Genotype-Driven Resolution of Panagglutination Over a Decade of Korean Rare Blood Program Case Archives

As populations age and chronic disease burden rises, transfusion demand grows in both volume and immunohematologic complexity. When reagent red blood cells (RBCs) in antibody screening and identification panels show uniform reactivity with a negative autocontrol and direct antiglobulin test, an alloantibody to a high-frequency antigen (HFA) is suspected. These cases pose persistent diagnostic challenges and may necessitate least-incompatible transfusions, potentially compromising safety. We evaluated whether a structured molecular approach within a national rare-blood program improves diagnostic resolution and transfusion planning in such cases.

We retrospectively reviewed suspected HFA alloantibody cases referred to the Korean Rare Blood Program (KRBP) case registry between 2013 and 2024. All cases underwent a two-tier molecular workflow consisting of allele-specific real-time PCR for targeted variants, followed by confirmatory Sanger sequencing when indicated. Clinical data, serology, genotyping results, and impact on transfusion management were abstracted and analyzed.

Of 1031 referrals, 28 met inclusion criteria. Molecular testing identified underlying rare antigen-negative phenotypes in most cases, including Jr(a-) in 13/28 (46.4%) and Yk(a-) in 11/28 (39.3%) cases. The tiered genotyping strategy enabled accurate genotype-phenotype correlation and directly informed the selection of antigen-compatible RBC units and donor search strategies.

Suspected HFA alloantibodies frequently reflect clinically significant antigen deficiencies that cannot be resolved by serologic testing alone. Integration of a centralized molecular workflow with a national registry substantially improves diagnostic accuracy and transfusion safety. Expansion of family-based donor identification and systematic rare-phenotype surveillance is recommended to enhance national transfusion preparedness.