N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance

Chion, Alain; O’Sullivan, Jamie M.; Drakeford, Clive; Bergsson, Gudmundur; Dalton, Niall; Águila, Sonia; Ward, Soracha E.; Fallon, Padraic G.; Brophy, Teresa M.; Preston, Roger J. S.; Brady, Lauren; Sheils, Orla; Laffan, Michael; McKinnon, Thomas A. J.; O’Donnell, James S.

doi:10.1182/blood-2016-04-709436

Cited by 31 publications

(64 citation statements)

References 67 publications

(128 reference statements)

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“…In keeping with these in vivo data, in vitro studies have shown that primary human macrophages bind VWF in a dose‐dependent and saturable manner (van Schooten et al , ; Castro‐Nunez et al , ; Chion et al , ). Furthermore, this macrophage binding was followed by VWF uptake and degradation (van Schooten et al , ).…”

Section: Cellular Basis Of Vwf Clearancementioning

confidence: 81%

“…LRP1 binding can also be accelerated by truncation of the N‐linked glycans of VWF (O'Sullivan et al , ). In keeping with the importance of shear, the A1 domain of VWF has been shown to be important in modulating interaction with LRP1 (Wohner et al , ; Chion et al , ). In vitro studies further suggest that additional domains of VWF (including D'D3 and D4) may also contribute to LRP1 binding (Wohner et al , ) (Fig B).…”

Section: Scavenger Receptors and Vwf Clearancementioning

confidence: 97%

“…Furthermore, this macrophage binding was followed by VWF uptake and degradation (van Schooten et al , ). Several groups have reported that VWF binding to macrophages is significantly enhanced in the presence of shear stress or ristocetin, suggesting that VWF conformation plays a critical role in regulating macrophage‐mediated clearance (Castro‐Nunez et al , ; Chion et al , ). Together, these data demonstrate that macrophages play a prominent role in regulating VWF clearance and thereby modulating plasma levels of the VWF‐FVIII complex.…”

Section: Cellular Basis Of Vwf Clearancementioning

confidence: 99%

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von Willebrand factor clearance – biological mechanisms and clinical significance

et al. 2018

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The mechanisms involved in regulating von Willebrand factor (VWF) clearance remain poorly understood. However recent studies have shown that macrophages play a critical role in regulating the half-life of VWF, and have identified specific lectin (including asialoglycoprotein, macrophage galactose-type lectin, Sigec-5 and C-type lectin domain family 4 member M) and scavenger receptors (including low-density lipoprotein receptor-related protein-1, scavenger receptor A1 and stabilin-2) that are involved in VWF clearance. Further studies will be required to determine the relative importance of these individual receptors with respect to physiological and pathological VWF clearance. Nevertheless, recent clinical data have highlighted the importance of enhanced VWF clearance in the pathogenesis of type 1 von Willebrand disease (VWD). Moreover, increased clearance also contributes to reduced VWF levels in many patients with type 2 and type 3 VWD. Improved understanding regarding VWF clearance is not only of direct biological relevance, but may also have important implications for the development of novel therapeutic agents with extended plasma half-lives for the treatment of both VWD and haemophilia A.

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Section: Cellular Basis Of Vwf Clearancementioning

confidence: 81%

Section: Scavenger Receptors and Vwf Clearancementioning

confidence: 97%

Section: Cellular Basis Of Vwf Clearancementioning

confidence: 99%

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von Willebrand factor clearance – biological mechanisms and clinical significance

et al. 2018

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“…Where indicated, clearance studies were repeated in the presence of either clodronate or asialo-orosomucoid (ASOR) as previously described. 8,12 Specific clearance studies were performed after inhibition of MGL using a polyclonal goat anti-mouse MGL1/2 antibody. All in vivo clearance experiments were performed as detailed in the supplemental Methods in accordance with the Health Product Regulatory Authority, Ireland.…”

Section: Methodsmentioning

confidence: 99%

A novel role for the macrophage galactose-type lectin receptor in mediating von Willebrand factor clearance

Ward

O’Sullivan

Drakeford

et al. 2018

Blood

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Previous studies have shown that loss of terminal sialic acid causes enhanced von Willebrand factor (VWF) clearance through the Ashwell-Morrell receptor (AMR). In this study, we investigated (1) the specific importance of - vs-linked sialic acid in protecting against VWF clearance and (2) whether additional receptors contribute to the reduced half-life of hyposialylated VWF. α2-3-linked sialic acid accounts for <20% of total sialic acid and is predominantly expressed on VWF -glycans. Nevertheless, specific digestion with α2-3 neuraminidase (α2-3Neu-VWF) was sufficient to cause markedly enhanced VWF clearance. Interestingly, in vivo clearance experiments in dual mice demonstrated enhanced clearance of α2-3Neu-VWF even in the absence of the AMR. The macrophage galactose-type lectin (MGL) is a C-type lectin that binds to glycoproteins expressing terminal -acetylgalactosamine or galactose residues. Importantly, the markedly enhanced clearance of hyposialylated VWF in mice was significantly attenuated in the presence of an anti-MGL inhibitory antibody. Furthermore, dose-dependent binding of human VWF to purified recombinant human MGL was confirmed using surface plasmon resonance. Additionally, plasma VWF:Ag levels were significantly elevated in mice compared with controls. Collectively, these findings identify MGL as a novel macrophage receptor for VWF that significantly contributes to the clearance of both wild-type and hyposialylated VWF.

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“…In contrast to the specific effect of α2‐6–linked sialylation in enhancing VWF proteolysis by ADAMTS‐13, current evidence suggests that both α2‐6–linked and α2‐3–linked linked sialylation play roles in protecting VWF against clearance . Similarly to their specific role in modulating susceptibility to ADAMTS‐13 proteolysis, the N‐linked glycans at positions 1515 and 1574 within the A2 domain also play a key role in protecting VWF against in vivo clearance . The major effect of α2‐3–linked sialylation in regulating clearance is interesting, as this sialic acid accounts for less than 20% of the total sialylation on human plasma‐derived VWF, and is expressed predominantly on O‐glycans …”

Section: Vwf Sialylation Determines Clearance Through Multiple Pathwaysmentioning

confidence: 93%

von Willebrand factor sialylation—A critical regulator of biological function

Ward

O’Sullivan

O’Donnell

2019

Journal of Thrombosis and Haemostasis

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von Willebrand factor (VWF) undergoes complex post-translational modification prior to its secretion into the plasma. Consequently, VWF monomers contain complex N-glycan and O-glycan structures that, together, account for approximately 20% of the final monomeric mass. An increasing body of evidence has confirmed that these carbohydrate determinants play critical roles in regulating multiple aspects of VWF biology. In particular, studies have demonstrated that terminal ABO blood group has an important effect on plasma VWF levels. This effect is interesting, given that only 15% of the N-glycans and 1% of the O-glycans of VWF actually express terminal ABO(H) determinants. In contrast, the vast majority of the N-glycans and O-glycans on human VWF are capped by terminal negatively charged sialic acid residues. Recent data suggest that sialylation significantly regulates VWF functional activity, susceptibility to proteolysis, and clearance, through a number of independent pathways. These findings are of direct clinical relevence, in that quantitative and qualitative variations in VWF sialylation have been described in patients with VWD, as well as in patients with a number of other physiologic and pathologic conditions. Moreover, platelet-derived VWF is significantly hyposialylated as compared with plasma-derived VWF, whereas the recently licensed recombinant VWF therapeutic is hypersialylated. In this review, we examine the evidence supporting the hypothesis that VWF sialylation plays multiple biological roles. In addition, we consider data suggesting that quantitative and qualitative variations in VWF sialylation may play specific roles in the pathogenesis of VWD, and that sialic acid expression on VWF may also differ across a number of other physiologic and pathologic conditions. K E Y W O R D S ADAMTS-13, glycosylation, von Willebrand disease, von Willebrand factor | INTRODUC TI ONvon Willebrand factor (VWF) is a large multimeric plasma glycoprotein that plays essential roles in maintaining normal hemostasis. 1 First, VWF binds to exposed subendothelial tissues at sites of vascular injury and subsequently facilitates platelet tethering to form a primary platelet plug. Second, VWF also binds to procoagulant factor VIII (FVIII), thereby protecting it from proteolysis and significantly extending its plasma half-life. 2 von Willebrand disease (VWD) is the commonest inherited human bleeding disorder, and is caused by quantitative or qualitative reductions in plasma VWF levels. 3,4 In contrast, elevated plasma levels of the VWF-FVIII complex represent a dose-dependent risk factor for both arterial | 1019 WARD et Al. How to cite this article: Ward S, O'Sullivan JM, O'Donnell JS. von Willebrand factor sialylation-A critical regulator of biological function.

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N-linked glycans within the A2 domain of von Willebrand factor modulate macrophage-mediated clearance

Cited by 31 publications

References 67 publications

von Willebrand factor clearance – biological mechanisms and clinical significance

von Willebrand factor clearance – biological mechanisms and clinical significance

A novel role for the macrophage galactose-type lectin receptor in mediating von Willebrand factor clearance

von Willebrand factor sialylation—A critical regulator of biological function

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