Alpha‐gal sensitization and the transfusion medicine diagnostic gap: A single‐center study with multi‐institutional TriNetX validation

Background Transfusion‐related‐alpha‐gal syndrome (TRAGS) is an emerging transfusion complication in which alpha‐gal (α‐Gal)‐sensitized recipients may experience allergic reactions to B antigen‐containing plasma‐rich blood products. Group O recipients appear to be at greatest risk; group A recipients may also be at risk, whereas group B/AB individuals appear relatively protected in most studies. Identifying at‐risk patients requires both knowledge of α‐Gal sensitization status and ABO blood group, yet ABO typing among sensitized patients is poorly characterized. Study Design and Methods We retrospectively reviewed alpha‐gal‐specific IgE (sIgE) tests performed at an academic center in Madison, Wisconsin (2015–2026), assessing documented ABO blood group among patients with sIgE ≥0.10 kIU/L, and reviewing alpha‐gal syndrome (AGS) diagnosis, transfusion history, and transfusion reactions. Findings were validated using TriNetX, a federated Network of de‐identified U.S. electronic health records, with sensitivity analyses at published sIgE thresholds relevant to sensitization and clinical AGS (≥0.35, ≥0.54, ≥2.0, and ≥5.5 kIU/L). Results At the single center, 24 patients had sIgE ≥0.10 kIU/L; 11 (45.8%) confirmed AGS. Only 3 of 24 (12.5%) had a documented ABO group. In the TriNetX cohort, 9003 patients met the primary sensitization threshold; 1648 (18.3%) had ABO typing. Sensitivity analyses at higher thresholds confirmed over 80% of sensitized patients lacked ABO testing. Among sensitized patients, 211 were identified with both ABO group and transfusion history. Conclusions Most α‐Gal‐sensitized patients lack documented ABO type, representing a possible gap in TRAGS preparedness. Allergy‐Transfusion Medicine collaboration when α‐Gal sensitization is identified may facilitate preemptive ABO typing and transfusion risk stratification.