Reframing ATR: from the immunologic/nonimmunologic dichotomy to adaptive, innate, and physicochemical drivers within the allergy–inflammation–coagulation axis

Background Allergic transfusion reactions (ATRs) remain a significant challenge in transfusion medicine. The traditional binary classification—immunologic versus nonimmunologic, or IgE-mediated versus non-IgE-mediated—fails to capture the full complexity of ATR pathophysiology, as specific allergens are rarely identified. Study design and methods 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. Results We propose the inflammation–coagulation–allergy (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 “primed” 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. Discussion 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.