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N-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor

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dc.contributor.authorÁguila Martínez, Sonia
dc.contributor.authorO'Sullivan, J.M.
dc.contributor.authorMcRae, E.
dc.contributor.authorWard, S.E.
dc.contributor.authorRawley, O.
dc.contributor.authorFallon, P.G.
dc.contributor.authorBrophy, T.M.
dc.contributor.authorPreston, R.J.S.
dc.contributor.authorBrady, L.
dc.contributor.authorSheils, O.
dc.contributor.authorChion, A.
dc.contributor.authorO'Donnell, J.S.
dc.contributor.departmentMedicina
dc.date.accessioned2026-02-16T08:50:39Z
dc.date.available2026-02-16T08:50:39Z
dc.date.copyright© 2016 International Society on Thrombosis and Haemostasis
dc.date.issued2016-12-09
dc.description.abstractBackground: Enhanced von Willebrand factor (VWF) clearance is important in the etiology of both type 1 and type 2 von Willebrand disease (VWD). In addition, previous studies have demonstrated that VWF glycans play a key role in regulating in vivo clearance. However, the molecular mechanisms underlying VWF clearance remain poorly understood. Objective: To define the molecular mechanisms through which VWF N-linked glycan structures influence in vivo clearance. Methods: By use of a series of exoglycosidases, different plasma-derived VWF (pd-VWF) glycoforms were generated. In vivo clearance of these glycoforms was then assessed in VWF−/− mice in the presence or absence of inhibitors of asialoglycoprotein receptor (ASGPR), or following clodronate-induced macrophage depletion. Results Reduced amounts of N-linked and O-linked sialylation resulted in enhanced pd-VWF clearance modulated via ASGPR. In addition to this role of terminal sialylation, we further observed that progressive N-linked glycan trimming also resulted in markedly enhanced VWF clearance. Furthermore, these additional N-linked glycan effects on clearance were ASGPR-independent, and instead involved enhanced macrophage clearance that was mediated, at least in part, through LDL receptor-related protein 1. Conclusion: The carbohydrate determinants expressed on VWF regulate susceptibility to proteolysis by ADAMTS-13. In addition, our findings now further demonstrate that non-sialic acid carbohydrate determinants expressed on VWF also play an unexpectedly important role in modulating in vivo clearance through both hepatic ASGPR-dependent and macrophage-dependent pathways. In addition, these data further support the hypothesis that variation in VWF glycosylation may be important in the pathophysiology underlying type 1C VWD.
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dc.identifier.citationO'Sullivan JM, Aguila S, McRae E, Ward SE, Rawley O, Fallon PG, Brophy TM, Preston RJ, Brady L, Sheils O, Chion A, O'Donnell JS. N-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor. J Thromb Haemost. 2016 Dec;14(12):2446-2457.
dc.identifier.doihttps://doi.org/10.1111/jth.13537
dc.identifier.eissn1538-7836
dc.identifier.issn1538-7933
dc.identifier.urihttp://hdl.handle.net/10201/205241
dc.languageeng
dc.publisherElsevier
dc.relationThe authors thank N. van Rooijen of the Foundation Clodronate Liposomes (Haarlem, the Netherlands) for generously providing the liposome-clodronate. This work was supported by a Science Foundation Ireland Principal Investigator Award (11/PI/1066; J. S. O’Donnell
dc.relation.publisherversionhttps://www.sciencedirect.com/science/article/pii/S1538783622025442
dc.rights.accessRightsinfo:eu-repo/semantics/restrictedAccess
dc.subjectGlycosylation
dc.subjectVon Willebrand factor
dc.subjectVon Willebrand disease
dc.subjectMetabolic clearance rate
dc.subjectMacrophages
dc.subject.odsObjetivo 3: Salud
dc.titleN-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor
dc.typeinfo:eu-repo/semantics/article
dc.type.versioninfo:eu-repo/semantics/publishedVersion
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relation.isAuthorOfPublication49779dfb-f4b4-4013-9b03-2ad7e3c247b7
relation.isAuthorOfPublication.latestForDiscovery49779dfb-f4b4-4013-9b03-2ad7e3c247b7
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