Platelet activation by SARS-CoV-2 implicates the release of active tissue factor by infected cells

Author:

Puhm Florian12ORCID,Allaeys Isabelle12ORCID,Lacasse Emile2,Dubuc Isabelle2,Galipeau Yannick3,Zaid Younes456,Khalki Loubna7,Belleannée Clemence2ORCID,Durocher Yves8,Brisson Alain R.9,Wolberg Alisa S.10ORCID,Langlois Marc-André3ORCID,Flamand Louis12ORCID,Boilard Eric12

Affiliation:

1. 1Département de Microbiologie-Infectiologie et d'Immunologie, Université Laval, Quebec City, QC, Canada;

2. 2Centre de Recherche du Centre Hospitalier Universitaire de Québec-Université Laval, Quebec City, QC, Canada;

3. 3Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada;

4. 4Immunology and Biodiversity Laboratory, Department of Biology, Faculty of Sciences Ain Chock, Hassan II University, Casablanca, Morocco;

5. 5Research Center of Abulcasis University of Health Sciences, Cheikh Zaïd Hospital, Rabat, Morocco;

6. 6Biology Department, Faculty of Sciences, Mohammed V University, Rabat, Morocco;

7. 7Faculty of Medicine, Mohammed 6 University of Health Sciences (UM6SS), Casablanca, Morocco;

8. 8Human Health Therapeutics Research Center, National Research Council Canada, Montreal, QC, Canada;

9. 9Unité Mixte de Recherche - Chimie et Biologie des Membranes et des Nano-Objets, Université de Bordeaux, Centre National de la Recherche Scientifique, Institut Polytechnique de Bordeaux, Pessac, France; and

10. 10Department of Pathology and Laboratory Medicine and UNC Blood Research Center, University of North Carolina Chapel Hill, Chapel Hill, NC

Abstract

Abstract Platelets are hyperactivated in coronavirus disease 2019 (COVID-19). However, the mechanisms promoting platelet activation by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are not well understood. This may be due to inherent challenges in discriminating the contribution of viral vs host components produced by infected cells. This is particularly true for enveloped viruses and extracellular vesicles (EVs), as they are concomitantly released during infection and share biophysical properties. To study this, we evaluated whether SARS-CoV-2 itself or components derived from SARS-CoV-2-infected human lung epithelial cells could activate isolated platelets from healthy donors. Activation was measured by the surface expression of P-selectin and the activated conformation of integrin αIIbβ3, degranulation, aggregation under flow conditions, and the release of EVs. We find that neither SARS-CoV-2 nor purified spike activates platelets. In contrast, tissue factor (TF) produced by infected cells was highly potent at activating platelets. This required trace amounts of plasma containing the coagulation factors FX, FII, and FVII. Robust platelet activation involved thrombin and the activation of protease-activated receptor (PAR)-1 and -4 expressed by platelets. Virions and EVs were identified by electron microscopy. Through size-exclusion chromatography, TF activity was found to be associated with a virus or EVs, which were indistinguishable. Increased TF messenger RNA (mRNA) expression and activity were also found in lungs in a murine model of COVID-19 and plasma of severe COVID-19 patients, respectively. In summary, TF activity from SARS-CoV-2–infected cells activates thrombin, which signals to PARs on platelets. Blockade of molecules in this pathway may interfere with platelet activation and the coagulation characteristic of COVID-19.

Publisher

American Society of Hematology

Subject

Hematology

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