ADAMTS13 regulation of VWF multimer distribution in severe COVID-19
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.comPublished 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 2021External DOI
PubMed ID
34053187Department/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
WileyVersion
- Published Version (Version of Record)