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Sustained VWF-ADAMTS13 axis imbalance and endotheliopathy in Long COVID syndrome is related to immune dysfunction, 2022, Fogarty et al

Discussion in 'Long Covid research' started by Andy, Jul 25, 2022.

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  1. Andy

    Andy Retired committee member

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    Abstract

    Background
    Prolonged recovery is common after SARs-CoV-2 infection, however the pathophysiological mechanisms underpinning Long COVID syndrome remain unknown. VWF-ADAMTS13 imbalance, dysregulated angiogenesis and immuno-thrombosis are hallmarks of acute COVID-19. We hypothesized that VWF-ADAMTS13 imbalance persists in convalescence together with EC activation and angiogenic disturbance. Additionally, we postulate that ongoing immune cell dysfunction may be linked to sustained EC and coagulation activation.

    Patients and Methods
    Fifty patients were reviewed at a minimum of 6 weeks following acute COVID-19. ADAMTS13, WPB proteins and angiogenesis-related proteins were assessed and clinical evaluation and immunophenotyping performed. Comparisons were made with healthy controls (n=20) and acute COVID-19 patients (n=36).

    Results
    ADAMTS13 levels were reduced (p=0.009) and the VWF/ADAMTS13 ratio was increased in convalescence (p=0.0004). Levels of Platelet Factor 4 (PF4), a putative protector of VWF, were also elevated (p=0.0001). A non-significant increase in WPB proteins Angiopoietin-2 (Ang-2) and Osteoprotegerin (OPG) was observed in convalescent patients and WPB markers correlated with EC parameters. Enhanced expression of 21 angiogenesis-related proteins was observed in convalescent COVID-19. Finally, immunophenotyping revealed significantly elevated intermediate monocytes and activated CD4+ and CD8+ T cells in convalescence, which correlated with thrombin generation and endotheliopathy markers, respectively.

    Conclusion
    Our data provide insights into sustained EC activation, dysregulated angiogenesis and VWF/ADAMTS13 axis imbalance in convalescent COVID-19. In keeping with the pivotal role of immuno-thrombosis in acute COVID-19, our findings support the hypothesis that abnormal T cell and monocyte populations may be important in the context of persistent EC activation and hemostatic dysfunction during convalescence.

    Paywall, https://onlinelibrary.wiley.com/doi/10.1111/jth.15830
     
    Andy, Jul 25, 2022
    #1
    hotblack, Dolphin, hibiscuswahine and 3 others like this.
  2. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights) Staff Member

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    SNT Gatchaman, Jul 25, 2022
    #2
    hotblack, hibiscuswahine, Trish and 1 other person like this.
  3. SNT Gatchaman

    SNT Gatchaman Senior Member (Voting Rights) Staff Member

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    Aotearoa New Zealand
    See also —

    SARS-CoV-2 S protein activates NLRP3 inflammasome and deregulates coagulation factors in endothelial and immune cells (2024)
    Villacampa, Alicia; Alfaro, Enrique; Morales, Cristina; Díaz-García, Elena; López-Fernández, Cristina; Bartha, José Luis; López-Sánchez, Francisco; Lorenzo, Óscar; Moncada, Salvador; Sánchez-Ferrer, Carlos F.; García-Río, Francisco; Cubillos-Zapata, Carolina; Peiró, Concepción

    Hyperinflammation, hypercoagulation and endothelial injury are major findings in acute and post-COVID-19. The SARS-CoV-2 S protein has been detected as an isolated element in human tissues reservoirs and is the main product of mRNA COVID-19 vaccines. We investigated whether the S protein alone triggers pro-inflammatory and pro-coagulant responses in primary cultures of two cell types deeply affected by SARS-CoV-2, such are monocytes and endothelial cells.

    In human umbilical vein endothelial cells (HUVEC) and monocytes, the components of NF-κB and the NLRP3 inflammasome system, as well as coagulation regulators, were assessed by qRT-PCR, Western blot, flow cytometry, or indirect immunofluorescence.

    S protein activated NF-κB, promoted pro-inflammatory cytokines release, and triggered the priming and activation of the NLRP3 inflammasome system resulting in mature IL-1β formation in both cell types. This was paralleled by enhanced production of coagulation factors such as von Willebrand factor (vWF), factor VIII or tissue factor, that was mediated, at least in part, by IL-1β. Additionally, S protein failed to enhance ADAMTS-13 levels to counteract the pro-coagulant activity of vWF multimers. Monocytes and HUVEC barely expressed angiotensin-converting enzyme-2. Pharmacological approaches and gene silencing showed that TLR4 receptors mediated the effects of S protein in monocytes, but not in HUVEC.

    S protein behaves both as a pro-inflammatory and pro-coagulant stimulus in human monocytes and endothelial cells. Interfering with the receptors or signaling pathways evoked by the S protein may help preventing immune and vascular complications driven by such an isolated viral element.

    Link | PDF (Cell Communication and Signaling) [Open Access]

     
    SNT Gatchaman, Sep 9, 2024
    #3
    Lindberg and hotblack like this.

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