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SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19.
J Hematol Oncol. 2020 09 04; 13(1):120.JH

Abstract

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, 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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, NHC Key Laboratory of Glycoconjugates Research, School of Basic Medical Sciences, Fudan University, Shanghai, 200032, China. zhangsi@fudan.edu.cn.Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, 450052, China.Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, 450052, China.Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.Department of Emergency, Affiliated Hospital of Anhui Medical University, Hefei, China.Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), and Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, 450052, China.Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, 450052, China.Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), and Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.School of Public Health (Shenzhen), Sun Yat-sen University, Guangzhou, China.Department of Hematology, Wenzhou Key Laboratory of Hematology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.Department of Immunology, School of Medicine, UConn Health, Farmington, CT, 06030, USA.Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, 450052, China.Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), and Department of Medical Microbiology and Parasitology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China.Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, 450052, China.Biotherapy Center, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China. yizhang@zzu.edu.cn.Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Cardiovascular Institute of Zhengzhou University, Zhengzhou, 450052, China. fcchul@zzu.edu.cn.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

32887634

Citation

Zhang, Si, et al. "SARS-CoV-2 Binds Platelet ACE2 to Enhance Thrombosis in COVID-19." Journal of Hematology & Oncology, vol. 13, no. 1, 2020, p. 120.
Zhang S, Liu Y, Wang X, et al. SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. J Hematol Oncol. 2020;13(1):120.
Zhang, S., Liu, Y., Wang, X., Yang, L., Li, H., Wang, Y., Liu, M., Zhao, X., Xie, Y., Yang, Y., Zhang, S., Fan, Z., Dong, J., Yuan, Z., Ding, Z., Zhang, Y., & Hu, L. (2020). SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. Journal of Hematology & Oncology, 13(1), 120. https://doi.org/10.1186/s13045-020-00954-7
Zhang S, et al. SARS-CoV-2 Binds Platelet ACE2 to Enhance Thrombosis in COVID-19. J Hematol Oncol. 2020 09 4;13(1):120. PubMed PMID: 32887634.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - SARS-CoV-2 binds platelet ACE2 to enhance thrombosis in COVID-19. AU - Zhang,Si, AU - Liu,Yangyang, AU - Wang,Xiaofang, AU - Yang,Li, AU - Li,Haishan, AU - Wang,Yuyan, AU - Liu,Mengduan, AU - Zhao,Xiaoyan, AU - Xie,Youhua, AU - Yang,Yan, AU - Zhang,Shenghui, AU - Fan,Zhichao, AU - Dong,Jianzeng, AU - Yuan,Zhenghong, AU - Ding,Zhongren, AU - Zhang,Yi, AU - Hu,Liang, Y1 - 2020/09/04/ PY - 2020/07/17/received PY - 2020/08/19/accepted PY - 2020/9/5/entrez PY - 2020/9/6/pubmed PY - 2020/9/22/medline KW - ACE2 KW - COVID-19 KW - Platelet activation KW - TMPRSS2 KW - Thrombosis SP - 120 EP - 120 JF - Journal of hematology & oncology JO - J Hematol Oncol VL - 13 IS - 1 N2 - 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, 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. SN - 1756-8722 UR - https://www.unboundmedicine.com/medline/citation/32887634/SARS_CoV_2_binds_platelet_ACE2_to_enhance_thrombosis_in_COVID_19_ L2 - https://jhoonline.biomedcentral.com/articles/10.1186/s13045-020-00954-7 DB - PRIME DP - Unbound Medicine ER -