SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19

doi:10.1186/s13045-020-00954-7

科研成果详情

题名	SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19
作者	Zhang, Si 2; Liu, Yangyang 1; Wang, Xiaofang 1; Yang, Li 3; Li, Haishan 4; Wang, Yuyan 5; Liu, Mengduan 1; Zhao, Xiaoyan 1; Xie, Youhua 5; Yang, Yan 6; Zhang, Shenghui7; Fan, Zhichao 8; Dong, Jianzeng 1; Yuan, Zhenghong 5; Ding, Zhongren 1; Zhang, Yi 3; Hu, Liang 1
发表日期	2020-09-04
发表期刊	JOURNAL OF HEMATOLOGY & ONCOLOGY 影响因子和分区
语种	英语
原始文献类型	Article
关键词	COVID-19 Thrombosis Platelet activation ACE2 TMPRSS2
其他关键词	ACTIVATED PROTEIN-KINASE ; VON-WILLEBRAND-FACTOR ; SPIKE PROTEIN ; P2Y(12) RECEPTOR ; CORONAVIRUS ; INFECTION ; ANTIPLATELET ; HEMOSTASIS ; TMPRSS2 ; DRIVEN
摘要	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, FeCl3-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, alpha 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.
资助项目	National Natural Science of Foundation of ChinaNational Natural Science Foundation of China (NSFC) [81803522, 81970305, 81770137, 81573423, 81903603, 81900378, 81400323]; China Postdoctoral Research FoundationChina Postdoctoral Science Foundation [2020M672292]; Emergency Prevention and Control of COVID-19 Project of Henan Province [201100310900]; Novel Coronavirus Prevention and Control Emergency Project of Zhongshan University
出版者	BMC
出版地	LONDON
ISSN	1756-8722
EISSN	1756-8722
卷号	13 期号:1 页码:120
DOI	10.1186/s13045-020-00954-7
页数	22
WOS类目	Oncology ; Hematology
WOS研究方向	Oncology ; Hematology
WOS记录号	WOS:000568424700001
收录类别	SCIE ; PUBMED ; SCOPUS
URL	查看原文
PubMed ID	32887634
PMC记录号	PMC7471641
SCOPUSEID	2-s2.0-85090508287
ESI热点论文	2021-09 ; 2022-03 ; 2022-07
ESI高被引论文	2021-05 ; 2021-07 ; 2021-11 ; 2022-01 ; 2022-03 ; 2022-07 ; 2022-09 ; 2022-11 ; 2023-01 ; 2023-03 ; 2023-05 ; 2023-07 ; 2023-09 ; 2023-11 ; 2024-01 ; 2024-03 ; 2024-05 ; 2024-07 ; 2024-09 ; 2024-11
自科自定义期刊分类	T3(B)类
通讯作者地址	[Hu, Liang]Department of Cardiology,First Affiliated Hospital of Zhengzhou University,Cardiovascular Institute of Zhengzhou University,Zhengzhou,450052,China
Scopus学科分类	Molecular Biology;Hematology;Oncology;Cancer Research
TOP期刊	TOP期刊
引用统计	被引频次：292[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/19545
专题	附属第一医院
通讯作者	Hu, Liang
作者单位	1.Department of Cardiology,First Affiliated Hospital of Zhengzhou University,Cardiovascular Institute of Zhengzhou University,Zhengzhou,450052,China; 2.Department of Biochemistry and Molecular Biology,Nhc Key Laboratory of Glycoconjugates Research,Fudan University,Shanghai,200032,China; 3.Biotherapy Center,First Affiliated Hospital of Zhengzhou University,Zhengzhou,450052,China; 4.Department of Emergency,Affiliated Hospital of Anhui Medical University,Hefei,China; 5.Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS),Department of Medical Microbiology and Parasitology,School of Basic Medical Sciences,Shanghai Medical College,Shanghai,China; 6.School of Public Health (Shenzhen),Sun Yat-sen University,Guangzhou,China; 7.Department of Hematology,Wenzhou Key Laboratory of Hematology,First Affiliated Hospital of Wenzhou Medical University,Wenzhou,China; 8.Department of Immunology,School of Medicine,UConn Health,Farmington,06030,United States
推荐引用方式 GB/T 7714	Zhang, Si,Liu, Yangyang,Wang, Xiaofang,et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19[J]. JOURNAL OF HEMATOLOGY & ONCOLOGY,2020,13(1):120.
APA	Zhang, Si., Liu, Yangyang., Wang, Xiaofang., Yang, Li., Li, Haishan., ... & Hu, Liang. (2020). SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. JOURNAL OF HEMATOLOGY & ONCOLOGY, 13(1), 120.
MLA	Zhang, Si,et al."SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19".JOURNAL OF HEMATOLOGY & ONCOLOGY 13.1(2020):120.