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

• 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: English
• Subjects: ADAMTS13; ADAMTS13 Protein; COVID-19; Cross-Sectional Studies; Endothelium; Humans; Inflammation; rADAMTS13; Recombinant Proteins - therapeutic use; SARS-COV-2; Thrombosis; von Willebrand Factor
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2021.02.012

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.