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Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia

Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are th...

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Autores principales: Perdomo, José, Leung, Halina H. L., Ahmadi, Zohra, Yan, Feng, Chong, James J. H., Passam, Freda H., Chong, Beng H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428879/
https://www.ncbi.nlm.nih.gov/pubmed/30899022
http://dx.doi.org/10.1038/s41467-019-09160-7
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author Perdomo, José
Leung, Halina H. L.
Ahmadi, Zohra
Yan, Feng
Chong, James J. H.
Passam, Freda H.
Chong, Beng H.
author_facet Perdomo, José
Leung, Halina H. L.
Ahmadi, Zohra
Yan, Feng
Chong, James J. H.
Passam, Freda H.
Chong, Beng H.
author_sort Perdomo, José
collection PubMed
description Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are thought to activate platelets leading to thrombocytopenia and thrombosis. Here we show that HIT immune complexes induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil-platelet association. HIT immune complexes induce formation of thrombi containing neutrophils, extracellular DNA, citrullinated histone H3 and platelets in a microfluidics system and in vivo, while neutrophil depletion abolishes thrombus formation. Absence of PAD4 or PAD4 inhibition with GSK484 abrogates thrombus formation but not thrombocytopenia, suggesting they are induced by separate mechanisms. NETs markers and neutrophils undergoing NETosis are present in HIT patients. Our findings demonstrating the involvement of NETosis in thrombosis will modify the current concept of HIT pathogenesis and may lead to new therapeutic strategies.
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spelling pubmed-64288792019-03-25 Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia Perdomo, José Leung, Halina H. L. Ahmadi, Zohra Yan, Feng Chong, James J. H. Passam, Freda H. Chong, Beng H. Nat Commun Article Heparin-induced thrombocytopenia/thrombosis (HIT) is a serious immune reaction to heparins, characterized by thrombocytopenia and often severe thrombosis with high morbidity and mortality. HIT is mediated by IgG antibodies against heparin/platelet factor 4 antigenic complexes. These complexes are thought to activate platelets leading to thrombocytopenia and thrombosis. Here we show that HIT immune complexes induce NETosis via interaction with FcγRIIa on neutrophils and through neutrophil-platelet association. HIT immune complexes induce formation of thrombi containing neutrophils, extracellular DNA, citrullinated histone H3 and platelets in a microfluidics system and in vivo, while neutrophil depletion abolishes thrombus formation. Absence of PAD4 or PAD4 inhibition with GSK484 abrogates thrombus formation but not thrombocytopenia, suggesting they are induced by separate mechanisms. NETs markers and neutrophils undergoing NETosis are present in HIT patients. Our findings demonstrating the involvement of NETosis in thrombosis will modify the current concept of HIT pathogenesis and may lead to new therapeutic strategies. Nature Publishing Group UK 2019-03-21 /pmc/articles/PMC6428879/ /pubmed/30899022 http://dx.doi.org/10.1038/s41467-019-09160-7 Text en © The Author(s) 2019 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
Perdomo, José
Leung, Halina H. L.
Ahmadi, Zohra
Yan, Feng
Chong, James J. H.
Passam, Freda H.
Chong, Beng H.
Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
title Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
title_full Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
title_fullStr Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
title_full_unstemmed Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
title_short Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
title_sort neutrophil activation and netosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6428879/
https://www.ncbi.nlm.nih.gov/pubmed/30899022
http://dx.doi.org/10.1038/s41467-019-09160-7
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