ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

S.E. Ward; H. Fogarty; E. Karampini; M. Lavin; S. Schneppenheim; R. Dittmer; H. Morrin; S. Glavey; C. Ni Cheallaigh; C. Bergin; I. Martin‐Loeches; P.W. Mallon; G.F. Curley; R.I. Baker; U. Budde; J.M. O’Sullivan; J.S. O’Donnell; N. O’Connell; M. Byrne; L. Townsend; N.L. McEvoy; J. Clarke; M. Boylan; R. Alalqam; A.P. Worrall; C. Kelly; E. de Barra; R. Preston; D. Kenny

doi:10.1111/jth.15409

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ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

Journal article

Peer reviewed

ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19

S.E. Ward, H. Fogarty, E. Karampini, M. Lavin, S. Schneppenheim, R. Dittmer, H. Morrin, S. Glavey, C. Ni Cheallaigh, C. Bergin, …

Journal of Thrombosis and Haemostasis, Vol.19(8), pp.1914-1921

2021

DOI: https://doi.org/10.1111/jth.15409

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Abstract

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.

Details

Title: ADAMTS13 regulation of VWF multimer distribution in severe COVID‐19
Authors/Creators: S.E. Ward (Author/Creator) - Royal College of Surgeons in Ireland
H. Fogarty (Author/Creator) - Royal College of Surgeons in Ireland
E. Karampini (Author/Creator) - Royal College of Surgeons in Ireland
M. Lavin (Author/Creator) - Royal College of Surgeons in Ireland
S. Schneppenheim (Author/Creator) - Department of Hämostaseology Medilys Laborgesellschaft mbH Hamburg Germany
R. Dittmer (Author/Creator) - Department of Hämostaseology Medilys Laborgesellschaft mbH Hamburg Germany
H. Morrin (Author/Creator) - Royal College of Surgeons in Ireland
S. Glavey (Author/Creator) - Beaumont Hospital
C. Ni Cheallaigh (Author/Creator) - St. James's Hospital
C. Bergin (Author/Creator) - St. James's Hospital
I. Martin‐Loeches (Author/Creator)
P.W. Mallon (Author/Creator) - University College Dublin
G.F. Curley (Author/Creator) - Royal College of Surgeons in Ireland
R.I. Baker (Author/Creator) - Western Australia Centre for Thrombosis and Haemostasis Perth Blood InstituteMurdoch University Perth Australia
U. Budde (Author/Creator) - Department of Hämostaseology Medilys Laborgesellschaft mbH Hamburg Germany
J.M. O’Sullivan (Author/Creator) - Royal College of Surgeons in Ireland
J.S. O’Donnell (Author/Creator) - Royal College of Surgeons in Ireland
N. O’Connell (Author/Creator)
M. Byrne (Author/Creator)
L. Townsend (Author/Creator)
N.L. McEvoy (Author/Creator)
J. Clarke (Author/Creator)
M. Boylan (Author/Creator)
R. Alalqam (Author/Creator)
A.P. Worrall (Author/Creator)
C. Kelly (Author/Creator)
E. de Barra (Author/Creator)
R. Preston (Author/Creator)
D. Kenny (Author/Creator)
Publication Details: Journal of Thrombosis and Haemostasis, Vol.19(8), pp.1914-1921
Publisher: Wiley-Blackwell
Identifiers: 991005542346907891
Copyright: © 2021 The Authors.
Murdoch Affiliation: Western Australian Centre for Thrombosis and Haemostasis
Language: English
Resource Type: Journal article

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Collaboration types: Domestic collaboration; International collaboration
Citation topics: 1 Clinical & Life Sciences; 1.104 Virology - General; 1.104.1353 Coronavirus Research
Web Of Science research areas: Hematology; Peripheral Vascular Disease
ESI research areas: Clinical Medicine