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Persistent endothelial dysfunction a potential cause of long COVID

Elevated markers of endothelial dysfunction in severe COVID-19 and long COVID indicate a potential causal link between these two factors.

The presence of symptoms such as fatigue, dyspnoea have been identified in patients with long COVID though the underlying cause of the conditions remains uncertain. One particular clinical finding which remains after an acute COVID-19 infection, in both hospitalised and non-hospitalised patients, is the presence of an elevated D-dimer level in just over a quarter (25.3%) of hospitalised patients some 4 months later. Moreover, several autopsy studies of patients who died of COVID-19 have revealed the presence severe endothelial damage and widespread vascular thrombosis, raising the possibility that this higher incidence of thromboembolic events might be due to a COVID-19-induced coagulopathy. In fact, autopsies have revealed how thrombosis is a prominent feature in multiple organs, despite full anticoagulation. Furthermore, a systemic analysis of 41 autopsies found endothelial dysfunction as evidenced by the expression of markers of endothelial damage and concluded that COVID-19 infection largely occurs in the lungs. Further support for the notion that endothelial dysfunction is an important contributor to COVID-19 comes from a single centre study that observed elevation of markers associated with such dysfunction e.g., von Willebrand Factor (VWF) antigen, were significantly higher among intensive care patients.

Given the autopsy findings, a team from the Irish Centre Vascular Biology, Royal College of Surgeons, Dublin, Ireland, speculated that the presence of persistent endothelial cell activation may be a contributing factor or even underlying cause for long COVID. The team enrolled patients both hospitalised and non-hospitalised patients from a post-COVID-19 review clinic at a single hospital, a minimum of 6 weeks after resolution of the acute infection symptoms. Plasma samples were analysed for several markers of endothelial dysfunction including VWF antigen, VWF propeptide, Factor VII activity and soluble thrombomodulin.

A total of 50 patients with a mean age of 50 years, the majority of whom (74%) had been hospitalised because of their infection, were assessed a median of 68 days after acute COVID-19 symptom resolution. Thrombin lag times (which is a measure of clotting time) were significantly shorter in symptomatic patients compared with healthy, non-hospitalised controls (6.2 minutes vs 8.2 minutes, p < 0.0001). There were also significantly higher endogenous thrombin potential and peak thrombin levels in hospitalised patients. However, these pro-thrombotic changes were found to be independent of acute infection phase markers such as C-reactive protein, which had normalised. In addition, endothelial dysfunction biomarkers such as VWF antigen were also elevated in hospitalised patients compared with controls.
The authors speculated that this sustained endothelial cell activation, as evidenced by elevated markers of endothelial dysfunction up to 10 weeks after resolution of the acute COVID-19 symptoms, could help explain the symptoms of long COVID. They concluded by calling for further work to determine if this sustained endothelial cell activation has a role in the pathogenesis of long COVID.

Fogarty H et al. Persistent Endotheliopathy in the Pathogenesis of Long COVID Syndrome. J Thromb Haemost 2021

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