SARS-CoV-2 Infected Cells Trigger Host Tissue Factors That Leads To Platelet Activation And Coagulation


New study findings by Canadian researchers from Université Laval-Quebec, Canada CHU de Quebec, Canada University of Ottawa, Ottawa and National Research Council Canada are helping to explain the mechanisms promoting platelet activation by the SARS-CoV-2 resulting in thrombosis and coagulation…hallmarks of COVID-19.

The study that was also supported by scientist from the University of North Carolina at Chapel Hil-USA, UMR-CBMN CNRS-University Bordeaux-France.

Abulcasis University-Morocco and the Mohammed VI University of Health Sciences-Morocco found that SARS-CoV-2 infected cells trigger host tissue factors (TFs) that leads to platelet activation and coagulation.

The study findings were published in the peer reviewed journal: Blood Advances.

  • Coronavirus Disease-19  (COVID-19) is a respiratory tract infection  caused by the Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 Since the onset of this pandemic, millions of people have died.2 Acute respiratory distress syndrome is  one  of  the  main  characteristics  of  severe  COVID-19   and  its  manifestation influences the outcome of infection.3 A high degree of generalized inflammation and thrombosis is also reported.1,4–6
  • Autopsies show that the formation of microthrombi is common  in  the  lung  vasculature  and  in  other  organs  distant  from  the  lungs, suggesting a  role  for dysregulated  coagulation.7–10 
  • Furthermore,  age, hypertension, diabetes  and  coronary  heart disease, well known risk  factors for thrombosis and associated with chronic inflammation, are the main determinants of COVID-19 severity and mortality.3,4,11,12
  • Platelets are anucleated cells at the interface of thrombosis and inflammation.13–15 They are critical in hemostasis, interact with pathogens and can alert other immune cells.14,15 It is notable that hyper-activated platelets are present in COVID-19.16–22 Hyper-activation  is  characterized  by  high  expression  of  P-selectin  (CD62P), degranulation (release of platelet-factor 4 (PF4) and serotonin (5-HT)), and release of  platelet  extracellular  vesicles  (EVs),  as  well  as  increased  aggregation  and adhesion of platelets to other cells, particularly monocytes, and changes in platelet gene expression.16–22
  • Different laboratories have detected SARS-CoV-2 RNA in association with platelets in patients.16,17,23  While compelling studies confirmed  that SARS-CoV-2  can be taken up by platelets, leading to programmed cell death, platelets failed to activate in these conditions.23  Angiotensin  converting  enzyme-2  (ACE2),  abundantly  expressed  by epithelial cells in the lungs, is the cognate cell receptor for the SARS-CoV-2 spike protein.24,25    
  • An ACE2-dependent  SARS-CoV-2/platelet interaction has been suggested as a potential mechanism for platelet hyper-activation.26 However, platelet expression of ACE2 could not be conclusively demonstrated,27 and some studies indicated  SARS-CoV-2  interacts  with  platelets  through  ACE2-dependent  and independent mechanisms.23,28
  • Another putative receptor for a SARS-CoV-2 platelet interaction  is  CD147.29–31  While  evidence of interaction  between SARS-CoV-2   and CD147 have been challenged,32 one study suggests that SARS-CoV-2 pseudo virus and recombinant Spike proteins activate platelets, characterized by the release of HMGB1+  EVs  and  soluble  P-Selectin,  in  a  CD147-dependent  manner.33  
  • Another study  suggests  that  Spike  may  engage  platelet  CD42b,  thereby  promoting interactions with monocytes and cytokine production by monocytes.34
  • However, overexpression of Spike protein – resulting from vaccination – did not result in platelet activation.35 Thus, there exists conflicting data as to whether and how SARS-CoV-2 activates platelets.
  • Initiation  of  the  coagulation  cascade  may  also  underlie  platelet  activation. Coagulation abnormalities have been reported in COVID-1936, which may be the consequence of extensive tissue damage associated with SARS-CoV-2 infection and subsequent engagement of the coagulation cascade. Tissue Factor (TF) is the main cellular initiator of coagulation and a highly potent stimulus that is absent in blood
  • under physiological conditions.37–39
  • Active TF in blood activates the extrinsic (TF)-pathway of coagulation, leading to the conversion of prothrombin to thrombin and subsequent fibrin clot formation. Thrombin is a highly potent stimulus of platelet activation and has been previously found to contribute to H1N1-mediated activation of  platelets.40 
  • Several  studies  detected  TF  activity  in  the  blood  of  COVID-19 patients.41–43  Moreover,  SARS-CoV-2  spike  protein  pseudotyped  viral  infection  of human monocyte-derived macrophages induces the expression of active TF in vitro.44 Furthermore, SARS-CoV-2 infection of endothelial cells or endothelial dysfunction have been suggested as a potential source of TF.45
  • SARS-CoV-2 is an enveloped virus that may acquire host molecules during the budding  process.46–51  The propagation  of viruses  in  cell  lines is  essential, as   viral replication requires a cellular host.52 Infected cell supernatants are thus used as a source of virus, but the potential role of concomitantly released host molecules and EVs must be considered when examining effects of cell supernatants on target cells.
  • Supernatants  containing  virus  may  be  pelleted  by  centrifugation  to  reduce the presence     of    soluble     molecules.53,54     Moreover,    polyethylene     glycol    (PEG) precipitation can be used to concentrate viruses from supernatants. However, both centrifugation  and  PEG  precipitation  can  also  enrich  EVs.54,55 
  • Given  that viruses, protein   aggregates   and   EVs   share   biophysical   properties,53,54   they   cannot be efficiently separated from each other using any of these approaches.53,54
  • Whether SARS-CoV-2, or host-derived molecules, activate platelets has not been studied.
  • In this study, we examined whether SARS-CoV-2 or components from infected cells could activate platelets.


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