Red blood cell immunization in sickle cell disease: evidence of a large responder group and a low rate of anti-Rh linked to partial Rh phenotype | Haematologica

摘要

The main side-effect of transfusion is alloimunization against red blood cell (RBC) antigens. Thirteen percent of the general population were shown to be responders and 30% of responders make antibodies indicating a rate of alloimmunization of 3.9%.1 However, alloimmunization is more frequent in sickle cell disease (SCD) patients2,3 and is associated with life-threatening complications.4–6 This is a major concern in transfusion medicine since transfusion is widely used to treat the complications of SCD and to prevent their occurrence.To identify which SCD patients are at risk for RBC immunization, and which mismatch antigens are the most immunogenic, we investigated immunization in a cohort of 403 D-positive SCD transfused in the same center. The only inclusion criterion was a known history of transfusion in the center. Patient records were accessed in accordance with protocols approved by the local ethics board (Medical Ethics Committee, agreement n. 10-011). Patients were phenotyped as fully as possible prior to transfusion and were genotyped only when phenotype was not feasible. Transfusion-protocol was based on phenotypically-matched leuko-reduced RBC units for ABO, Rh and Kell. Once a patient developed a clinically significant antibody, matching is extended to the antigen against which the antibody was produced. Patients received 1–940 RBC units (total 41,349) and 170 of 403 patients (42.1%) were immunized with 1–10 antibodies (total 460). Immunization was defined as the presence of reactivity detected by the screening test either in the patient’s history or on the day of inclusion, including antibodies of undetermined specificity because such antibodies: i) are frequently related to antibodies against low-prevalence antigens; and ii) may be important allo-antibodies in development.7 Since the antibody count was weakly dependent on the number of transfusion (Spearman r=0.2856), we assessed whether SCD patients had a responder phenotype by applying the procedure developed by Higgins and Sloan.1 The distribution of the numbers of patients producing different numbers of antibodies was geometric; the frequency of producing an additional antibody was 61.0%, and 69% of the SCD patients were responders (Figure 1). This model was strengthened using an independent validation set of SCD patients (n=198) undergoing transfusion under the same protocol. Among the 460 antibodies detected, 33.5% were directed against Rh antigens (154 antibodies in 93 patients). Seventy of 154 anti-Rh antibodies were developed in patients negative for the corresponding antigen; this was unexpected in view of the routine practice of Rh/Kell-matched RBCs for transfusion in France. Similar observations were also reported by Chou et al.8 with a similar rate for unexplained anti-Rh. Other anti-Rh antibodies (n=84) were found in patients with a positive phenotype for the corresponding antigen and could be linked to expression of partial-Rh phenotype.9,10 Thus, to determine the contribution of Rh variants to alloimmunization, we characterized the RHD and RHCE variant alleles in patients (Online Supplementary Appendix). Based on the presence of homozygosity or compound heterozygosity of partial allele(s), we deduced that 34 (8.4%) of the 403 patients of our population carried a partial-D phenotype; 21 (20.8%) of 101 C-positive patients were predicted to express a partial-C phenotype; 14 (3.5%) of 400 could be considered partial-e (Table 1). The occurrence of anti-D was more prevalent in partial-D (17.6%) than in wild-type (3.4%) individuals. Similarly, anti-C was more common in partial than non-partial-C individuals. These differences were not statistically significant, but this was probably due to the small numbers of patients with the various partial phenotypes. Unexpectedly, anti-e was the most frequent anti-Rh antibodies observed, although only 3.5% of patients had a predicted partial-e phenotype. Moreover, anti-e was equally prevalent in partial