Transfusion-Related Alpha-Gal Syndrome Studied in JAMA

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A paper published in JAMA Internal Medicine reported on the findings regarding Transfusion-Related Alpha-Gal Syndrome from an epidemiologic study that sought to, “investigate the possibility that severe allergic transfusion reactions (ATRs) to B or AB plasma or platelet units may reflect a manifestation of Alpha-gal syndrome (AGS).” The authors explained that, “Alpha-gal syndrome is an acquired food allergy transmitted by tick bites. Patients with AGS characteristically develop allergic reactions 2 to 6 hours after eating mammalian meat, with presentations ranging from mild urticaria or gastrointestinal symptoms to fatal anaphylaxis.”

The researchers hypothesized that, “if transfusion-related Alpha-gal syndrome (TRAGS) is a true clinical entity, then in AGS high-prevalence regions-only (where many inhabitants have preformed alpha-gal IgE), we should observe excess ATRs among patients with blood type O receiving B antigen–containing units.” The international, multicenter, retrospective cohort study took place from January 2020 through December 2024. “Study sites were academic medical centers in the U.S., Australia, Japan, Germany, and France. [Each site] extracted data from hospital records for its assigned study period on all platelet and plasma transfusions administered to consecutive patients with blood type O and reported ATRs. [At all sites,] clinical testing for serum alpha-gal IgE had been performed using the same commercial ImmunoCAP assay (Thermo Fisher/Phadia).” The study defined ATRs as, “a transfusion-associated adverse event reported by a clinician and documented as an ATR in the medical record by a transfusion medicine physician. Sites categorized all ATRs as mild or as moderate to severe.”

Findings from Studying Transfusion-Related Alpha-Gal Syndrome

The authors noted that, “[i]n total, 558,823 platelet and plasma transfusions at 40 sites in five countries were analyzed, among which ATRs occurred in 1,744 transfusions (0.3 percent). U.S. data were obtained from 26 sites. The AGS-high cluster had 9 sites (3 in U.S. counties with >87 suspected AGS cases/1M PPY and 6 in U.S. counties with 11-87 suspected cases/1M PPY). The AGS-low cluster had 15 sites (14 in U.S. counties with <11 suspected cases/1M PPY and 1 in a U.S. county with 0 suspected cases/1M PPY).” The researchers found that, “in the AGS-low cluster, there was no significant difference in ATR rates between patients with blood type O receiving B or AB units and patients with blood type O receiving O units. In the AGS-high cluster in contrast, ATR rates were significantly higher among patients with blood type O receiving B or AB units vs patients with blood type O receiving O units (overall risk ratio (RR), 3.93; 95 percent CI, 2.96-5.21; P < .001). Excess ATRs were not observed at AGS-high sites among patients with blood type B receiving B or AB units. [Additionally,] in the AGS-high cluster, group A plasma or platelet transfusions were not associated with excess risk for ATR. In contrast, AB plasma or platelet transfusions were associated with a higher ATR risk vs the reference group of patients with blood type O receiving O units (overall RR, 2.53; 95 percent CI, 1.59-4.01; P < .001). B plasma or platelet transfusions were associated with an even higher ATR risk (RR, 4.48; 95 percent CI, 3.32-6.06; P < .001). In the AGS-low cluster, no significant overall differences in ATR rates were seen between patients with blood type O receiving B, AB, or A units vs those with blood type O receiving O units.”

The authors also explained that, “[f]or patients with blood type O receiving A units in the Alpha-gal syndrome-low cluster, the overall RR for moderate to severe ATRs was 1.60 (95 percent CI, 1.09-2.36; P = .02). The overall RR in the AGS-high cluster was identical, although it showed no significant difference from the reference group. Among patients with blood type O receiving B units in the AGS-low cluster, the RR for moderate to severe ATRs was 2.15 (95 percent CI, 1.34-3.47; P = .002). Among patients with blood type O receiving B units in the AGS-high cluster, the RR for moderate to severe ATRs was 9.14 (95 percent CI, 5.39-15.52; P < .001). [Consistent with their observations, the researchers] would expect the ability of allergens to cross-link alpha-gal IgE to be greater for B than AB and much greater for AB than A (some alpha-gal antibodies can recognize A⁶). Finally, [the findings] suggest that TRAGS reactions tend to be moderate to severe more often than other ATRs, although [the study’s] statistical power was constrained by low event rates.”

Additionally, the paper noted that in, “U.S. sites in regions where AGS was highly prevalent, there were significantly more ATRs among patients with blood type O receiving B or AB platelets or plasma than among patients with blood type O receiving O platelets or plasma (the reference group). At these Alpha-gal syndrome-high sites, excess ATRs were not observed when patients with blood type B were transfused with B or AB units. Individuals with blood types B or AB are relatively protected from producing IgE to alpha-gal and developing AGS. [Recent case] reports, French hemovigilance data, and this study’s results are consistent with a putative allergic reaction mechanism whereby transfused B carbohydrate antigens cross-link recipient alpha-gal IgE.”

Conclusion Regarding Transfusion-Related Alpha-Gal Syndrome

The researchers concluded that, “[t]his study provides provocative epidemiologic evidence consistent with TRAGS representing a newly recognized risk to recipients of blood transfusions. Case reports suggest that TRAGS can be lethal. Because there are important clinical implications, prospective validation of [the] results is warranted. Meanwhile, hospitals in AGS high-prevalence regions may wish to evaluate their local ATR rates by blood product and patient ABO group and consider practice changes to reduce risk. Blood collectors can consider curtailing the collection of plasma and platelets from donors of type B or redistributing B and AB units to Alpha-gal syndrome low-prevalence regions. Hemovigilance systems could track suspected TRAGS cases prospectively. Finally, further investigation is needed to better elucidate the mechanism of TRAGS, clarify the risk among patients with blood type A, and identify blood product modifications that could reduce risk to patients.”

Some limitations of the paper acknowledged by the authors included: “[g]iven that this was a retrospective study, it was not feasible to test patient sera for alpha-gal IgE to confirm the proposed association of ATRs with AGS; we cannot exclude the possibility that clinicians at AGS high-prevalence sites may have been more likely to investigate and report suspected ATRs to B or AB units; and [i]t is formally possible that geographic factors unrelated to AGS could explain the finding of excess ATRs to B or AB units.”

Commentary

An accompanying Invited Commentary titled “Ticks and Transfusion at the Crossroads—Alpha-Gal Syndrome” explained that, “Anti–alpha-Gal IgE has recently been implicated in allergic transfusion reactions. While traditional thinking has been that donor and recipient ABO blood groups are not relevant in considering risk for allergic transfusion reactions, investigators have recently hypothesized that some allergic reactions following transfusion of B antigen–containing products [to be] the result of recipient IgE antibodies related to AGS. [This study provides the strongest data to date supporting the existence of TRAGS. Strengths of the study included the large number of transfusions evaluated, [the] number and broad geographic distribution of study sites, and [the] study design that allowed evaluation of the association of O vs B recipient status and AGS prevalence with the incidence of allergic transfusion reactions.” The authors of the commentary concluded by explaining that, “[the study] presented new findings that support the existence of allergic reactions associated with group B or AB products transfused to O recipients in regions of high prevalence of AGS. This report should motivate further studies of allergic transfusion reactions.”

Additional Alpha-Gal Syndrome Resources

America’s Blood Centers has developed an AGS resource that includes frequently asked questions (FAQs). Last month, the Centers for Disease Control and Prevention’s (CDC) Morbidity and Mortality Weekly Report published a paper titled “Alpha-gal Immunoglobulin E Seroprevalence Among Blood Donors—10 States, 2024–2025.”

Citations: Kaufman, R.M., Hoen, A.G., Khan, J., et al. “Epidemiologic Study of Transfusion-Related Alpha-Gal Syndrome.” JAMA Internal Medicine. 2026.

Hollenhorst, M.A. Anderson, J.R., and Dzik, W. “Ticks and Transfusion at the Crossroads—Alpha-Gal Syndrome.” JAMA Internal Medicine. 2026.