Publication: N-linked glycan truncation causes enhanced clearance of plasma-derived von Willebrand factor
Authors
Águila Martínez, Sonia ; O'Sullivan, J.M. ; McRae, E. ; Ward, S.E. ; Rawley, O. ; Fallon, P.G. ; Brophy, T.M. ; Preston, R.J.S. ; Brady, L. ; Sheils, O. ; Chion, A. ; O'Donnell, J.S.
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Publisher
Elsevier
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DOI
https://doi.org/10.1111/jth.13537
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info:eu-repo/semantics/article
Description
Abstract
Background: 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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Citation
O'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.
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