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Persistent endotheliopathy in the pathogenesis of long COVID syndrome

SNT Gatchaman

Senior Member
New Zealand
Authors: Fogarty et al
Published: 10th Aug 2021
DOI: 10.1111/jth.15490
Full Text: J Thromb Haemostat (open access PDF)


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 endo- theliopathy and microvascular immunothrombosis in acute COVID-19.

Objectives: To assess whether endothelial cell activation may be sustained in conva- lescent 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, endothelial cell (EC) activation and NETosis parameters and thrombin generation were assessed.

Results: Thrombin 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 cor- related inversely with 6-min 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.


  • Ongoing endotheliopathy is a common finding in convalescent COVID-19 patients and is independent of the acute phase response.
  • Plasma FVIII:C levels and thrombin generation are significantly increased in convalescent COVID-19 patients compared to healthy controls.
  • Plasma VWF:Ag, VWFpp and sTM levels remain persistently elevated in a proportion of patients following apparent resolution of acute COVID-19.
  • Markers of endotheliopathy correlate inversely with 6-min walk tests in patients with ongoing symptoms after COVID-19.