Regions With High Alpha-Gal Prevalence May Represent Potential Transfusion Risk

Patients with blood type O who received group B or AB platelets or plasma had significantly higher rates of allergic transfusion reactions (ATRs) in U.S. regions where alpha-gal syndrome (AGS) is common, according to a large international cohort study published in JAMA Internal Medicine. The findings provide epidemiologic evidence that transfusion-related alpha-gal syndrome (TRAGS) may represent a previously unrecognized transfusion risk.

Alpha-gal syndrome is a tick-associated allergy to galactose-α-1,3-galactose (alpha gal), a carbohydrate found in most mammals but not humans. Its structure closely resembles the human blood group B antigen, and many alpha-gal IgE antibodies cross-react with B antigen. Because transfusion services routinely give group B or AB plasma and platelets to type O patients to avoid product outdating or in bleeding emergencies, investigators from the Biomedical Excellence for Safer Transfusion (BEST) Collaborative hypothesized that if TRAGS occurs as proposed, excess reactions to B antigen–containing units should appear only where alpha-gal sensitization is widespread.

The retrospective study analyzed 558,823 platelet and plasma transfusions at 40 sites across five countries from 2020 to 2024. In the U.S., sites were sorted into AGS high- or low-prevalence clusters using county-level estimates of suspected AGS prevalence. At each site, ATR rates among type O patients receiving B or AB units were compared with rates among type O patients receiving O units, so every site served as its own control.

In the U.S. high-prevalence cluster, type O recipients of B or AB units had nearly four times the risk of an ATR of any severity compared with those receiving O units (relative risk, 3.93). In contrast, in the U.S. low-prevalence cluster, there was no significant overall difference in relative risk between the exposed and reference groups

In AGS high-prevalence regions, the risk of an ATR was higher among patients receiving group B units than among those receiving AB units, while group A units were not associated with excess risk. Among type O patients receiving B units specifically, the relative risk of a moderate-to-severe ATR was 9.14 in high-prevalence regions, versus 2.15 in low-prevalence regions. No excess ATRs were detected among type B patients receiving B antigen–containing units, consistent with previous evidence that individuals with B or AB blood types are relatively protected from developing AGS.

The study did not identify a similar TRAGS signal outside the U.S. No excess reactions were detected in Australia, France, Germany or Japan. The authors noted that detecting a TRAGS signal required frequent out-of-group transfusion of B or AB units, accurate classification of high-prevalence sites, and robust reaction reporting, factors that may have limited detection outside the U.S.

The authors noted several important limitations. The retrospective design meant patient sera could not be tested to confirm alpha-gal IgE, and no patient AGS history was available, so the link to sensitization remains inferential. Reported ATR rates were low (occurring in 0.3% of the 558,823 transfusions analyzed) and passive reporting likely undercounts reactions. Rising awareness of TRAGS during the study period may also have prompted clinicians at high-prevalence sites to investigate suspected reactions more actively.

The investigators suggested several potential approaches to reduce risk, including limiting B antigen–containing units in type O patients, incorporating alpha-gal IgE testing into appropriate reaction evaluations and using group A rather than AB plasma in bleeding emergencies. Blood collectors could consider redistributing B and AB units toward lower-prevalence regions. Further work is needed to clarify the risk to type A recipients and to identify product modifications that could make out-of-group transfusions safer.