Neutrophil extracellular traps induced by activated platelets as a cause of neutrophil–platelet aggregation in β-thalassaemia/haemoglobin E patients
Issued Date
2026-01-01
Resource Type
ISSN
00071048
eISSN
13652141
Scopus ID
2-s2.0-105040359104
Journal Title
British Journal of Haematology
Rights Holder(s)
SCOPUS
Bibliographic Citation
British Journal of Haematology (2026)
Suggested Citation
Thubthed R., Praneetponkang R., Sittipaisankul P., Thiengtavor C., Chumpuchanaphai S., Paiboonsukwong K., Fucharoen S., Pattanapanyasat K., Vadolas J., Smith D.R., Svasti S., Chaichompoo P. Neutrophil extracellular traps induced by activated platelets as a cause of neutrophil–platelet aggregation in β-thalassaemia/haemoglobin E patients. British Journal of Haematology (2026). doi:10.1111/bjh.70577 Retrieved from: https://repository.li.mahidol.ac.th/handle/123456789/117116
Title
Neutrophil extracellular traps induced by activated platelets as a cause of neutrophil–platelet aggregation in β-thalassaemia/haemoglobin E patients
Corresponding Author(s)
Other Contributor(s)
Abstract
The hypercoagulable state is a major contributor to thromboembolic events and mortality in β-thalassaemia. The mechanisms underlying platelet-induced neutrophil activation leading to immunothrombosis remain poorly understood. Three-dimensional confocal microscopy demonstrated that platelets induced neutrophil extracellular trap (NET) formation through P-selectin- or high mobility group box 1 protein (HMGB1)-mediated binding to P-selectin glycoprotein ligand-1 (PSGL-1) or receptor for advanced glycation end products (RAGE), respectively, on neutrophils. Molecular signalling pathways involved in NETs—focusing on mitogen-activated protein kinase kinase (MAPKK) or mitogen-activated protein kinase kinase 1/2 (MAP2K) (MEK)/extracellular signal–regulated kinase (ERK), reactive oxygen species (ROS), ofnicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex 2 (NOX2), myeloperoxidase (MPO) and peptidylarginine deiminase 4 (PAD4)—were investigated in neutrophils from β-thalassaemia/haemoglobin E (HbE) patients (splenectomy and non-splenectomy) and from normal subjects by priming neutrophils with specific inhibitors before treatment with either platelets, recombinant P-selectin or disulphide HMGB1. In splenectomised patients, neutrophils primed with U0126, but not an ERK inhibitor, exhibited reduced web-like NETs and cell aggregation, associated with antioxidant effects. In non-splenectomised patients and normal subjects, P-selectin activated MEK/ERK, NOX2, MPO and PAD4 pathways, promoting web-like NETs and cell aggregation. HMGB1 activated neutrophils via MEK/ERK, NOX2, MPO and PAD4 pathways, in all groups, resulting in NETs without aggregation-associated NET morphology. These findings indicate that splenectomy alters P-selectin and HMGB1 expression on platelets, leading to altered signalling dynamics in neutrophils and promoting neutrophil–platelet aggregation. ROS pathway could be a key regulator of NET-driven thrombosis in splenectomised β-thalassaemia/HbE disease and highlight its potential as a therapeutic target.