Influence Of RHCE Variant Genotypes On Anti-e Alloimmunization Risk In SCD Patients

A higher incidence of Red Blood Cell (RBC) alloimmunization exists in Sickle Cell Disease (SCD) than in any other multiply transfused population. The majority of the RBC alloantibodies are to Rh (D, C, c, E, e) and K antigens. Transfusing Rh and Kell matched RBCs substantially decreases alloimmunization rates in SCD patients; however clinically significant Rh antibodies with apparent common specificities persist as a result of altered RH alleles in SCD patients.

SCD patients with a history of ≥15 transfusions or having RBC alloantibody(ies) were consented and asked to complete an ethnicity survey defining patients as “African” (patient or both parents African-born), African American (parents and patient US-born), or other. RH genotyping was performed on all patients using RH Variant Beadchips (BioArray, Warren NJ). Medical records of patients were retrospectively reviewed and compared to RH genotype and ethnicity to determine the clinical impact of RH variants on alloimmunization. Fisher’s Exact test was used to determine statistical significance of correlations.

Among 117 SCD patients genotyped, 67 (57.3%) had alloantibodies, with a median of 50 transfusion exposures. RHCE variant haplotype frequencies for (C)ce^s, ce^s, ceAR, ceMO and ce^s(340) were 6.8%, 20.1%, 0.9%, 1.3% and 0.4%, respectively. Twenty-two patients were either homozygous (7), compound-heterozygous (5), or heterozygous for these RHCE variant haplotypes with a conventional RH E allele in-trans (10). Of these, approximately 32% (7/22) formed an anti-e alloantibodies after a median of 6 Rhe+ RBC transfusion exposures compared to 7.3% (7/95) of all other patients (p=0.0048). No anti-e alloantibodies were detected in 15/22 patients within the RHCE variant subgroup after 1436 Rhe+ RBC transfusions (median 66 transfusions/patient), yielding an anti-e alloantibody frequency of 0.45/100 units. Fifty percent (11/22) of patient in the RHCE variant subgroup formed an autoantibody, compared with 24% (19/78) of all other patients (p=0.0345). Approximately 32% (8/25) of the “African” patients were homozygous or compound heterozygous for a variant, as opposed to 10.7% of “Non-African” patients (p=0.0312); only 12.5% (1/8) of African patients with RHCE variant subgroup formed anti-e alloantibodies versus 46% of “Non-African” patients this subgroup (p= NS).

SCD patients with RHCE variant haplotypes are at increased risk for the formation of clinically significant anti-e alloantibodies, which may be inaccurately identified as autoantibodies in the absence of RH genotyping. This implies that RH genotyping should be either incorporated into the standard RBC phenotype evaluation in all SCD patients, or at least into the evaluation of any SCD patient with an autoantibody that demonstrates “e” specificity. We report similar RHCE variant allele frequencies compared to previously published SCD population studies; however we found a higher prevalence of homozygous and compound heterozygous RHCE variant genotypes in SCD patients less then two generations removed from African immigration. Confounding factors for anti-e alloimmunization risk in SCD patients with RHCE variant genotypes other than antigen disparity exist which may explain why “African” patients within the RHCE variant subgroup demonstrated lower anti-e alloimmunization compared to other patients in this group. Further study is warranted to further characterize the immunogenic potential of high incidence Rh antigens in individuals with RH variants, and the immunogenetic variables that affect alloimmunization overall.

Fasano:ApoPharma: Honoraria.