Regular Article TRANSFUSION MEDICINE High prevalence of red blood cell alloimmunization in sickle cell disease despite transfusion from Rh-matched minority donors

The use of transfusion therapy for sickle cell disease (SCD) is increasing due to expanded indications, increased availability of erythrocytapheresis, and oral chelators to treat transfusional iron overload. However, alloimmunization to red blood cell (RBC) blood group antigens remains a major complication for patients with SCD and often presents significant challenges in their medical management. The incidence of alloimmunization in patients with SCD ranges from 7% to 47%, dependent on age, RBC exposures, and extent of antigen matching for blood groups other than ABO and RhD. An estimated 4% to 11% of patients with SCD who receive transfusions develop overt delayed hemolytic transfusion reactions (DHTRs), but mild DHTRs may be unrecognized. Sensitization to Rh antigens (D, C, c, E, and e) and to K comprise the majority of the RBC antibodies encountered in SCD. One major explanation of the high rates of alloimmunization is the disparate distribution of RBC antigens between donors primarily of European ancestry and patients with SCD primarily of African ancestry. One strategy to decrease alloimmunization in SCD is provision of phenotype matched RBCs for C, E, and K antigens. Transfusion with units from African American donors has also been suggested, although an increase in production of antibodies to low incidence antigens present primarily in minority groups is predicted. Phenotype matching for additional minor antigens in the Kidd, Duffy, andMNS systems reveal that more stringent matching results in lower alloimmunization rates, but there is no standard of practice. The Rh system is a complex blood group system and includes .50 different serologic specificities. The RH locus is comprised of 2 homologous genes, RHD and RHCE, which encode the D antigen and the CE antigens in various combinations (ce, cE, Ce, or CE), respectively. RHD and RHCE are inherited as haplotypes, and expression of the proteins is exclusive to erythrocytes. Genetic diversity of the RH locus has been revealed in the last decade, with .200 RHD and 80 RHCE alleles reported. These potentially encode variant or altered antigens due to amino acid changes in the Rh proteins. The RBCs may lack common Rh antigenic epitopes or carry novel epitopes. Standard RBC antigen typing does not distinguish the presence of Rh variants, which are more prevalent in individuals of African ancestry. For example, RHD encodes the D antigen (“Rh positive”), but individuals with altered RHD encoding partial D, defined as missing some D epitopes, may form anti-D when exposed to conventional D antigen. In contrast, individuals with altered RHD encoding weak D, defined as expressing a reduced amount of D antigen but not lacking epitopes, are not typically at risk for anti-D. Variant RHCE alleles are also prevalent in individuals of African descent, with alleles encoding partial e antigen most often encountered.