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ADAMTS13 regulation of VWF multimer distribution in severe COVID-19

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posted on 13.08.2021, 12:43 by Soracha Enright WardSoracha Enright Ward, Helen FogartyHelen Fogarty, Ellie KarampiniEllie Karampini, Michelle LavinMichelle Lavin, Sonja Schneppenheim, Rita Dittmer, Hannah Morrin, Siobhan GlaveySiobhan Glavey, Cliona Ni Cheallaigh, Colm Bergin, Ignacio Martin-Loeches, Patrick W Mallon, Gerard CurleyGerard Curley, Ross I Baker, Ulrich Budde, Jamie O'SullivanJamie O'Sullivan, James O'DonnellJames O'Donnell, Irish COVID-19 Vasculopathy Study (iCVS) investigators, Roger PrestonRoger Preston

Background: Consistent with fulminant endothelial cell activation, elevated plasma von Willebrand factor (VWF) antigen levels have been reported in patients with COVID-19. The multimeric size and function of VWF are normally regulated through A Disintegrin And Metalloprotease with ThrombSpondin Motif type 1 motif, member 13 (ADAMTS-13)--mediated proteolysis.

Objectives: This study investigated the hypothesis that ADAMTS-13 regulation of VWF multimer distribution may be impaired in severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection contributing to the observed microvascular thrombosis.

Patients and methods: Patients with COVID-19 (n = 23) were recruited from the Beaumont Hospital Intensive Care Unit (ICU) in Dublin. Plasma VWF antigen, multimer distribution, ADAMTS-13 activity, and known inhibitors thereof were assessed.

Results: We observed markedly increased VWF collagen-binding activity in patients with severe COVID-19 compared to controls (median 509.1 versus 94.3 IU/dl). Conversely, plasma ADAMTS-13 activity was significantly reduced (median 68.2 IU/dl). In keeping with an increase in VWF:ADAMTS-13 ratio, abnormalities in VWF multimer distribution were common in patients with COVID-19, with reductions in high molecular weight VWF multimers. Terminal sialylation regulates VWF susceptibility to proteolysis by ADAMTS-13 and other proteases. We observed that both N- and O-linked sialylation were altered in severe COVID-19. Furthermore, plasma levels of the ADAMTS-13 inhibitors interleukin-6, thrombospondin-1, and platelet factor 4 were significantly elevated.

Conclusions: These findings support the hypothesis that SARS-CoV-2 is associated with profound quantitative and qualitative increases in plasma VWF levels, and a multifactorial down-regulation in ADAMTS-13 function. Further studies will be required to determine whether therapeutic interventions to correct ADAMTS-13-VWF multimer dysfunction may be useful in COVID-microvascular thrombosis and angiopathy.

Funding

Health Research Board COVID-19 Rapid Response award (COV19- 2020-086)

3M Foundation to RCSI University of Medicine and Health Sciences in support of COVID-19 research

Irish Clinical Academic Training (ICAT) Programme, supported by the Wellcome Trust and the Health Research Board (Grant Number 203930/B/16/Z)

Health Service Executive, National Doctors Training and Planning

Health and Social Care, Research and Development Division, Northern Ireland

National Children’s Research Centre Project Award (C/18/1)

IReL

History

Comments

The original article is available at https://onlinelibrary.wiley.com

Published Citation

Ward SE, et al. ADAMTS13 regulation of VWF multimer distribution in severe COVID-19. J Thromb Haemost. 2021:10.1111/jth.15409.

Publication Date

30 May 2021

PubMed ID

34053187

Department/Unit

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

Research Area

  • Health Professions Education
  • Vascular Biology
  • Cancer
  • Immunity, Infection and Inflammation

Publisher

Wiley

Version

  • Published Version (Version of Record)