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The mechanisms underlying platelet\u2010induced neutrophil activation leading to immunothrombosis remain poorly understood. Three\u2010dimensional confocal microscopy demonstrated that platelets induced neutrophil extracellular trap (NET) formation through P\u2010selectin\u2010 or high mobility group box\u00a01 protein (HMGB1)\u2010mediated binding to P\u2010selectin glycoprotein ligand\u20101 (PSGL\u20101) or receptor for advanced glycation end products (RAGE), respectively, on neutrophils. Molecular signalling pathways involved in NETs\u2014focusing on mitogen\u2010activated protein kinase kinase (MAPKK) or mitogen\u2010activated protein kinase kinase 1\/2 (MAP2K) (MEK)\/extracellular signal\u2013regulated kinase (ERK), reactive oxygen species (ROS), ofnicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2), myeloperoxidase (MPO) and peptidylarginine deiminase 4 (PAD4)\u2014were investigated in neutrophils from \u03b2\u2010thalassaemia\/haemoglobin E (HbE) patients (splenectomy and non\u2010splenectomy) and from normal subjects by priming neutrophils with specific inhibitors before treatment with either platelets, recombinant P\u2010selectin or disulphide HMGB1. In splenectomised patients, neutrophils primed with U0126, but not an ERK inhibitor, exhibited reduced web\u2010like NETs and cell aggregation, associated with antioxidant effects. In non\u2010splenectomised patients and normal subjects, P\u2010selectin activated MEK\/ERK, NOX2, MPO and PAD4 pathways, promoting web\u2010like NETs and cell aggregation. HMGB1 activated neutrophils via MEK\/ERK, NOX2, MPO and PAD4 pathways, in all groups, resulting in NETs without aggregation\u2010associated NET morphology. These findings indicate that splenectomy alters P\u2010selectin and HMGB1 expression on platelets, leading to altered signalling dynamics in neutrophils and promoting neutrophil\u2013platelet aggregation. ROS pathway could be a key regulator of NET\u2010driven thrombosis in splenectomised \u03b2\u2010thalassaemia\/HbE disease and highlight its potential as a therapeutic target.<\/jats:p>","DOI":"10.1111\/bjh.70577","type":"journal-article","created":{"date-parts":[[2026,5,28]],"date-time":"2026-05-28T01:40:27Z","timestamp":1779932427000},"page":"703-717","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Neutrophil extracellular traps induced by activated platelets as a cause of neutrophil\u2013platelet aggregation in \u03b2\u2010thalassaemia\/haemoglobin E patients"],"prefix":"10.1111","volume":"209","author":[{"given":"Rattanawan","family":"Thubthed","sequence":"first","affiliation":[{"name":"Department of Pathobiology, Faculty of Science Mahidol University  Bangkok 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