Persistent endotheliopathy in the pathogenesis of long COVID syndrome

Abstract

Background Persistent symptoms including breathlessness, fatigue and decreased exercise tolerance have been reported in patients after acute SARS‐CoV‐2 infection. The biological mechanisms underlying this ‘ Long COVID ’ syndrome remain unknown. However, autopsy studies have highlighted the key roles played by pulmonary endotheliopathy and microvascular immunothrombosis in acute COVID‐19. We hypothesized that endothelial cell activation may be sustained in convalescent COVID‐19 patients and contribute to Long COVID pathogenesis. Patients and Methods Fifty patients were reviewed at a median of 68 days following SARS‐CoV‐2 infection. In addition to clinical workup, acute phase markers, EC activation and NETosis parameters and thrombin generation were assessed. Results Thrombin generation assays revealed significantly shorter lag times (p<0.0001, 95% CI ‐2.57– ‐1.02min), increased endogenous thrombin potential (ETP) (p=0.04, 95% CI 15–416nM/min) and peak thrombin (p<0.0001, 95% CI 39–93nM) in convalescent COVID‐19 patients. These pro‐thrombotic changes were independent of ongoing acute phase response or active NETosis. Importantly, EC biomarkers including VWF:Ag, VWF propeptide (VWFpp) and Factor VIII (FVIII:C) were significantly elevated in convalescent COVID‐19 compared to controls (p=0.004, 95% CI 0.09–0.57IU/ml; p=0.009, 95% CI 0.06–0.5IU/ml; p=0.04, 95% CI 0.03–0.44IU/ml, respectively). In addition, plasma soluble thrombomodulin (sTM) levels were significantly elevated in convalescent COVID‐19 (p=0.02, 95% CI 0.01–2.7ng/ml). Sustained endotheliopathy was more frequent in older, comorbid patients and those requiring hospitalization. Finally, both plasma VWF:Ag and VWFpp levels correlated inversely with 6‐minute walk tests. Conclusions Collectively, our findings demonstrate that sustained endotheliopathy is common in convalescent COVID‐19 and raise the intriguing possibility that this may contribute to Long COVID pathogenesis.

An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

“…Altered endothelial dysfunction-related microRNAs were found in plasma from ME/CFS patients recently [ 5 ]. In Covid-19 infection the endothelium is severely affected and the disturbance seems to persist in post-Covid Syndrome (PCS) [ 8 , 12 , 20 , 23 , 34 ]. Particularly the finding of severe endothelial affection in Covid-19 and the persisting endothelial dysfunction corroborates our hypothesis of a role of endothelial and vascular dysfunction in the pathogenesis of PCS.…”

Pathogenic Basis of Thromboinflammation and Endothelial Injury in COVID-19: Current Findings and Therapeutic Implications

“…From mechanistic points of view, it remains unclear whether dysregulated immune response is the primary pathogenic mechanism in severe COVID-19, although in the acute phase of severely ill patients with COVID-19, anti-inflammation agents are effective. In a retrospective observational study, persistent endotheliopathy with increased levels of factor VIII, VWF, and thrombomodulin, compared with healthy subjects, was observed in convalescent COVID-19 patients, independent of ongoing acute phase response or NETosis [ 215 , 216 ]. The hypercoagulable state observed in severe COVID-19 patients was associated with elevated levels of factor VIII and VWF, suggesting the involvement of endothelial cells [ 110 ].…”

“…However, it remains unclear which of the two mechanisms mainly contribute to activation of the kallikrein–kinin system in COVID-19. It was reported that systemic factor XIIa levels were not elevated in patients with long COVID-19 syndrome, compared with healthy subjects, while factor VIII and VWF levels were higher in these patients, suggesting that ACE2 internalization might be the main contributor to activation of the kallikrein–kinin system in COVID-19 [ 215 ]. ACE2 decoys and bradykinin inhibitors could be therapeutic candidates for COVID-19 that target endothelial dysfunction, in addition to statin and nitric oxide.…”

Endothelial dysfunction in COVID-19: A potential predictor of long-COVID?

“…A growing body of evidence suggests a high prevalence of long-COVID, a clinical constellation that is difficult to grasp since most routine clinical tests are inconspicuous even in highly symptomatic patients. Based on blood biomarker assessment, Fogarty et al [ 10 ] have just recently proclaimed a potential role of persistent endotheliopathy in long-COVID. Future prospective studies combining PAT assessment with laboratory and clinical patient data will help to investigate a potential association of endothelial dysfunction with long-COVID.…”