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CC BY-NC-ND 4.0 · Thromb Haemost 2022; 122(02): 240-256
DOI: 10.1055/s-0041-1740182
Blood Cells, Inflammation and Infection

Associations between the von Willebrand Factor—ADAMTS13 Axis, Complement Activation, and COVID-19 Severity and Mortality

György Sinkovits 
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
Marienn Réti
2   Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
Veronika Müller
3   Department of Pulmonology, Semmelweis University, Budapest, Hungary
,
Zsolt Iványi
4   Department of Anaesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary
,
János Gál
4   Department of Anaesthesiology and Intensive Therapy, Semmelweis University, Budapest, Hungary
,
László Gopcsa
2   Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
Péter Reményi
2   Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
Beáta Szathmáry
5   Department of Infectology, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
Botond Lakatos
5   Department of Infectology, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
János Szlávik
5   Department of Infectology, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
Ilona Bobek
6   Department of Anaesthesiology and Intensive Therapy, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
Zita Z. Prohászka
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
Zsolt Förhécz
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
Blanka Mező
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
7   Research Group for Immunology and Haematology, Semmelweis University – Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
,
Dorottya Csuka 
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
Lisa Hurler 
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
Erika Kajdácsi
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
László Cervenak
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
Petra Kiszel
7   Research Group for Immunology and Haematology, Semmelweis University – Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
,
Tamás Masszi
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
,
István Vályi-Nagy   *
2   Department of Haematology and Stem Cell Transplantation, Central Hospital of Southern Pest, Institute of Haematology and Infectious Diseases, Budapest, Hungary
,
Zoltán Prohászka   *
1   Department of Internal Medicine and Haematology, Semmelweis University, Budapest, Hungary
7   Research Group for Immunology and Haematology, Semmelweis University – Eötvös Loránd Research Network (Office for Supported Research Groups), Budapest, Hungary
› Institutsangaben
Funding The research was financed by the Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary, within the framework of the molecular biology thematic programme of the Semmelweis University, by the National Office for Innovation and Research (KH130355, and 2020-1.1.6-JOVO-2021-00013 “JOVO” to Z.P.). The study was performed in frame of the Premium Postdoctoral Fellowship Program of the Hungarian Academy of Sciences (PPD2018-016/2018 to D.C.). Z.P. and L.H. are supported by funds of the EU MSCA project CORVOS 860044.
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Abstract

Background Endothelial and complement activation were both associated with immunothrombosis, a key determinant of COVID-19 severity, but their interrelation has not yet been investigated.

Objectives We aimed to determine von Willebrand factor (VWF) antigen (VWF:Ag) concentration, VWF collagen binding activity (VWF:CBA), a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) activity (ADAMTS13:Ac), and their ratios in hospitalized COVID-19 patients, and to investigate how these parameters and their constellation with complement activation relate to disease severity and in-hospital mortality in COVID-19.

Methods Samples of 102 hospitalized patients with polymerase chain reaction-confirmed severe acute respiratory syndrome coronavirus 2 positivity were included in our observational cohort study. Patients were stratified according to the peak severity of COVID-19 disease in agreement with the World Health Organization ordinal scale. Twenty-six convalescent plasma donors with previous COVID-19 disease formed the control group. VWF:Ag concentration and VWF:CBA were determined by enzyme-linked immunosorbent assay (ELISA); ADAMTS13:Ac was determined by fluorescence resonance energy transfer. Complement C3 and C3a were measured by turbidimetry and ELISA, respectively. Clinical covariates and markers of inflammation were extracted from hospital records.

Results VWF:Ag and VWF:CBA were elevated in all groups of hospitalized COVID-19 patients and increased in parallel with disease severity. ADAMTS13:Ac was decreased in patients with severe COVID-19, with the lowest values in nonsurvivors. High (> 300%) VWF:Ag concentrations or decreased (< 67%) ADAMTS13:Ac were associated with higher risk of severe COVID-19 disease or in-hospital mortality. The concomitant presence of decreased ADAMTS13:Ac and increased C3a/C3 ratio—indicating complement overactivation and consumption—was a strong independent predictor of in-hospital mortality.

Conclusion Our results suggest that an interaction between the VWF-ADAMTS13 axis and complement overactivation and consumption plays an important role in the pathogenesis of COVID-19.

Keywords

ADAMTS13 protein - complement activation - COVID-19 - survival analysis - von Willebrand factor

Author Contributions

G.S., B.M., D.C., L.H., E.K., L.C., and P.K. designed and performed laboratory determinations, interpreted data, and drafted the manuscript. G.S., Z.Z.P., and Z.P. conceptualized research, collected and analyzed clinical information and laboratory data, conducted statistical analysis, interpreted data, and wrote the manuscript. M.R., V.M., Z.F., Z.I., J.G., L.G., P.R., B.S., B.L., J.S., I.B., T.M., I.V.-N. took part in the conceptualization, collected and analyzed clinical information, interpreted and supervised data, and drafted the manuscript. All authors critically revised the final manuscript.


* Shared authorship.


Supplementary Material



Publikationsverlauf

Eingereicht: 30. Juni 2021

Angenommen: 10. Oktober 2021

Artikel online veröffentlicht:
21. Januar 2022

© 2022. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commercial purposes, or adapted, remixed, transformed or built upon. (https://creativecommons.org/licenses/by-nc-nd/4.0/)

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