{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T16:04:15Z","timestamp":1791821055570,"version":"4.3.4"},"reference-count":96,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T00:00:00Z","timestamp":1788393600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Allergic transfusion reactions (ATRs) remain a significant challenge in transfusion medicine. The traditional binary classification\u2014immunologic versus nonimmunologic, or IgE-mediated versus non-IgE-mediated\u2014fails to capture the full complexity of ATR pathophysiology, as specific allergens are rarely identified.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Study design and methods<\/jats:title>\n                    <jats:p>This review synthesizes interdisciplinary insights from hemostasis, immunology, and allergy, particularly regarding the pathogenesis of chronic spontaneous urticaria (CSU) to reconstruct the pathophysiology of ATRs and propose a comprehensive new mechanistic framework.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We propose the inflammation\u2013coagulation\u2013allergy (ICA) axis as the primary driver of many ATRs. In this model, the coagulation and complement systems directly activate mast cells via anaphylatoxins and protease-activated receptors (PARs), independent of classical IgE pathways. The components in blood products, particularly biological response modifiers (BRMs) and microparticles (MPs) resulting from storage lesion and potentially anti-endothelial cell antibodies (AECAs) act as triggers. When transfused into a recipient in a physiologically \u201cprimed\u201d state due to aging, invasion, or infection, these factors ignite localized thrombo-inflammatory pathways via interaction between coagulation and complement systems, leading to tissue mast cell activation. Consequently, while the basophil activation test (BAT) improves the detection of classical IgE-mediated reactions, it may not capture these coagulation-driven, tissue mast cell-mediated mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>We argue for reframing ATRs not merely as localized cutaneous reactions but as systemic thrombo-inflammatory events. This paradigm shift highlights the potential utility of thrombotic biomarkers (e.g., D-dimer) in endotyping ATRs and points toward novel, mechanism-based therapeutic strategies beyond standard antihistamines.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1892622","type":"journal-article","created":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T06:43:49Z","timestamp":1788417829000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Reframing ATR: from the immunologic\/nonimmunologic dichotomy to adaptive, innate, and physicochemical drivers within the allergy\u2013inflammation\u2013coagulation axis"],"prefix":"10.3389","volume":"17","author":[{"given":"Yoshihiko","family":"Sakurai","sequence":"first","affiliation":[{"name":"Department of Legal Medicine, Nara Medical University","place":["Kashihara, Nara, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"B1","volume-title":"Haemovigilance by JRCS 2024","year":"2026"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.waojou.2019.100066","article-title":"Time to revisit the definition and clinical criteria for anaphylaxis","volume":"12","author":"Turner","year":"2019","journal-title":"World Allergy Organ J"},{"key":"B3","volume-title":"The 2024 Annual SHOT Report. 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