Experimental and Molecular Pathology · Published 2026-07-30 · DOI 10.1016/j.yexmp.2026.105070
Suishin Arai, Koki Takai, Hiyori Miyatake, Yuka Oshima, Riku Manabe, Yuka Nishibata, Takumi Abe, Ayana Sasaki, Mizuki Fukuyama, China Washio, Naho Ogawa, Hodaka Ogawa, Ikuma Hori, Kanako Watanabe-Kusunoki, Daigo Nakazawa, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
Antiphospholipid syndrome (APS) is an autoimmune thrombotic disorder characterized by the presence of antiphospholipid antibodies, including anti-phosphatidylserine/prothrombin antibodies (aPS/PT). While neutrophil extracellular traps (NETs) are implicated in the pathogenesis of APS, the role of aPS/PT in NET induction and its contribution to thrombosis remain unclear. This study aimed to clarify the effects of NETs induced by a monoclonal aPS/PT antibody on platelet activation and their potential contribution to thrombo-inflammatory responses. NETs were induced by stimulating peripheral blood neutrophils from healthy donors with aPS/PT. Their morphology and platelet-activating capacity were compared with NETs induced by anti-neutrophil cytoplasmic antibodies (ANCAs). Proteomic analyses were conducted to comprehensively compare protein compositions of these NETs, and candidate proteins associated with platelet activation in aPS/PT-induced NETs were identified. Functional inhibition assays were then conducted to assess whether blocking these candidates would suppress aPS/PT-induced NET-mediated platelet activation. We found that binding of aPS/PT to neutrophils induced NET formation, with a larger and more fibrous morphology compared to ANCA-induced NETs. Platelets trapped in aPS/PT-induced NETs showed significantly higher activation compared to those trapped in ANCA-induced NETs. Proteomic analyses identified histone H3 as a potential mediator of platelet activation in aPS/PT-induced NETs. Correspondingly, plasma concentrations of H3.1 nucleosome were significantly higher in patients with APS than in healthy controls. Blockade of histone H3 using a neutralizing antibody significantly suppressed platelet activation mediated by aPS/PT-induced NETs. These findings suggest that aPS/PT-induced NETs contribute to platelet activation and may promote thrombo-inflammatory responses in APS. Targeting histone H3 within aPS/PT-induced NETs may provide a potential therapeutic strategy for thrombo-inflammatory processes in APS.
Abstract from DOAJ. Public domain (CC0 1.0).
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Arai, S., Takai, K., Miyatake, H., et al. (2026). Neutrophil extracellular traps induced by a monoclonal anti-phosphatidylserine/prothrombin antibody activate platelets in vitro. Experimental and Molecular Pathology. https://doi.org/10.1016/j.yexmp.2026.105070