Alloimmunization to red blood cell (RBC) antigens remains a major complication in transfusion-dependent patients with sickle cell disease (SCD), primarily due to antigenic disparities between predominantly African-descent recipients and largely Caucasian donor pools. Despite serologic matching beyond ABO and RhD, many patients continue to develop clinically significant alloantibodies. Extended molecular matching offers the potential to enhance antigen compatibility and improve transfusion outcomes in this high-risk population.

This study evaluated the impact of extended molecular RBC matching on alloimmunization and transfusion-related outcomes in patients with SCD and assessed the frequency and clinical significance of genotype-phenotype discrepancies.

We conducted a retrospective analysis of 108 SCD patients who received at least three transfusions. Patients underwent phenotyping and molecular genotyping for clinically relevant RBC antigens, and were divided into two groups: those who received extended serologic matched RBCs (n = 55) and those who received extended molecular matched RBCs (n = 53). Primary outcomes included the rate of alloimmunization, incidence of delayed hemolytic transfusion reactions (DHTRs), and the identification of antigen mismatches or discrepancies between genotype and phenotype.

Molecular genotyping revealed clinically significant antigen mismatches in 42% of patients who had been considered matched by serologic testing. Partial RH alleles were identified in 17% of patients and were significantly associated with alloantibody formation. Discrepancies between genotyping and phenotyping were observed in 21.3% of patients, most commonly involving the FY02N.01 allele. Alloimmunized patients were significantly more likely to have undetected mismatches, particularly within the RH, FY, and JK systems. Delayed Hemolytic Transfusion Reactions (DHTRs) following transfusion with units that were serologically matched but not molecularly compatible were observed in two patients.

Extended RBC molecular matching mproves the detection of clinically relevant antigen mismatches not identified by routine serologic methods and is associated with a lower risk of alloimmunization and transfusion-related complications. Molecular matching represents a major advance in transfusion safety and precision, especially for high-risk and chronically transfused populations. By enabling more accurate donor-recipient compatibility, it offers a pathway to reduce alloimmunization, improve transfusion outcomes, and support personalized care.