Recombinant ADAMTS13 reduces abnormally up-regulated von Willebrand factor in plasma from patients with severe COVID-19

Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-...

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Bibliographic Details
Published in:	Thrombosis research 2021-05, Vol.201, p.100-112
Main Authors:	Turecek, Peter L., Peck, Rachel C., Rangarajan, Savita, Reilly-Stitt, Christopher, Laffan, Michael A., Kazmi, Rashid, James, Izabela, Dushianthan, Ahilanandan, Schrenk, Gerald, Gritsch, Herbert, Ewenstein, Bruce M., Mellgard, Bjorn, Erdlenbruch, Wolfhard, Jain, Nisha, Binder, Nikolaus B., Mumford, Andrew D.
Format:	Article
Language:	eng
Subjects:	ADAMTS13 ADAMTS13 Protein Blood clot COVID-19 Cross-Sectional Studies Endothelium Hospitals Humans Inflammation Proteases rADAMTS13 Recombinant Proteins - therapeutic use SARS-COV-2 Thrombosis Von Willebrand factor
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Summary:	Thrombosis affecting the pulmonary and systemic vasculature is common during severe COVID-19 and causes adverse outcomes. Although thrombosis likely results from inflammatory activation of vascular cells, the mediators of thrombosis remain unconfirmed. In a cross-sectional cohort of 36 severe COVID-19 patients, we show that markedly increased plasma von Willebrand factor (VWF) levels were accompanied by a partial reduction in the VWF regulatory protease ADAMTS13. In all patients we find this VWF/ADAMTS13 imbalance to be associated with persistence of ultra-high-molecular-weight (UHMW) VWF multimers that are highly thrombogenic in some disease settings. Incubation of plasma samples from patients with severe COVID-19 with recombinant ADAMTS13 (rADAMTS13) substantially reduced the abnormally high VWF activity, reduced overall multimer size and depleted UHMW VWF multimers in a time and concentration dependent manner. Our data implicate disruption of normal VWF/ADAMTS13 homeostasis in the pathogenesis of severe COVID-19 and indicate that this can be reversed ex vivo by correction of low plasma ADAMTS13 levels. These findings suggest a potential therapeutic role for rADAMTS13 in helping restore haemostatic balance in COVID-19 patients. •VWF was highly elevated in patients with severe COVID-19 admitted to intensive care units whereas ADAMTS13 was reduced in most patients.•VWF/ADAMTS13 imbalance in severe COVID-19 enables persistence of thrombogenic ultra-high molecular weight VWF multimers.•Incubation of COVID-19 plasma with recombinant ADAMTS13 corrects the abnormally high VWF activity and depletes abnormal multimers.
ISSN:	0049-3848 1879-2472