| Title: |
Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy |
| Authors: |
South, K; Mann, E; Menon, M; Konkel, JE; Ustianowsk, A; Bakerly, ND; Dark, PM; Felton, T; Horsley, A; Hussell, T; CIRCO; Roberts, Lucy; Morris, Lucy; Knight, Sean Blandin; Grainger, John R; Smith, Craig J; Allan, Stuart M |
| Source: |
South, K, Mann, E, Menon, M, Konkel, JE, Ustianowsk, A, Bakerly, ND, Dark, PM, Felton, T, Horsley, A, Hussell, T, CIRCO, Roberts, L, Morris, L, Knight, S B, Grainger, J R, Smith, C J & Allan, S M 2020, Severity-stratified and longitudinal analysis of VWF/ADAMTS13 imbalance, altered fibrin crosslinking and inhibition of fibrinolysis as contributors to COVID-19 coagulopathy. https://doi.org/10.1101/2020.08.18.20159608 |
| Publication Year: |
2020 |
| Collection: |
The University of Manchester: Research Explorer - Publications |
| Description: |
Background Early clinical reports have suggested that the prevalence of thrombotic complications in the pathogenesis of COVID-19 may be as high as 30% in intensive care unit (ICU)-admitted patients and could be a major factor contributing to mortality. However, mechanisms underlying COVID-19-associated thrombo-coagulopathy, and its impact on patient morbidity and mortality, are still poorly understood. Methods We performed a comprehensive analysis of coagulation and thromboinflammatory factors in plasma from COVID-19 patients with varying degrees of disease severity. Furthermore, we assessed the functional impact of these factors on clot formation and clot lysis. Results Across all COVID-19 disease severities (mild, moderate and severe) we observed a significant increase (6-fold) in the concentration of ultra-large von Willebrand factor (UL-VWF) multimers compared to healthy controls. This is likely the result of an interleukin (IL)-6 driven imbalance of VWF and the regulatory protease ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motifs, member 13). Upregulation of this key pro-coagulant pathway may also be influenced by the observed increase (~6-fold) in plasma α-defensins, a consequence of increased numbers of neutrophils and neutrophil activation. Markers of endothelial, platelet and leukocyte activation were accompanied by increased plasma concentrations of Factor XIII (FXIII) and plasminogen activator inhibitor (PAI)-1. In patients with high FXIII we observed alteration of the fibrin network structure in in vitro assays of clot formation, which coupled with increased PAI-1, prolonged the time to clot lysis by the t-PA/plasmin fibrinolytic pathway by 52% across all COVID-19 patients (n=23). Conclusions We show that an imbalance in the VWF/ADAMTS13 axis causing increased VWF reactivity may contribute to the formation of platelet-rich thrombi in the pulmonary vasculature of COVID-19 patients. Through immune and inflammatory responses, COVID-19 also alters the balance of factors ... |
| Document Type: |
other/unknown material |
| Language: |
English |
| DOI: |
10.1101/2020.08.18.20159608 |
| Availability: |
https://research.manchester.ac.uk/en/publications/90b18210-3fc9-4d79-8d21-152fad76d167; https://doi.org/10.1101/2020.08.18.20159608; http://europepmc.org/abstract/PPR/PPR203815 |
| Rights: |
info:eu-repo/semantics/restrictedAccess |
| Accession Number: |
edsbas.E485F347 |
| Database: |
BASE |