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

[Andy]

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

 

[SNT Gatchaman]

See also this preprint (2020, doesn't appear to have been accepted)
Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy

 

[SNT Gatchaman]

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]

Here we identify S protein as a direct stimulator of monocyte activation by triggering the NF-κB pathway and releasing cytokines such as IL-6, which is elevated in the circulation of COVID-19 patients where it correlates with T cell depletion

in human endothelial cells the viral S protein evokes a disbalance in the vWF:ADAMTS-13 ratio which may favor thrombi formation

In conclusion, the S protein from SARS-CoV-2 acts as a unifying stimulus directly promoting pro-inflammatory and pro-coagulant activation of human immune and endothelial cells. Interfering with the S protein-host receptor binding or attenuating the deleterious signaling triggered by this isolated viral element might provide therapeutical approaches to confront COVID-19 vaccine-derived complications or acute and long-term complications of the disease.