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SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19
BACKGROUND: Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk. Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471641/ https://www.ncbi.nlm.nih.gov/pubmed/32887634 http://dx.doi.org/10.1186/s13045-020-00954-7 |
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author | Zhang, Si Liu, Yangyang Wang, Xiaofang Yang, Li Li, Haishan Wang, Yuyan Liu, Mengduan Zhao, Xiaoyan Xie, Youhua Yang, Yan Zhang, Shenghui Fan, Zhichao Dong, Jianzeng Yuan, Zhenghong Ding, Zhongren Zhang, Yi Hu, Liang |
author_facet | Zhang, Si Liu, Yangyang Wang, Xiaofang Yang, Li Li, Haishan Wang, Yuyan Liu, Mengduan Zhao, Xiaoyan Xie, Youhua Yang, Yan Zhang, Shenghui Fan, Zhichao Dong, Jianzeng Yuan, Zhenghong Ding, Zhongren Zhang, Yi Hu, Liang |
author_sort | Zhang, Si |
collection | PubMed |
description | BACKGROUND: Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk. Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear. METHODS: Using platelets from healthy volunteers, non-COVID-19 and COVID-19 patients, as well as wild-type and hACE2 transgenic mice, we evaluated the changes in platelet and coagulation parameters in COVID-19 patients. We investigated ACE2 expression and direct effect of SARS-CoV-2 virus on platelets by RT-PCR, flow cytometry, Western blot, immunofluorescence, and platelet functional studies in vitro, FeCl(3)-induced thrombus formation in vivo, and thrombus formation under flow conditions ex vivo. RESULTS: We demonstrated that COVID-19 patients present with increased mean platelet volume (MPV) and platelet hyperactivity, which correlated with a decrease in overall platelet count. Detectable SARS-CoV-2 RNA in the blood stream was associated with platelet hyperactivity in critically ill patients. Platelets expressed ACE2, a host cell receptor for SARS-CoV-2, and TMPRSS2, a serine protease for Spike protein priming. SARS-CoV-2 and its Spike protein directly enhanced platelet activation such as platelet aggregation, PAC-1 binding, CD62P expression, α granule secretion, dense granule release, platelet spreading, and clot retraction in vitro, and thereby Spike protein enhanced thrombosis formation in wild-type mice transfused with hACE2 transgenic platelets, but this was not observed in animals transfused with wild-type platelets in vivo. Further, we provided evidence suggesting that the MAPK pathway, downstream of ACE2, mediates the potentiating role of SARS-CoV-2 on platelet activation, and that platelet ACE2 expression decreases following SARS-COV-2 stimulation. SARS-CoV-2 and its Spike protein directly stimulated platelets to facilitate the release of coagulation factors, the secretion of inflammatory factors, and the formation of leukocyte–platelet aggregates. Recombinant human ACE2 protein and anti-Spike monoclonal antibody could inhibit SARS-CoV-2 Spike protein-induced platelet activation. CONCLUSIONS: Our findings uncovered a novel function of SARS-CoV-2 on platelet activation via binding of Spike to ACE2. SARS-CoV-2-induced platelet activation may participate in thrombus formation and inflammatory responses in COVID-19 patients. |
format | Online Article Text |
id | pubmed-7471641 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-74716412020-09-04 SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19 Zhang, Si Liu, Yangyang Wang, Xiaofang Yang, Li Li, Haishan Wang, Yuyan Liu, Mengduan Zhao, Xiaoyan Xie, Youhua Yang, Yan Zhang, Shenghui Fan, Zhichao Dong, Jianzeng Yuan, Zhenghong Ding, Zhongren Zhang, Yi Hu, Liang J Hematol Oncol Research BACKGROUND: Critically ill patients diagnosed with COVID-19 may develop a pro-thrombotic state that places them at a dramatically increased lethal risk. Although platelet activation is critical for thrombosis and is responsible for the thrombotic events and cardiovascular complications, the role of platelets in the pathogenesis of COVID-19 remains unclear. METHODS: Using platelets from healthy volunteers, non-COVID-19 and COVID-19 patients, as well as wild-type and hACE2 transgenic mice, we evaluated the changes in platelet and coagulation parameters in COVID-19 patients. We investigated ACE2 expression and direct effect of SARS-CoV-2 virus on platelets by RT-PCR, flow cytometry, Western blot, immunofluorescence, and platelet functional studies in vitro, FeCl(3)-induced thrombus formation in vivo, and thrombus formation under flow conditions ex vivo. RESULTS: We demonstrated that COVID-19 patients present with increased mean platelet volume (MPV) and platelet hyperactivity, which correlated with a decrease in overall platelet count. Detectable SARS-CoV-2 RNA in the blood stream was associated with platelet hyperactivity in critically ill patients. Platelets expressed ACE2, a host cell receptor for SARS-CoV-2, and TMPRSS2, a serine protease for Spike protein priming. SARS-CoV-2 and its Spike protein directly enhanced platelet activation such as platelet aggregation, PAC-1 binding, CD62P expression, α granule secretion, dense granule release, platelet spreading, and clot retraction in vitro, and thereby Spike protein enhanced thrombosis formation in wild-type mice transfused with hACE2 transgenic platelets, but this was not observed in animals transfused with wild-type platelets in vivo. Further, we provided evidence suggesting that the MAPK pathway, downstream of ACE2, mediates the potentiating role of SARS-CoV-2 on platelet activation, and that platelet ACE2 expression decreases following SARS-COV-2 stimulation. SARS-CoV-2 and its Spike protein directly stimulated platelets to facilitate the release of coagulation factors, the secretion of inflammatory factors, and the formation of leukocyte–platelet aggregates. Recombinant human ACE2 protein and anti-Spike monoclonal antibody could inhibit SARS-CoV-2 Spike protein-induced platelet activation. CONCLUSIONS: Our findings uncovered a novel function of SARS-CoV-2 on platelet activation via binding of Spike to ACE2. SARS-CoV-2-induced platelet activation may participate in thrombus formation and inflammatory responses in COVID-19 patients. BioMed Central 2020-09-04 /pmc/articles/PMC7471641/ /pubmed/32887634 http://dx.doi.org/10.1186/s13045-020-00954-7 Text en © The Author(s) 2020 Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Zhang, Si Liu, Yangyang Wang, Xiaofang Yang, Li Li, Haishan Wang, Yuyan Liu, Mengduan Zhao, Xiaoyan Xie, Youhua Yang, Yan Zhang, Shenghui Fan, Zhichao Dong, Jianzeng Yuan, Zhenghong Ding, Zhongren Zhang, Yi Hu, Liang SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19 |
title | SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19 |
title_full | SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19 |
title_fullStr | SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19 |
title_full_unstemmed | SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19 |
title_short | SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19 |
title_sort | sars-cov-2 binds platelet ace2 to enhance thrombosis in covid-19 |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471641/ https://www.ncbi.nlm.nih.gov/pubmed/32887634 http://dx.doi.org/10.1186/s13045-020-00954-7 |
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