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Alloimmunization to red cell blood group antigens is a major complication for patients with sickle cell disease which limits the usefulness of red cell transfusion. Here, we report our experiences with extended red cell antigen matching for SCD patients.
Study Design and Methods: Records for 99 SCD patients between 1993 and 2006 were reviewed. Patients and donors were phenotyped for twenty blood group antigens and red cell units which were negative for antigens not expressed by the recipient were provided. Mismatches were allowed at Lea, Leb, Fyb and MNSs. Antigen matched red cell units (6,946) were provided to 99 patients (average 70 units/patient, range 1-519). 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 Rh(D) mosaic and would have been mistyped with serologic techniques. Alloimmunization was decreased compared to ABO/Rh(D) matching at our institution and others. Twelve autoantibodies and no hemolytic transfusion reactions were reported.
Conclusion: Exactly matching for ABO, Rhesus, Kell, Kidd, and Fya and extending this match whenever possible is an effective strategy to reduce alloimmunization to red cell antigens. Consideration should be given to exploring this conclusion further with a controlled, multi-institutional trial to determine efficacy, cost-benefit analysis and reproducibility of this approach on a broader scale.
Key Words: sickle cell disease, red cell transfusion, antigen matching, alloimmunization
Worldwide, sickle cell disease (SCD) affects individuals of many different racial and ethnic groups; but in the United States, most patients are of African-American descent.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 cell 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 red blood cell antigens between the largely donors of 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 red blood cell (RBC) alloantibodies creates the potential for serologic incompatibility, makes the selection of appropriate units for future transfusions more 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 recent review by the College of American Pathologists (CAP) concludes that most laboratories surveyed do not routinely perform phenotyping of red cell antigens for SCD patients beyond A, B and Rh(D); and, those that did, most commonly limited the extended matching to C, E, and K.21 Many centers caring for SCD patients allow for the initial development of alloantibodies before organizing matching beyond ABO and Rh(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, et al 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.10
In this article, we describe our experience with an extended antigen-matched RBC transfusion protocol for SCD patients receiving care through a regional, university-based comprehensive sickle cell disease 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 red cell antigen matching in a larger number of patients for a wider variety of indications since 1993 are presented here.
MATERIALS AND METHODS
Patients were identified either through a neonatal screening program or when they sought care at the Colorado Sickle Cell Treatment and Research Center (CSCTRC) at a later age and received transfusions at The Children's Hospital (TCH) Denver, University of Colorado Hospital (UCH, Denver), and Memorial Hospital (Colorado Springs). Chart review was completed under a protocol approved by the Colorado Multiple Institutional Review Board, COMIRB, (TCH, UCH) and Memorial Hospital IRB. Clinical records from patients with homozygous HbSS, HbSC, HbS β-thalassemia (β+ or β°) were reviewed from January 1, 1993 to December 31, 2006. Attempts were made to treat ninety-nine patients with red cell transfusions under the extended match protocol. For each patient, age, gender, sickle cell disease categories, red cell phenotype and indications for transfusion were recorded. The extent of phenotype match was analyzed by a computer program structured to evaluate each unit of packed RBCs transfused to each patient enrolled. Adverse events associated with any transfusion were noted. Finally, the presence and characteristics of any allo- or auto-antibody detected during the matching protocol were documented. Control data for SCD patients receiving transfusions matched for ABO and Rh(D) only was obtained from records prior to our extended matching and previously reported.4
Laboratory Testing and Extended Matching
Patients' red cells were phenotyped for multiple blood group systems and antigens including ABO; Rhesus (C, c, D, E, e); Kell (K, k); Duffy (Fya, Fyb); Kidd (Jka, Jkb); Lewis (Lea, Leb); and MNS (M, N, S, s) by standard serologic techniques. To assure accuracy of typing, tests were repeated twice as previously described.4 Antibody screening was completed at visits to the comprehensive clinic, prior to each transfusion, or 3-4 weeks after each transfusion in the case of chronically transfused patients in preparation for the next transfusion. Positive antibody screening tests were further evaluated by standard serologic techniques by transfusion services at the specific institution and the Reference Laboratory at Bonfils Blood Center to characterize allo- or auto-antibodies.
Since 1978, donors for this program have been tested for the red cell antigens noted above by standard serologic techniques.4 Phenotypes were confirmed on a second occasion; and over 120,000 donors have been studied and used as a source for transfusion products since 1978.
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 PRBCs matched only for ABO and Rh(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. Initially, washed or frozen, deglycerolized red cells 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 Bonferonni employing the program Stat Exact (Cytel Inc, Cambridge, MA). For multiple comparisons, each test must be p=0.0023 or less.
Ninety-nine patients managed 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 β-thalassemia. The average 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 packed red blood cells administered to the group was nearly 7,000 with an average of 70 transfusions per patient, a range of 1-519 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, red cell exchange or erythrocytapheresis; and 19, both types of transfusion during their clinical course. While the program was flexible enough to provide red cell components with an extended match on most occasions, a few transfusions (13 RBC units in 8 patients) were released with only ABO, Rh(D) typing because of the clinical situation (see 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, Rh(D). None of these patients developed auto- or allo-antibodies.
As was described in 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 6,946 (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, MNSs, Lea and Leb. 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, 6,217 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 transfusions for these patients was 54 (median 62, 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, anti-Kpa, anti-M, and anti-D mosaic. The patient who developed the anti-Lea experienced a mild delayed hemolytic reaction, which 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.25 Anti-M is not usually associated with hemolytic transfusion reactions.25 No antibodies to Fyb were detected. With any serologic matching protocol, mosaic Rh(D) will likely be typed as Rh(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 Rh(D) who would have been mistyped by usual serologic procedures, 4% of patients were determined to have alloantibodies at a rate 0.05 antibodies per hundred units transfused. With both analyses, percent 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 percent 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 Rh(D) matched units for which complete comparative data is available (Table 5, references 9-11). These studies provide more contemporary observations and address limitations for the historical control which are older than the study group and have possible differences in management of sickle cell disease, provision of blood products and services, and schedules of transfusions.
During the study period, 12 of the 99 transfused patients had positive antiglobulin tests associated with the appearance of autoantibodies (data shown in Table 3). Almost 60% were warm (IgG) and the rest were cold (IgM) antibodies. Patients with autoantibodies tended to receive higher numbers of transfusions (2 in the second quartile, 5 in the third, and 5 in the fourth, mean 173, median 76, range 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.
In spite of the importance of red cell 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 and Rh(D) until alloimmunization occurs. Several studies have demonstrated that 18-47% of patients managed with this approach develop antibodies at a rate of 1.7-3.8 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 packed red cells compounding the morbidity of the sickle cell disease complications.
Some groups advocate matching for C, E, and K (Table 5) in addition to ABO, Rh(D). Vinchinsky, et al, in a retrospective study of ABO and Rh(D) matched transfusions supported this approach with a report that 82% of antibodies in their patients had specificity for C,E,K and Kidd.7 A retrospective study by Castro, et al suggested that if matching for C,E, and K were completed, 53% of alloantibodies would be avoided.10 Sakhalkar, et al, supported additional matching for C, E, and K with a report of 113 patients given 2,300 units.11 This study recorded 5% alloimmunization with a rate of 0.26 antibodies/100 units. In 2001, Vinchinsky and co-workers reviewed the effects of matching ABO, Rh(D), C, E, and K in 61 patients for 1,830 transfusions.13 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, et al, described a subset of 40 patients matched for C, c, E, e, k, S, and Fy and given Rh(D) negative units.8 None developed alloantibodies as compared with a control group (46 patients) who received of matched and mismatched units resulting in 30% developing 20 new alloantibodies. The retrospective study by Castro, et al suggested that if C, E, k, S, Fyb and Jkb were matched, all alloantibodies would have been prevented in the 351 patients receiving 8,939 transfusions.10
Our composite experience with extended red cell matching is summarized in Table 4. Before initiating our program of extended matching in 1978, our blood center provided ABO and Rh(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 demonstrated a small decrease in the percent of alloimmunization and a nearly ten-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 Rh(D) only matched transfusions, and several were difficult to phenotype initially because of mixed field reactions. Subsequently, we reported a 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 we confirm and expand our experience with a larger number of patients 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 labs 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 percent of patients sensitized and number of antibodies per unit transfused was different with our historical control and three studies matching ABO and Rh(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 Vichinski, et al,13 and Sakhalkar, et al.11 Our rates of alloantibody formation compared to the Vichinski study were significantly decreased (p<0.0007). Finally, our results are comparable to the one reported study with a smaller number of patients which 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 Rh(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.26 An important consideration in transfusion therapy for patients with SCD is that, in the absence of extended matched red cells, alloantibodies develop in as many as one-third of these individuals which may necessitate expensive searches for appropriate red cell units and delay potentially lifesaving treatment. The impact of the delay may exacerbate morbidity or mortality and increase cost of care, issues which have not been included in most analyses.14,15,18 One of the main objections to extended red cell matching for SCD patients to the level described by Tahhan 8 and us 4,22 and is the additional cost for identifying suitable donors. While we did not perform a cost/benefit analysis, we previously described the most significant issue as related to start-up costs.4 Tahhan, et al, 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 Rh(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.
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. 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 biochemical structure of the antigen (Fyb), 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 Rh(D) patients. Moreover, the availability of molecular techniques for typing multiple red cell antigens in a rapid multiplexed fashion offers accurate typing of both donors and patients at a considerably lower cost than serologic techniques.27 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 red cell antigen matching for SCD.
Our results demonstrate that extended matching of red cell 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.
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Table 1. Demographics, Patient Characteristics and Numbers of Transfusions for Patients Receiving Extended Matching for Transfusions
Median age, first transfusion (mean age)
6.6 years (7.4)
5 months - 19 years, 7 months
2. Disease Type
Number of Patients
3. Indications for Transfusion
Number of Complications
Acute chest syndrome
Abnormal findings on CNS evaluation
4. Transfusions Received
Total number of units transfused
Average units per patient
Range units trasfused
1stquartile, 1-3; 2ndquartile, 3-16; 3rdquartile, 17-111; 4thquartile, 131-519
Table 2. Percent Transfusions Mismatched by Antigen
% Transfusions Mismatched
% Transfusions Mismatched
Table 3. Development of Alloantibodies, Autoantibodies and Adverse Events of Transfusions in 99 Patients on Extended Matching Protocol
7 alloantibodies, one each in 7 patients.
Antigen specificity: 1 each of Lea, Kpa; 2 for M; 3 Rh(D)*.
12 patients developed DAT** attributable to autoantibodies.
Type: warm (IgG); 5 anti-e; 1 anti-E; 3 panagglutinins.
Cold (IgM); 3 I specificity, 3 unspecified.
9/12 with 1 autoantibody; 3/12 with 2 autoantibodies.
1/12 with both 1 auto- and 1 alloantibody.
3. Adverse Events
10 patients (10%) had reported reactions to 13 units (0.2%) transfused.
5 allergic; 3 febrile; 1 moderate citrate reaction; 1 mild, delayed hemolytic transfusion reactions.
*All three patient who developed Rh(D) alloantibodies were determined to be Rh(D) mosaic, testing serologically as Rh(D) positive.
** DAT, Direct Antiglobulin Test
Table 4. Alloimmunization in Patients Treated with Extended Matching Protocol
% Patients Immunized
Rate (antibodies/100 units transfused)
N = 85
N = 12
All had previously received ABO, Rh(D)
N = 13
Extended matching only
Chronic and intermittent
N = 104
All - 7%*
Eliminate D mosaic - 4%*
* Different from historical control, p < 0.00005
Table 5. Studies Evaluating Alloimmunization and Matching for Red Cell Antigens
Matching ABO, Rh(D) Only
Number of Patients / Transfusions
% Alloimmunized / Number of Alloantibodies per 100 units Transfused
85 / 1,941
34% / 3.4
1,044 / -*
18-31% (27% in study group) / -
107 / -
30% / -
140 / 3,239**
(pediatric and adult patients)
37% / 2.8**
351 / 8,939**
29-35% / 3.8**
387 / 14,263**
31% / 1.7**
Matching Extended Beyond ABO, Rh(D), Including C, E, K
Number of Patients / Transfusions
% Alloimmunized / Rate, Alloantibodies per 100 units Transfused
Extended matching for C, E, K
61 / 1,830
8-11% / 0.5
Extended matching for C, E, K
113 / 2,345
5% / 0.26