HbS b-thalassemia. The mean interval between the first and last transfusion was 4.8 years. None of the patients received hydroxyurea during the time of this study. Major indications for transfusion are listed in Table 1. The total number of units of RBCs administered to the group was nearly 7000 with a mean of 70 transfusions per patient, a median of 16, and a range of 1 to 519 units transfused (Table 1). The range of units transfused is also listed in quartiles. The majority of patients (57/99) received intermittently administered transfusions defined as transfusion support lasting less than 3 months for an acute SCD complication. Thirty percent had only chronically administered transfusions. A small number of patients (11/99) had periods of both intermittent and chronic transfusions. In all, 50 patients received simple, direct transfusion; 30, RBC exchange or erythrocytapheresis; and 19, both types of transfusion during their clinical course. While the program was flexible enough to provide RBC components with an extended match on TABLE 1. Demographics, patient characteristics, and numbers of transfusions for patients receiving extended matching for transfusions Demographics Evaluable patients Male/female Median age (years) of first transfusion (mean age) Range Disease type* HbSS HbSC HbS b-thalassemia Indications for transfusion† Acute chest syndrome Vaso-occlusive crises Cerebrovascular accident and/or abnormal findings on CNS evaluation (including radiologic or Doppler flow studies) Aplastic crises Splenic sequestration Surgery Priaprism Other Transfusions received† Total number of units transfused Mean number of units per patient Range of number of units transfused * Number of patients (%). † Number of complications (%). 1734 TRANSFUSION Volume 51, August 2011 99 53/46 6.6 years (7.4) 5 months-19 years, 7 months Number of patients 85 11 3 Number of complications 52 40 25 23 24 16 7 15 (%) 86 11 3 (%) 25.7 19.8 12.3 11.9 11.9 7.9 3.5 7.4 6946 70 1-519 First quartile, 1-3; second quartile, 3-16; third quartile, 17-111; fourth quartile, 131-519 MINOR ANTIGEN MATCHING FOR SICKLE CELL DISEASE most occasions, a few transfusions (13 RBC units in eight patients) were released with only ABO, D typing because of the clinical situation (see Materials and Methods). The severity and acuity of the complication did not allow time for delivery of extended-matched units and the transfusions were matched for ABO, D. None of these patients developed auto- or alloantibodies. As described under Materials and Methods, our strategy was to match units transfused as closely as possible. However, this goal was not always possible. When necessary, mismatches were allowed for antigens which have a lower risk for alloimmunization or whose antibodies do not cause immediate hemolytic transfusion reactions. Considering data for each unit transfused to the patient group, 2354 units of 6946 (34%) were exactly matched for all antigens not present on the patient’s cells. Table 2 summarizes mismatching by antigen. The most frequent antigens mismatched were Fyb, Lea, and Leb, M, and S. Jka was mismatched in a frequency higher than other antigens with C/c, E/e, K/k, and Fya mismatched in less than 2% of the transfusions. Considering mismatches, 39% of the transfusions had one mismatch, 14.4% two mismatches, and 12.8% three mismatches. When mismatches were permitted at Lea, Leb, M, N, and Fyb, 6217 units matched exactly, a rate of 90% of transfused units. Seven of the 99 transfused patients developed one alloantibody each (Table 3). The mean number of transfu- TABLE 2. Percentage of transfusions mismatched by antigen Antigen D C c E e K k Fya Percentage of transfusions mismatched 0 0.1 0.8 1.8 0.8 1.3 0.2 1.25 Antigen Fyb Jka Jkb M N S s Lea Leb Percentage of transfusions mismatched 44.6 8.2 0.3 6.5 3.6 8.6 4.4 5.5 11.9 sions for these patients was 54 (median, 62 transfusions; range, 15-85 transfusions). One was in the second quartile for number of transfusions, three in the third, and three in the fourth quartile. Six of the seven had more than 17 transfusions. These antibodies included anti-Lea, antiKpa, anti-M, and anti-D mosaic. The patient who developed the anti-Lea experienced a mild decrease in expected survival of transfused cells reported by the transfusion service without other symptoms or signs, a reaction that is rare for this antibody. Anti-Kpa was not an antigen routinely tested in our protocol but can result in delayed transfusion reactions and hemolytic disease of the newborn both of which are mild to moderate in severity.23 Anti-M is not usually associated with hemolytic transfusion reactions.23 No antibodies to Fyb were detected. With any serologic matching protocol, mosaic D will likely be typed as D positive and the resultant sensitization would be expected. Considering all antibodies in our current study, 7% of the patients became alloimmunized with a rate of 0.1 antibodies per hundred units transfused (Table 4). However, excluding patients with mosaic D who would have been mistyped by usual serologic procedures, 4% of patients were determined to have alloantibodies at a rate of 0.05 antibodies per hundred units transfused. With both analyses, the percentage of patients alloimmunized and rate of antibodies were significantly different (p < 0.00005) from our historical control group (see Table 4). The new alloantibodies were easily detected and subsequent transfusions were not significantly delayed in any patient. In addition to the comparison with our own historical controls, significant differences in both the percentage of patients with alloantibodies and the number of antibodies per 100 units transfused (p < 0.0005) were also noted between our study group and published studies for patients receiving ABO- and D-matched units for which complete comparative data are available (Table 5; Aygun et al.,9 Castro et al.,10 Sakhalkar et al.11). These studies provide more contemporary observations and address limitations for our historical control that are older than the study group and have possible differences in TABLE 3. Development of alloantibodies, autoantibodies, and adverse events of transfusions in 99 patients on extended matching protocol Alloantibodies Autoantibodies Adverse events Seven alloantibodies, one each in seven patients. Antigen specificity: one each of Lea, Kpa; two for M; three Rh(D)*. Twelve patients developed DAT associated with autoantibodies. Warm (IgG, negative complement): four anti-e; one anti-E; 1 anti-D, three panagglutinins. Cold (IgM, complement positive): four I-specificity, two unspecified. Nine of 12 with one autoantibody; 3 of 12 with two autoantibodies (warm and cold). One patient with both, one autoantibody also had one alloantibody. Ten patients (10%) had reported reactions to 13 units (0.2% total) transfused. Five allergic: skin manifestations (hives) only. Three febrile, nonhemolytic transfusion reactions (>1°C fever). One moderate citrate reaction during apheresis requiring decreased flow rate and oral calcium. One reported decrease in survival of RBCs as mild delayed hemolytic transfusion reaction. * All three patients who developed D alloantibodies were determined to be D mosaic, testing initially as D+. Volume 51, August 2011 TRANSFUSION 1735 LASALLE-WILLIAMS ET AL. TABLE 4. Alloimmunization in patients treated with extended matching protocol* Period, reference Before 1978 (control), Ambruso et al.4 1979-1983, Ambruso et al.4 Patient group Chronic transfusions n = 85 Chronic transfusions n = 12 1983-1990, Ambruso et al.22 1993-2006, Present report Chronic transfusions n = 13 Chronic and intermittent n = 99 Percentage of patients immunized 34% Matching ABO, D Extended matching All had previously received ABO, D Extended matching only Extended matching Rate (antibodies/100 units transfused) 3.4 25% 0.3 8% 0.08 All—7%† Eliminate D mosaic—4%† 0.10† 0.06† * Patients described in each period group were analyzed spearately and not included in the summary for any other group. † Different from historical control, p < 0.00005. TABLE 5. Studies evaluating alloimmunization and matching for RBC antigens Reference Ambruso et al.4 Rosse et al.6 Vichinsky et al.7 Aygun et al.9 Castro et al.10 Sakhalkar et al.11 Vichinsky et al.13 Sakhalkar et al.11 Tahhan et al.8 Number of patients/transfusions 85/1,941 1,044/—* 107/— 140/3,239† (pediatric and adult patients) 351/8,939† 387/14,263† Matching ABO, D only Percentage alloimmunized/number of alloantibodies per 100 units transfused 34%/3.4 18-31% (27% in study group)/— 30%/— 37%/2.8† 29%-35%/3.8† 31%/1.7† Matching extended beyond ABO, D, including C, E, K Percentage alloimmunized/rate, Number of patients/transfusions alloantibodies per 100 units transfused Extended matching for C, E, K 8-11%/0.5 61/1,830 Extended matching for C, E, K 5%/0.26 113/2,345 Matching extended beyond ABO, D, in addition to C, E, K Percentage alloimmunized/rate, Number of patients/transfusions alloantibodies per 100 units transfused 0/— Extended matching to K, C, E, S, Fya, Fyb 40/— * Bar notes data not provided or available. † Different from results for present report, Table 4, p < 0.00005. management of SCD, provision of blood products and services, and schedules of transfusions. During the study period, 12 of the 99 transfused patients had positive direct antiglobulin tests (DATs) associated with the appearance of autoantibodies (data shown in Table 3). Almost 60% were warm (immunoglobulin [Ig]G) and the rest were cold (IgM) antibodies. For warm autoantibodies, antigen specificities were determined as described under Materials and Methods with phenotype comparisons. Cold autoantibodies with I specificity had maximal reactivity at 4°C, detectable reactivity at RT only, and negative reactivity with cord blood RBCs. Patients with autoantibodies tended to receive higher numbers of transfusions (two in the second quartile, five in the third, and five in the fourth; mean, 173; median, 76; range, 1736 TRANSFUSION Volume 51, August 2011 9-519). The appearance of the autoantibodies, particularly those characterized as warm IgG, were associated with a short delay in delivery of transfusions to the patients until the serologic incompatibility was clarified. Ten patients (Table 3) experienced an adverse event of transfusion with 13 transfusion reactions (0.2% of all transfusions). All were considered mild by physicians caring for the patients. DISCUSSION In spite of the importance of RBC transfusions for treating the severe complications of this disease, there is no general agreement about matching strategies for SCD patients requiring transfusions. Most groups caring for these patients do not complete matching beyond ABO MINOR ANTIGEN MATCHING FOR SICKLE CELL DISEASE and D until alloimmunization occurs. Several studies have demonstrated that 18% to 47% of patients managed with this approach develop antibodies at a rate of 1.7 to 3.8 alloantibodies per 100 units transfused (Table 5).4,6,7,9-11 The risk of a significant, even life-threatening transfusion reaction is increased in sensitized patients.4,7,13 In situations where antibodies are identified, there may be long delays in identifying suitable units of RBCs compounding the morbidity of the SCD complications. Some groups advocate matching for C, E, and K (Table 5) in addition to ABO, D. Vichinsky and colleagues7 in a retrospective study of ABO- and D-matched transfusions supported this approach with a report that 82% of antibodies in their patients had specificity for C, E, K, and Kidd. A retrospective study by Castro and colleagues10 suggested that if matching for C, E, and K were completed, 53% of alloantibodies would be avoided. Sakhalkar and colleagues11 supported additional matching for C, E, and K with a report of 113 patients given 2300 units. This study recorded 5% alloimmunization with a rate of 0.26 antibodies/100 units. In 2001, Vichinsky and coworkers13 reviewed the effects of matching ABO, D, C, E, and K in 61 patients for 1830 transfusions. Eleven percent of the patients became alloimmunized. A small subset of patients developed E or Kell antibodies from a total of 29 units not matched for these antigens. Outcomes from protocols that provide even more extensive matching have been reported (Table 5). Tahhan and coworkers8 described a subset of 40 patients matched for C, c, E, e, k, S, and Fy and given D– units. None developed alloantibodies compared with a control group (46 patients) who received matched and mismatched units resulting in 30% developing 20 new alloantibodies. The retrospective study by Castro and colleagues10 suggested that if C, E, K, S, Fyb, and Jkb were matched, all alloantibodies would have been prevented in the 351 patients receiving 8939 transfusions. Our composite experience with extended RBC matching is summarized in Table 4. Before initiating our program of extended matching in 1978, our blood center provided ABO- and D-matched units resulting in an alloimmunization rate of 34% with 3.4 antibodies per hundred units transfused. These results are similar to more contemporary data shown by other groups.6,7,9-11 The patients in our first analysis (n = 12) demonstrated a small decrease in the percentage of alloimmunization and a nearly 10-fold reduction in rate of alloantibodies.4 These patients received chronic transfusions for the more severe complications of SCD, most had prior exposure to routine ABO and D only matched transfusions, and several were difficult to phenotype initially because of mixed-field reactions. Subsequently, we reported a separate cohort that included patients receiving chronic transfusions who were treated only with extended matching protocol.22 Alloimmunization was dramatically reduced by 77%. In our current study of a third separate group we confirm and expand our experience with a larger number of patients (n = 99) over a 14-year period. One limitation of the comparison of our study data with historical controls may relate to the time interval between the two. Changes in sickle cell therapy and provision of blood services may have varied, limiting the validity of the comparison. None of the patients included in this study were treated with hydroxyurea, which has the potential to affect alloimmunization. Most transfusions were with leukoreduced blood products. Assays used in detecting antibodies were completed in a small number of laboratories including our regional reference laboratory providing a consistent technical approach. Indications for acute or chronic transfusion therapy have remained consistent over the course of the study except for those few related to results with transcranial Doppler testing. Most importantly, the decrease in percentage of patients sensitized and number of antibodies per unit transfused was different with our historical control and three studies matching ABO and D only, completed contemporaneously with ours. Furthermore, our protocol resulted in lower levels of alloimmunization and rates of antibody formation compared with programs using intermediate matching with testing for C, E, and K presented by Vichinsky and colleagues13 and Sakhalkar and colleagues.11 Our rates of alloantibody formation compared to those of Vichinsky and colleagues were significantly decreased (p < 0.0007). Finally, our results are comparable to the one reported study with a smaller number of patients that extended matching beyond C, E, and K.8 Our program was flexible enough to meet most transfusion needs for all SCD patients. Only a very small number of transfusions to this patient group were matched for only ABO and D because of the urgency of the indication for transfusion. Autoantibodies were documented in our patients and appeared to be more frequent than alloantibodies (11.5% of patients and 0.25 autoantibodies per 100 units transfused). Adverse events documented in our study were infrequent and mild. Blood transfusion for SCD remains an essential and life-saving therapy and more, not fewer, patients may be transfused in the future.24 An important consideration in transfusion therapy for patients with SCD is that, in the absence of extended matched RBCs, alloantibodies develop in as many as one-third of these individuals, which may necessitate expensive searches for appropriate RBC units and delay potentially life-saving treatment. The impact of the delay may exacerbate morbidity or mortality and increase cost of care, issues that have not been included in most analyses.14,15,18 One of the main objections to extended RBC matching for SCD patients to the level described by Tahhan and coworkers8 and us4,22 is the additional cost for identifying suitable donors. While we did not perform a cost-benefit analysis, we previously Volume 51, August 2011 TRANSFUSION 1737 LASALLE-WILLIAMS ET AL. described the most significant issue as related to start-up costs.4 Tahhan and coworkers reported antigen-matched transfusions for ABO, Rh(C, D, E), Kell, Fya, Fyb, and S in 40 patients and calculated the cost to be 1.5- to-1.8 fold greater than that for standard ABO and D matching.8 This study reminds us that it is extremely difficult to put a dollar value on complications incurred by patients alloimmunized to RBC antigens and their subsequent morbidity. Furthermore, cost is not the overarching consideration when supplying the safest blood products to other patient populations. An additional benefit to our program is that only 50% of matching requests are directed toward SCD patients; the remainder of our matching services provide products to patients with different diseases who have developed alloantibodies and subsequently require RBC transfusion. Several important issues have emerged from our experience with extended antigen matching. First, patients with SCD may receive care at multiple institutions, and alloimmunization outcomes may reflect the divergent approaches in use. This report includes experience with patients transfused only under our protocol. Second, exactly matching all antigens for which the patient is negative is neither practical nor necessary. Mismatching may be allowed for some antigens because of the GATA polymorphism resulting in failure of expression of Fyb in RBCs but not in other tissues of many African Americans, the nature of antibodies produced, or the type of adverse events associated with specific antibodies (Le and MNS blood group systems). Our data support the concept that matching for C, E, D, Kell, Kidd, and Fya are the critical antigens to match and dramatically minimize alloimmunization. Third, new technology using molecular techniques may be helpful to reduce the risk of alloimmunization by confirming serologic phenotype and eliminating the ambiguities we encountered with the mosaic D patients. Moreover, the availability of molecular techniques for typing multiple RBC antigens in a rapid multiplexed fashion offers accurate typing of both donors and patients at a considerably lower cost than serologic techniques.25 The results from this and other studies and the potential of molecular typing techniques suggest the need for a multi-institutional clinical trial to test the efficacy of phenotypically matched transfusions in preventing alloimmunization. Such a trial would incorporate cost-benefit analysis and clinical outcomes, the results of which could provide the consensus approach to extended RBC antigen matching for SCD. Our results demonstrate that extended matching of RBC antigens for transfusions in patients with the severe complications of SCD reduces the extent and rate of alloimmunization providing safer transfusions in a timely fashion and should be considered whenever these patients are transfused. Full acceptance of this approach may require a controlled clinical trial. 1738 TRANSFUSION Volume 51, August 2011 ACKNOWLEDGMENTS The authors thank Robert Chapman, MD; William Dickey, MD; Kevin Land, MD; Pete Peterson, MD; Peter Lane, MD; Wanda Boyd, RN; and Donna Dixon, RN, for their support of this protocol over the years. We also recognize Karen Evans, MT(ASCP) SBB; Monica LaSarre, MT(ASCP) SBB; Colleen Chiappa, MT(ASCP) SBB; and the technical staff of the Reference Laboratory and Transfusion Services, Bonfils Blood Center, for their ongoing efforts for this program. Shannon Winkelmann, Andy Gerber, and Christian Billington helped with data collection and analysis. Finally, we acknowledge the help of Flo Usechek and Christian Snyder in preparing the manuscript. CONFLICT OF INTEREST No conflicts of interest for any author. REFERENCES 1. National Heart, Lung, and Blood Institute. Sickle Cell Anemia. 2008 [cited 2010 May 28]. NIH publication no. 96-4057. Available from: URL: http://www.nhlbi.nih.gov/ health/public/blood/sickle/sca_fact.pdf 2. Shulman IA. Prophylactic phenotype matching of donors for the transfusion of nonalloimmunized patients with sickle cell disease. Immunohematology 2006;22:101-2. 3. Orlina AR, Unger PJ, Koshy M. Post-transfusion alloimmunization in patients with sickle cell disease. Am J Hematol 1978;5:101-6. 4. Ambruso DR, Githens JH, Alcorn R, Dixon DJ, Brown LJ, Vaughn WM, Hays T. Experience with donors matched for minor blood group antigens in patients with sickle cell anemia who are receiving chronic transfusion therapy. Transfusion 1987;27:94-8. 5. Cox JV, Steane E, Cunningham G, Frenkel EP. Risk of alloimmunization and delayed hemolytic transfusion reactions in patients with sickle cell disease. Arch Intern Med 1988;148:2485-9. 6. Rosse WF, Gallagher D, Kinney TR, Castro O, Dosik H, Moohr J, Wang W, Levy PS. Transfusion and alloimmunization in sickle cell disease. The Cooperative Study of Sickle Cell Disease. Blood 1990;76:1431-7. 7. Vichinsky EP, Earles A, Johnson RA, Hoag MS, Williams A, Lubin B. Alloimmunization in sickle cell anemia and transfusion of racially unmatched blood. N Engl J Med 1990;322: 1617-21. 8. Tahhan HR, Holbrook CT, Braddy LR, Brewer LD, Christie JD. Antigen-matched donor blood in the transfusion management of patients with sickle cell disease. Transfusion 1994;34:562-9. 9. Aygun B, Padmanabhan S, Paley C, Chandrasekaran V. Clinical significance of RBC alloantibodies and autoantibodies in sickle cell patients who received transfusions. Transfusion 2002;42:37-43. MINOR ANTIGEN MATCHING FOR SICKLE CELL DISEASE 10. Castro O, Sandler SG, Houston-Yu P, Rana S. Predicting the effect of transfusion only phenotype-matched RBCs to patients with sickle cell disease; theoretical and practical implications. Transfusion 2002;42:684-90. 11. Sakhalkar VS, Roberts K, Hawthorne LM, McCaskill DM, Veillon DM, Caldito GC, Cotelingam JD. Allosensitization in patients receiving multiple blood transfusions. Ann N Y Acad Sci 2005;1054:495-9. 12. Afenyi-Annan A, Bandarenko N. Transfusion practices for patients with sickle cell disease at a major academic medical center. Immunohematology 2006;22:103-7. 13. Vichinsky EP, Luban NL, Wright E, Olivieri N, Driscoll C, Pegelow CH, Adams RJ; Stroke Prevention Trial in Sickle 18. Talano JA, Hillery CA, Gottschall JL, Baylerian DM, Scott JP. Delayed hemolytic transfusion reaction/hyperhemolysis syndrome in children with sickle cell disease. Pediatrics 2003;111:e661-5. 19. Ameen R, Al-Shemmari S, Al-Humood S, Chowdury RO, Al-Eyaadi O, Al-Bashir A. RBC alloimmunization and autoimmunization among transfusion-dependent Arab thalassemia patients. Transfusion 2003;43:1604-10. 20. Young PP, Uzieblo A, Trulock E, Lublin DM, Goodnough LT. Autoantibody formation after alloimmunization: are blood transfusions a risk factor for autoimmune hemolytic anemia? Transfusion 2004;44:67-72. 21. Osby M, Shulman IA. Phenotype matching of donor red Cell Anemia. Prospective RBC phenotype matching in a blood cell units for nonalloimmunized sickle cell disease stroke-prevention trial in sickle cell anemia: a multicenter patients: a survey of 1182 North American laboratories. transfusion trial. Transfusion 2001;41:1086-92. 14. Flickinger C. In search of red blood cells for alloimmunized patients with sickle cell disease. Immunohematology 2006; 22:136-42. 15. Castellino SM, Combs MR, Zimmerman SA, Issitt PD, Ware RE. Erythrocyte autoantibodies in paediatric patients with sickle cell disease receiving transfusion therapy: frequency, characteristics and significance. Br J Haematol 1999;104: 189-94. 16. Singer ST, Wu V, Mignacca R, Kuypers FA, Morel P, Vichinsky EP. Alloimmunization and erythrocyte autoimmunization in transfusion-dependent thalassemia patients of predominantly Asian descent. Blood 2000;96:3369-73. 17. Zumber MS, Procter JL, Lottenberg R, Kitchens CS, Klein HG. Autoantibody formation in the alloimmunized red blood recipient: clinical and laboratory implications. Arch Intern Med 2001;161:285-90. Arch Pathol Lab Med 2005;129:190-3. 22. Ambruso DR, Pallas C, Dickey W, Githens JH, DixonHoward D, Hassell KL, Lane PA. Prevention of red cell alloimmunization in sickle cell disease: update on a successful and cost-effective regional program. Proceedings of the 20th Annual Meeting of the National Sickle Cell Disease Program, Boston, MA, 1995, p. 124. 23. Roback J, Combs MR, Grossman B, Hillyer C, editors. Technical manual. 16th ed. Bethesda (MD): American Association of Blood Banks Press; 2008. 24. Wahl G, Quirolo KC. Current issues in blood transfusion for sickle cell disease. Curr Opin Pediatr 2009;21:15-21. 25. Allen TI, Billingsley KL, Slaughter J, Nash R, Haywood J, Bruce T, Moulds JM. Red cell genotyping: a cost effective approach to screening large numbers of donors. Transfusion 2009;49(Suppl):135A-6A. Volume 51, August 2011 TRANSFUSION 1739 Copyright of Transfusion is the property of Wiley-Blackwell and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.