Abstract
BackgroundPersistent 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. ObjectivesTo assess whether endothelial cell activation may be sustained in convalescent COVID‐19 patients and contribute to long COVID pathogenesis. Patients and MethodsFifty patients were reviewed at a median of 68 days following SARS‐CoV‐2 infection. In addition to clinical workup, acute phase markers, endothelial cell (EC) activation and NETosis parameters and thrombin generation were assessed. ResultsThrombin generation assays revealed significantly shorter lag times (p < .0001, 95% CI −2.57 to −1.02 min), increased endogenous thrombin potential (p = .04, 95% CI 15–416 nM/min), and peak thrombin (p < .0001, 95% CI 39–93 nM) in convalescent COVID‐19 patients. These prothrombotic changes were independent of ongoing acute phase response or active NETosis. Importantly, EC biomarkers including von Willebrand factor antigen (VWF:Ag), VWF propeptide (VWFpp), and factor VIII were significantly elevated in convalescent COVID‐19 compared with controls (p = .004, 95% CI 0.09–0.57 IU/ml; p = .009, 95% CI 0.06–0.5 IU/ml; p = .04, 95% CI 0.03–0.44 IU/ml, respectively). In addition, plasma soluble thrombomodulin levels were significantly elevated in convalescent COVID‐19 (p = .02, 95% CI 0.01–2.7 ng/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‐min walk tests. ConclusionsCollectively, 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.
Highlights
Recent studies have reported sustained symptoms in a significant proportion of patients following acute SARS-CoV-2 infection.[1,2] Patients with this “long COVID” syndrome complain of persistent breathlessness, fatigue, and decreased exercise tolerance.[2]
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
The biological mechanisms underlying these ongoing symptoms remain unknown, we recently reported that persistent increased D-dimer levels were present in approximately 25% of convalescent COVID-19 patients up to 4 months following the apparent resolution of their acute infection.[3]
Summary
Recent studies have reported sustained symptoms in a significant proportion of patients following acute SARS-CoV-2 infection.[1,2] Patients with this “long COVID” syndrome complain of persistent breathlessness, fatigue, and decreased exercise tolerance.[2] the biological mechanisms underlying these ongoing symptoms remain unknown, we recently reported that persistent increased D-dimer levels were present in approximately 25% of convalescent COVID-19 patients up to 4 months following the apparent resolution of their acute infection.[3] Importantly, these increased D-dimers were seen in a significant number of both hospitalized and nonhospitalized COVID-19 patients, respectively. The biological mechanisms underlying these persistent procoagulant effects following acute COVID-19 remain poorly understood. Persistent symptoms including breathlessness, fatigue, and decreased exercise tolerance have been reported in patients after acute SARS-CoV-2 infection. Manuscript Handled by: Flora Peyvandi Final decision: Flora Peyvandi, 09 August 2021
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