Feasibility of RH Genetic Matching for Patients with Sickle Cell Disease with an African-American Donor Pool
Authors: Chou Stella T. , Friedman David F. , Jackson Tannoa , Vege Sunitha , Keller Margaret A. , Westhoff Connie M 
Published: October 2019

Abstract
Background RH gene variation is frequent in individuals of African descent and contributes to Rh alloimmunization among patients with sickle cell disease (SCD). Despite antigen matching for C, E, and K and transfusion from African American (AA) donors, patients with SCD continue to form antibodies against Rh antigens (Chou et al 2013, Blood, 122, 1062). RH genotyping of patients with SCD and selected African American (AA) donor groups has the potential to improve transfusion therapy. We developed a virtual matching program with groups of AA blood donors and patients with SCD to select blood based on RH genotype and tested whether a RH genotype matching strategy is feasible. Moreover, we evaluated the feasibility of considering patient and AA donor RH genotypes for individuals with SCD immunized to D and e antigens since providing D- and/or e- RBCs often exposes the patient to other antigens they may lack and results in further alloimmunization events.
Methods RH genotypes were determined in 657 patients with SCD and 625 AA blood donors by RH BeadChip (BioArray Solutions) and manual AS-PCR or exon sequence analysis for alleles ambiguous or not detected by Beadchip. Automated virtual donor matching for each patient with SCD was performed considering RHD and RHCE separately and together. Customized scripts in a Filemaker Pro database counted exact genetic matches as well as used more ÒinclusiveÓ criteria to select donors with only RH genes that would not encode Rh antigens absent in the patient.
Results The distributions of RHD and RHCE alleles in donors and patients were similar. Of 24 RHD genes detected in both groups, 5 (RHD*D, *DAU0, *deleted D, *weak D 4.0, and *inactive RHDψ) accounted for 91% of donor alleles and 90% of patient alleles. Of 23 RHCE genes, the 7 most common accounted for 92% of donor alleles, and 91% of patient alleles. Match results for patients with > 25 donor matches or no matches according to locus and stringency of criteria are summarized in the table.
Percent of 657 pts with > 25 or no matches by locus and stringency of criteria TableMatch by:RHDRHCERHD and RHCECriteria>25None>25None>25NoneExact68.2%4.4%41.7%5.0%9.9%19.0%Inclusive*100%0%76.7%0.91%61.8%1.4%
*Inclusive match includes donors with only RH genes that would not encode Rh antigens absent in the patient.
Thirty D+ individuals had formed anti-D and were subsequently transfused D- RBCs, accounting for 70% of units transfused to these individuals (9305 D- units of 13304 total units transfused). Twenty-three individuals had at least one conventional RHD allele (77%). Virtual matching revealed an average of 8 donors (1.3%, range 0 - 44) with exact genetic matches and 43 donors (6.9%, range 0 - 44) using ÒinclusiveÓ criteria, compared to 128 donors (20.5%, range 113 - 210) available if matching by serology for D, C, and E.
Twenty-one e+ individuals (7 E+e+ and 14 E-e+) had anti-e, and were transfused e-E+ RBCs if anti-e was demonstrating in their serum. Four of the 14 E-e+ subsequently formed anti-E. Virtual matching revealed an average of 7 donors (1.1%, range 0 - 22) with exact genetic matches and 34 donors (5.4%, range 5 - 107) using ÒinclusiveÓ criteria, compared to 133 donors (21.3%, range 113 - 166) available if matching by serology for D, C, and E.
Conclusions Automated selection of AA donors based on RHD, RHCE, or both would be feasible for the majority of patients with SCD given an adequate genotyped donor pool. These studies are necessary to determine the number of minority donors required to support patients with SCD with genetically Rh matched donor units. Compared to donor matching by serologic Rh types, genetic matching for this patient cohort may prevent exposure to a foreign RhD or RhCE protein, but does limit the number of donors versus standard phenotype matching for C and E. For patients immunized to Rh antigens, providing RH genotype matched units may decrease the need for D- donor units and avoid further alloimmunization. Future prospective studies are needed to determine whether transfusion with RH genotype matched donor units can decrease alloimmunization and improve transfusion safety for patients with SCD.

Disclosures
No relevant conflicts of interest to declare.