biostudies-literatureUnknownWard SEHealth Research Board COVID-19 Rapid Response awardWellcome Trust<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.Journal of thrombosis and haemostasis : JTHhttps://www.ebi.ac.uk/biostudies/studies/S-EPMC8237059biostudies-literatureADAMTS13 regulation of VWF multimer distribution in severe COVID-19.PMC8237059203930/B/16/ZCOV19-2020-086Fogarty HKarampini EMorrin HO'Donnell JSWorrall APKelly CCurley GFAlalqam RMallon PWIrish COVID-19 Vasculopathy Study (iCVS) investigatorsde Barra ELavin MBoylan MPreston RGlavey SBergin CO'Sullivan JMMcEvoy NLSchneppenheim SNi Cheallaigh CKenny DWard SEByrne MClarke JBudde UTownsend LDittmer RBaker RIO'Connell NMartin-Loeches IfalseADAMTS13 regulation of VWF multimer distribution in severe COVID-19.<h4>Background</h4>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.<h4>Objectives</h4>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.<h4>Patients and methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.2021-01-01T00:00:00Z2021 May2022-02-10T16:55:11.953Z2022-02-10T16:55:11.953ZS-EPMC82370593405318710.1111/jth.15409