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Persistent endotheliopathy in the pathogenesis of long COVID syndrome

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posted on 2021-09-29, 16:26 authored by Helen FogartyHelen Fogarty, Liam Townsend, Hannah Morrin, Azaz AhmadAzaz Ahmad, Claire ComerfordClaire Comerford, Ellie KarampiniEllie Karampini, Hanna Englert, Mary Byrne, Colm Bergin, Jamie O'SullivanJamie O'Sullivan, Ignacio Martin-Loeches, Parthiban Nadarajan, Ciaran Bannan, Patrick W Mallon, Gerard CurleyGerard Curley, Roger PrestonRoger Preston, Aisling Rehill, Dennis McGonagle, Cliona Ni Cheallaigh, Ross I Baker, Thomas Renné, Soracha Enright Ward, James O'DonnellJames O'Donnell, Irish COVID-19 Vasculopathy Study (iCVS) investigators

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.

Objectives: To assess whether 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, 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 correlated 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.


Health Research Board COVID-19 Rapid Response award, Grant/Award Number: COV19-2020-086

National Children’s Research Centre, Grant/Award Number: C/18/1

Wellcome Trust

3M Foundation

Health Research Board (Grant number 203930/B/16/Z)

Health Service Executive, National Doctors Training and Planning and the Health and Social Care, Research and Development Division, Northern Ireland

German Research Foundation (grants A11/SFB 877, P6/KFO 306 and B8/SFB 841)

IReL (open access funding)



The original article is available at

Published Citation

Fogarty H. et al. Persistent endotheliopathy in the pathogenesis of long COVID syndrome. J Thromb Haemost. 2021 Oct;19(10):2546-2553.

Publication Date

10 August 2021

PubMed ID



  • Anaesthetics and Critical Care
  • Irish Centre for Vascular Biology
  • School of Pharmacy and Biomolecular Sciences

Research Area

  • Vascular Biology




  • Published Version (Version of Record)