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.
