Original Article
Alloimmunization in Sickle Cell Anemia and Transfusion of Racially Unmatched Blood
N Engl J Med 1990; 322:1617-1621June 7, 1990
- Abstract
- Abstract
Transfusion therapy for sickle cell anemia is limited by the development of antibodies to foreign red cells. To evaluate the frequency and risk factors associated with such alloimmunization, we determined the transfusion history, red-cell phenotype, and development of alloantibodies in 107 black patients with sickle cell anemia who received transfusions. We compared the results with those from similar studies in 51 black patients with sickle cell disease who had not received transfusions and in 19 nonblack patients who received transfusions for other forms of chronic anemia. We assessed the effect that racial differences might have on the frequency of alloimmunization by comparing the red-cell phenotypes of patients and blood-bank donors (n = 200, 90 percent white).
Although they received transfusions less frequently, 30 percent of the patients with sickle cell anemia became alloimmunized, in contrast to 5 percent of the comparison-group patients with other forms of anemia (P<0.001). Of the 32 alloimmunized patients with sickle cell anemia, 17 had multiple antibodies and 14 had delayed transfusion reactions. Antibodies against the K, E, C, and Jkb antigens accounted for 82 percent of the alloantibodies. Comparison of red-cell phenotypes in the three study groups (the patients with sickle cell anemia, the patients with other forms of anemia, and the blood donors) revealed statistically significant differences between the patients with sickle cell anemia and the donors but not between the patients with other forms of anemia and the donors. These differences are most likely racial.
We conclude that alloimmunization is a common, clinically serious problem in sickle cell anemia and that it is partly due to racial differences between the blood-donor and recipient populations. (N Engl J Med 1990; 322: 1617–21.)
Media in This Article
Table 1
Frequency of Alloimmunization among Patients with Sickle Cell Anemia and Patients with Other Forms of Chronic Anemia.Table 2
Relation of the Number of Transfusions to the Appearance of Red-Cell Antibodies in Sickle Cell Anemia.Article Activity
- Article
SINCE the number of therapeutic options in sickle cell anemia is limited, red-cell transfusions have been used to treat certain complications of this disease.1 2 3 4 5 6 7 8 9 10 11 12 For example, the morbidity and mortality of cerebrovascular accidents,10 surgery,2 events related to anemia,8 and acute chest syndrome1 have been reported to be reduced by transfusion therapy. The majority of patients with sickle cell anemia have received a red-cell transfusion by the time they reach adulthood 7 , 8 , 13 , 14
Alloimmunization is a serious and unfortunate common complication in such patients. It results in difficulty obtaining compatible blood, delayed transfusion reactions, and occasional life-threatening events.14 15 16 17 18 19 20 21 22 23 The risk of alloimmunization in patients with sickle cell anemia has been reported to range from 4 to 40 percent.13 , 14 , 19 , 21 , 24 25 26 27 Although some studies suggest that the frequency of alloimmunization in patients with sickle cell anemia is not significantly higher than in other recipients of long-term transfusion,24 25 26 others report a higher rate of alloimmunization among patients with sickle cell anemia.7 , 14 , 18 , 24 , 28 The mechanism underlying the increased incidence of alloimmunization in these patients has been suggested to be an altered immune response, increased frequency of certain HLA antigens, or a lack of phenotypic compatibility between donor and recipient blood.21 , 24 , 29 30 31 32 33
Since there are limited data on transfusion practices and the role of racial differences between donors and recipients in the frequency of alloimmunization among patients with sickle cell anemia, we performed a prospective study to determine the frequency of red-cell alloimmunization, the importance of specific red-cell phenotypes of donors and recipients, whether the number of transfusions is related to antibody formation, and whether racial differences between donors and recipients account for alloimmunization.
Methods
Patients
All patients with sickle cell anemia or other disorders requiring long-term transfusion who received their primary care at Children's Hospital Oakland between 1978 and 1985 were eligible for study. A total of 158 black patients with sickle cell anemia and 19 nonblack patients receiving transfusions for chronic anemia (11 with thalassemia major and 8 with pure red-cell aplasia) were enrolled. Of the 158 patients with sickle cell anemia, 5 died and 9 were lost to follow-up; of the 19 with chronic anemia, 3 died and 2 were lost to follow-up. Records were available for all patients.
The diagnoses of sickle cell anemia and thalassemia were confirmed by standard hemoglobin electrophoresis, isoelectric focusing, measurement of hemoglobin A2 and hemoglobin F levels, and family studies. Both groups of patients received blood from the local blood bank; nondesignated donations not matched for phenotype were transfused unless an antibody was detected, at which time the donations were matched for the specific antibody.
Data Collection
The hospital records of all patients were reviewed. The list of patients was cross-checked with hospital transfusion records. Beginning in 1978, the collection of data on transfusions was standardized by the use of pretransfusion and post-transfusion (six weeks and one year) follow-up forms. These forms contained information about the indication for transfusion, the number of transfusions, and the clinical and laboratory evidence of complications resulting from transfusion. Patients who had jaundice, fever, or an inappropriate decrease in the hemoglobin level after transfusion underwent laboratory evaluation for alloantibodies.
Laboratory Protocol
Our transfusion protocol included determination of the red-cell phenotype for the following antigens: A, B, C, c, D, E, e, Lea, Leb, K, Fya, Fyb, Jka, Jkb, M, N, S, s, and P1. The red-cell phenotype was also determined in 200 units of blood supplied by the Alameda—Contra Costa County Blood Bank. Screening for antibodies was performed before and after transfusion, according to standard methods including enzymatic and antiglobulin techniques.34 If screening was positive, the antibody was identified by means of panels of reagent red cells; identification was confirmed by a regional reference laboratory. All patients underwent annual laboratory evaluation for red-cell alloantibodies.
Racial Background of Donors
A total of 12,497 blood donors voluntarily identified their racial background as part of the volunteer blood-donor program carried out at our community-based blood bank.
Results
The frequencies of alloimmunization in the patient groups are shown in Table 1Table 1
Frequency of Alloimmunization among Patients with Sickle Cell Anemia and Patients with Other Forms of Chronic Anemia.. These results reflect the transfusion records of all 158 patients with sickle cell anemia who were followed prospectively. Alloantibodies were detected in 32 (30 percent) of the 107 patients in this group who received transfusions and in none of those who did not. By contrast, such antibodies developed in only 1 (5 percent) of the 19 patients who received transfusions for other forms of anemia — a significantly lower frequency (P<0.001).Transfusion History
The transfusion histories of the patients were reviewed to determine whether the frequency of alloimmunization was related to the number of transfusions (Table 2Table 2
Relation of the Number of Transfusions to the Appearance of Red-Cell Antibodies in Sickle Cell Anemia.). The patients with chronic anemia received transfusions more frequently than the patients with sickle cell anemia. Among the patients with sickle cell anemia, those in whom antibodies did not develop received an average of only 13 transfusions per patient, whereas those in whom antibodies developed received an average of 23. The appearance of the first antibody occurred on the average after 12 transfusions, but some antibodies did not appear until after 31 transfusions; 75 percent of the new antibodies had developed by the 21st transfusion. These data suggest that the development of antibodies is related to the number of transfusions received.Sixty-eight alloantibodies were detected among the 107 patients with sickle cell anemia who received transfusions. These antibodies are listed in their order of frequency in Table 3Table 3
Distribution of the 68 Red-Cell Alloantibodies in 107 Patients Receiving Transfusions for Sickle Cell Anemia.. Seventy-six percent of the alloantibodies were the K, E, C, or Jkb antibodies. The 68 antibodies developed in 32 patients. Fifteen patients had single antibodies and 17 had multiple antibodies; 12 of the latter had more than three antibodies.In addition to alloimmunization, 13 of the 107 patients receiving transfusions (12 percent) had positive direct and indirect antiglobulin tests: 8 of the 32 with alloimmunization (25 percent), and 5 of the 75 without it (7 percent). In all 12 patients, the antibody was cold-reactive and specific for the I antigen. The antibody did not appear to be clinically important, since it became thermally reactive at 4°C and not at 37°C.
There were 14 delayed reactions to transfusion in 12 (11 percent) of the patients with sickle cell anemia, including jaundice, a decrease in the hemoglobin level, and a positive direct or indirect Coombs' test. Most of these patients had accompanying fever or pain (or both).
To determine whether the racial background of the blood-donor population was responsible for the high rate of alloimmunization among the patients with sickle cell anemia, we compared the racial background and phenotype of the donors with those of the recipients. Of the last 12,497 donors, 90 percent (11,120) were white, 5 percent (683) were black, 3 percent (425) were Asian, and 2 percent (269) were of other backgrounds. All 107 recipients of transfusions were black. The red-cell phenotypes of the 158 patients with sickle cell anemia were compared with those of 200 donors (Table 4Table 4
Red-Cell Phenotypes of Patients with Sickle Cell Anemia and Local Blood-Bank Donors.). These groups differed significantly in the decrease in antigen frequency, including the antigens that were responsible for most of the alloantibodies found in the group with sickle cell anemia (K, E, C, Jkb, Fya, Fyb, and Jka). When compared with all patients with sickle cell anemia or with the patients with sickle cell anemia who did not have alloimmunization, the patients with sickle cell anemia and alloimmunization had the lowest frequency of antigens responsible for most of the antibodies (K, 0 percent; Fya, 6 percent; C, 22 percent; E, 22 percent; and Jkb, 31 percent).To investigate why red-cell antibodies rarely developed in nonblack patients with chronic anemia, we compared their red-cell phenotypes with those of the blood donors for the antigens that were most likely to cause antibodies to develop in the patients with sickle cell anemia (K, E, C, and Jkb). There was no significant difference between these two groups in the frequency of any of these antigens (Table 5Table 5
Red-Cell Phenotypes of Patients with Chronic Anemia and Local Blood-Bank Donors.).We also compared the red-cell phenotypes of the nonblack patients with chronic anemia with those of the patients with sickle cell anemia. The patients with sickle cell anemia had a significant decrease in the frequency of the red-cell antigens responsible for most of the alloantibodies — for example, C (83 percent vs. 28 percent, P<0.001), E (50 percent vs. 24 percent, P<0.01), Jkb (75 percent vs. 39 percent, P<0.001), and K (7 percent vs. 2 percent, P<0.2).
Discussion
There are few published data to support the conclusion that the risk of alloimmunization is greater in patients receiving transfusions for sickle cell anemia than in patients receiving transfusions for other chronic diseases. The largest study of its type to date, the Cooperative Study of sickle cell anemia, found that the prevalence of alloimmunization was 20 percent among 1340 patients with sickle cell anemia.28 Previous studies have not consistently considered factors such as the patient's age, the number of red-cell units transfused, the transfusion history, laboratory monitoring for the development of antibodies, the red-cell phenotypes of the donor and recipient, and the donor's racial background.7 , 13 , 14 , 18 , 19 , 24 25 26 27 28 The present study was undertaken to investigate these factors.
Our results demonstrate that alloantibodies developed in more than 30 percent of patients receiving transfusions for sickle cell anemia. This represents a low estimate of the rate of alloimmunization, since not all antibodies are detected by standard techniques. The 34 percent frequency that we found among the adult patients is similar to or higher than previously reported rates.7 , 14 , 18 , 24 25 26 , 28 In contrast to the alloimmunization rate of 7.5 percent reported in a Detroit-based pediatric population,13 however, the rate among our pediatric patients was 24 percent. Since both studies evaluated similar patient populations and numbers of exposures to donated blood, the difference in the rates of alloimmunization could have resulted from differences in either the methods of monitoring patients or the racial composition of the donor population. Despite such differences, these studies in children confirm a relation between alloimmunization and the frequency of donor exposure.
In the present study, alloimmunization was a serious clinical problem. Multiple antibodies developed in 53 percent of the patients with alloimmunization and in 16 percent of all patients who received transfusions. The development of these antibodies often resulted in clinical complications and delayed transfusion therapy. The high frequency of autoantibodies among patients given transfusions resulted in additional problems in crossmatching.
Eleven percent of patients given blood had delayed transfusion reactions. This frequency is much higher than that reported by Cox et al., who found that 4 percent of patients with sickle cell disease had such reactions.18 However, the retrospective nature of their study may have underestimated the incidence of reactions. In the general population, the incidence of delayed transfusion reactions has been reported to range from 1 in 1500 exposures to transfused units to 1 in 11,650.18 , 20 , 35 , 36 A recent study of 530 patients (none with sickle cell anemia) who received 2500 units of blood found no evidence of delayed hemolytic transfusion reactions, even in patients in whom new alloantibodies could be demonstrated.35 The total of 14 episodes of clinically serious transfusion reactions in our controls who received approximately 2100 units of blood is much higher than the number observed in previous studies.35 Activation of the immune system may contribute to the increased incidence of delayed transfusion reactions.16 , 17 , 20 , 29 , 31
In contrast to the high frequency of alloimmunization among patients with sickle cell anemia, the alloimmunization rate in our patients with chronic anemia was 5 percent, despite the high number of transfusions. Several studies have reported an alloimmunization rate of approximately 5 to 10 percent among patients receiving long-term transfusion for thalassemia major.25 , 37 38 39 The largest study, by Sirchia et al., found an alloimmunization rate of 5.2 percent among 1435 such patients.39 The development of multiple antibodies is very unusual in patients receiving transfusions for thalassemia, in contrast to patients receiving transfusions for sickle cell anemia, and the selection of compatible blood is rarely a problem.37 38 39
The increased incidence of alloimmunization in sickle cell anemia has been suggested by some authors to be due to lack of phenotypic compatibility between donors and recipients.7 , 14 , 21 , 24 , 28 In an analysis of racial and genetic phenotypes, Giblett30 demonstrated that when black recipients were given blood obtained from white donors, the risk of alloimmunization was higher than when donors and recipients were matched for race. However, she did not predict a statistically significant increase in the incidence of antibody formation, and her analysis was based on exposure to few transfusions. One would expect black patients receiving multiple transfusions to have a significantly increased rate of alloimmunization. In fact, Kim et al. found a significantly higher frequency of alloimmunization among black patients than among white patients given a similar number of transfusions.40 Limited reports of the racial background of blood-bank donors suggest that patients with sickle cell disease mainly receive blood from white donors.7 , 14 , 24 In Washington, D.C., 88 percent of blood donors are white, and in Galveston, Texas, 98 percent.27 , 41 A lack of blood donors belonging to minority groups has also been implicated by Orlina et al. in the high frequency of alloimmunization among patients with sickle cell anemia residing in the Chicago area.14 On the basis of this preliminary information, some authors have recommended that such patients receive blood matched for race or antigens.7 , 14 , 24 , 28
To investigate whether the racial background and red-cell phenotype of the donors were major factors in the high alloimmunization rate among the patients with sickle cell anemia, we determined these variables in local blood-bank donors and our patients. Our results indicated that black persons and members of other minority groups accounted for a disproportionately small part of the donor population. Furthermore, racially explained differences between donors and recipients in red-cell phenotype account for most of the antibodies that developed in our patients with sickle cell anemia. In contrast, in the patients receiving transfusion for other chronic anemias, there were no antigenic differences between donors and recipients and a very low alloimmunization rate.
Our study illustrates a problem created by the lack of participation of black persons in an urban blood-banking program. In addition to increasing the availability of phenotypically matched blood for patients with sickle cell anemia, greater participation by the black community would enhance the ability of donor programs throughout the country to meet the national need for blood. At present, the requirements of alloimmunized patients with sickle cell anemia place the greatest demand for blood on the rare-donor registry of the American Red Cross, accounting for 20 percent of all units shipped.41 The requests to this registry for blood for these patients specify units lacking multiple common antigens. The blood types without these antigens are found predominantly in the black population. If the increase in requests for blood types found in black donors continues as it has over the past decade, demand will exceed supply. The screening of white donors to obtain compatible blood for alloimmunized patients with sickle cell anemia would result in a 10-fold increase in the costs of blood banking.7 However, Beattie and Shafer have recently demonstrated that the participation of the black community in blood-banking programs can be increased.42
In summary, our results demonstrate that 30 percent of patients with sickle cell anemia were alloimmunized and that 11 percent had delayed transfusion reactions. This was in contrast to the white patients receiving long-term transfusion, who despite receiving more units had a 5 percent incidence of alloimmunization. An analysis of the red-cell phenotypes and racial backgrounds of the donor and recipient populations demonstrated that alloimmunization in the patients with sickle cell anemia was in large part due to antigen mismatching between a largely white donor population and black recipients. We recommend that all patients with sickle cell anemia who undergo transfusion be matched with donors for the red-cell antigens commonly associated with alloimmunization and transfusion reactions. Ambruso et al. have demonstrated that this approach is cost effective and leads to a 10-fold decrease in alloantibody formation.24 To accomplish these goals, black persons must be aggressively recruited as blood-bank donors. This will enable patients with sickle cell anemia to obtain compatible blood and will help solve the national problem of identifying appropriate donors.
Supported by grants (HL-20985–12 and NO1-HB-73004) from the National Institutes of Health.
We are indebted to Clemencia Girardot, M.D., for assistance with data collection; to Evelyn Brown, M.T., for determining the red-cell phenotypes; to David Minkus, Ph.D., and Troy Duster, Ph.D., for comments on sociologic issues related to blood banking; and to Shanda Robertson for technical assistance.
Source Information
From the Department of Hematology/Oncology (E.P.V., A.E.), Children's Hospital Oakland (B.L.), Oakland, Calif.; the Adult Sickle Cell Program, Alta Bates Hospital, Berkeley, Calif. (R.A.J.); and the Alameda—Contra Costa County Blood Bank, Oakland, Calif. (M.S.H., A.W.). Address reprint requests to Dr. Vichinsky at the Department of Hematology/Oncology, Children's Hospital Oakland, 747 52nd St., Oakland, CA 94609.
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