Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom; Centre for Inflammatory Disease, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
Luigi Grassi
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Institute for Health Research BioResource, Rare Diseases, Cambridge University Hospitals, Cambridge, United Kingdom
Mattia Frontini
Department of Haematology, University of Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom; National Health Service Blood and Transplant, Cambridge Biomedical Campus, Cambridge, United Kingdom; British Heart Foundation Centre of Excellence, Cambridge Biomedical Campus, Cambridge, United Kingdom
Isabelle I Salles-Crawley
Centre for Haematology, Department of Immunology and Inflammation, Imperial College London, London, United Kingdom
Platelet-neutrophil interactions are important for innate immunity, but also contribute to the pathogenesis of deep vein thrombosis, myocardial infarction and stroke. Here we report that, under flow, von Willebrand factor/glycoprotein Ibα-dependent platelet ‘priming’ induces integrin αIIbβ3 activation that, in turn, mediates neutrophil and T-cell binding. Binding of platelet αIIbβ3 to SLC44A2 on neutrophils leads to mechanosensitive-dependent production of highly prothrombotic neutrophil extracellular traps. A polymorphism in SLC44A2 (rs2288904-A) present in 22% of the population causes an R154Q substitution in an extracellular loop of SLC44A2 that is protective against venous thrombosis results in severely impaired binding to both activated αIIbβ3 and VWF-primed platelets. This was confirmed using neutrophils homozygous for the SLC44A2 R154Q polymorphism. Taken together, these data reveal a previously unreported mode of platelet-neutrophil crosstalk, mechanosensitive NET production, and provide mechanistic insight into the protective effect of the SLC44A2 rs2288904-A polymorphism in venous thrombosis.
