Platelets Can Associate With SARS-CoV-2 RNA and Are Hyperactivated in COVID-19

  1. Younes Zaid
  2. Florian Puhm
  3. Isabelle Allaeys
  4. Abdallah Naya
  5. Mounia Oudghiri
  6. Loubna Khalki
  7. Youness Limami
  8. Nabil Zaid
  9. Khalid Sadki
  10. Rafiqua Ben El Haj
  11. Wissal Mahir
  12. Lamiae Belayachi
  13. Bouchra Belefquih
  14. Amina Benouda
  15. Amine Cheikh
  16. Marc-André Langlois
  17. Yahia Cherrah
  18. Louis Flamand
  19. Fadila Guessous
  20. Eric Boilard

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Abstract

In addition to the overwhelming lung inflammation that prevails in coronavirus disease 2019 (COVID-19), hypercoagulation and thrombosis contribute to the lethality of subjects infected with severe acute respiratory syndrome coronavirus 2. Platelets are chiefly implicated in thrombosis. Moreover, they can interact with viruses and are an important source of inflammatory mediators. While a lower platelet count is associated with severity and mortality, little is known about platelet function during COVID-19.

Objective:

To evaluate the contribution of platelets to inflammation and thrombosis in patients with COVID-19.

Methods and Results:

Blood was collected from 115 consecutive patients with COVID-19 presenting nonsevere (n=71) and severe (n=44) respiratory symptoms. We document the presence of severe acute respiratory syndrome coronavirus 2 RNA associated with platelets of patients with COVID-19. Exhaustive assessment of cytokines in plasma and in platelets revealed the modulation of platelet-associated cytokine levels in both patients with nonsevere and severe COVID-19, pointing to a direct contribution of platelets to the plasmatic cytokine load. Moreover, we demonstrate that platelets release their alpha- and dense-granule contents in both nonsevere and severe forms of COVID-19. In comparison to concentrations measured in healthy volunteers, phosphatidylserine-exposing platelet extracellular vesicles were increased in nonsevere, but not in severe cases of COVID-19. Levels of D-dimers, a marker of thrombosis, failed to correlate with any measured indicators of platelet activation. Functionally, platelets were hyperactivated in COVID-19 subjects presenting nonsevere and severe symptoms, with aggregation occurring at suboptimal thrombin concentrations. Furthermore, platelets adhered more efficiently onto collagen-coated surfaces under flow conditions.

Conclusions:

Taken together, the data suggest that platelets are at the frontline of COVID-19 pathogenesis, as they release various sets of molecules through the different stages of the disease. Platelets may thus have the potential to contribute to the overwhelming thrombo-inflammation in COVID-19, and the inhibition of pathways related to platelet activation may improve the outcomes during COVID-19.

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  1. ScreenIT

    SciScore for 10.1101/2020.06.23.20137596: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board Statementnot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    No key resources detected.

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: Please consider improving the rainbow (“jet”) colormap(s) used on page 20. At least one figure is not accessible to readers with colorblindness and/or is not true to the data, i.e. not perceptually uniform.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1161/circresaha.120.317703
  3. ScreenIT

    SciScore for 10.1101/2020.06.23.20137596: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementEthics Statement This study was approved by the Local Ethics Committee of Cheikh Zaid Hospital , Rabat , MoroccoRandomizationnot detected.Blindingnot detected.Power Analysisnot detected.Sex as a biological variablenot detected.Cell Line Authenticationnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    The presence of viral RNA in platelet cytosol may activate platelet TLR-7 , a process that occurs in cases of influenza and encephalomyocarditis virus infections.44,63 Influenza virus and herpes simplex virus-1 ( HSV-1 ) can trigger platelet degranulation when antibodies opsonize viral particles , and thereby activate platelet FcyRIIA.46,47 While antibodies specifically directed at SARS-CoV-2 are not expected in most individuals at an early stage of the pathogenesis , they might be produced at a later stage of infection , or prevailing cross-reacting antibodies against other more common coronaviruses that generate minor cold symptoms in humans ( 229E , NL63 , OC43 and HKU1 ) may suffice to form immune complexes and activate platelet FcyRIIA.4,5 Thus , differences in antibody profiles , especially in neutralizing antibodies , among severe and non-severe COVID-19 patients may contribute to platelet interaction with the virus , and to the overwhelming inflammation .
    TLR-7
    suggested: None
          <div style="margin-bottom:8px">
        <div><b>HSV-1</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>NL63</b></div>
        <div>suggested: None</div>
      </div>
    
      <div style="margin-bottom:8px">
        <div><b>HKU1</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;text-align:center; padding-top:4px;" colspan="2"><b>Experimental Models: Cell Lines</b></td></tr><tr><td style="min-width:100px;text=align:center"><i>Sentences</i></td><td style="min-width:100px;text-align:center"><i>Resources</i></td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">MIP1 α , MCP-1 , CXCL9 , IL-25 , RANTES) , and IL-3 the concentration of which was significantly reduced in COVID-19 ( non-severe and severe) , we identified 35 cytokines that were significantly elevated , including TNF , IL-1 , IL-6 , interferon ( IFN ) α and γ , and eotaxin ( Figure 1 and Online Figure VI) .</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>MCP-1</b></div>
        <div>suggested: None</div>
      </div>
    </td></tr><tr><td style="min-width:100px;text-align:center; padding-top:4px;" colspan="2"><b>Software and Algorithms</b></td></tr><tr><td style="min-width:100px;text=align:center"><i>Sentences</i></td><td style="min-width:100px;text-align:center"><i>Resources</i></td></tr><tr><td style="min-width:100px;vertical-align:top;border-bottom:1px solid lightgray">FP is recipient of a postdoctoral fellowship from FRQS.</td><td style="min-width:100px;border-bottom:1px solid lightgray">
      <div style="margin-bottom:8px">
        <div><b>FRQS</b></div>
        <div>suggested: (FRQS, <a href="https://scicrunch.org/resources/Any/search?q=SCR_011253">SCR_011253</a>)</div>
      </div>
    </td></tr></table>

    Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.

    Results from OddPub: We did not find a statement about open data. We also did not find a statement about open code. Researchers are encouraged to share open data when possible (see Nature blog).

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore is not a substitute for expert review. SciScore checks for the presence and correctness of RRIDs (research resource identifiers) in the manuscript, and detects sentences that appear to be missing RRIDs. SciScore also checks to make sure that rigor criteria are addressed by authors. It does this by detecting sentences that discuss criteria such as blinding or power analysis. SciScore does not guarantee that the rigor criteria that it detects are appropriate for the particular study. Instead it assists authors, editors, and reviewers by drawing attention to sections of the manuscript that contain or should contain various rigor criteria and key resources. For details on the results shown here, including references cited, please follow this link.

  4. Version published to 10.1101/2020.06.23.20137596v1 on medRxiv