Yoshihiko Sakurai
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.
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.