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dc.contributor.authorSwystun, Laura L.en
dc.contributor.authorNotley, Colleenen
dc.contributor.authorGeorgescu, Ilincaen
dc.contributor.authorLai, Jesse D.en
dc.contributor.authorNesbitt, Kateen
dc.contributor.authorJames, Paula D.en
dc.contributor.authorLillicrap, Daviden
dc.date.accessioned2019-04-24T17:05:39Z
dc.date.available2019-04-24T17:05:39Z
dc.date.issued2019-02-11
dc.identifier.urihttp://hdl.handle.net/1974/26120
dc.descriptionThis is the peer reviewed version of the following article:Swystun, L. L., Notley, C., Georgescu, I., Lai, J. D., Nesbitt, K., James, P. D., & Lillicrap, D. (2019). The endothelial lectin clearance receptor CLEC4M binds and internalizes factor VIII in a VWF-dependent and independent manner. Journal of Thrombosis and Haemostasis, 17(4), 681–694, which has been published in final form at https://doi.org/10.1111/jth.14404. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions.en
dc.description.abstractEssentials CLEC4M is an endocytic receptor for factor FVIII. CLEC4M interacts with FVIII in a VWF-dependent and independent manner. CLEC4M binds to mannose-containing glycans on FVIII. CLEC4M internalization of FVIII involves clathrin coated pits. Summary Background von Willebrand factor (VWF) and factor VIII (FVIII) circulate in the plasma as a non-covalent complex, and the majority of FVIII is likely to be cleared by VWF-dependent pathways. Clearance of VWF-free FVIII is rapid and underlies the pathological basis of some quantitative FVIII deficiencies. The receptor pathways that regulate the clearance of VWF-bound and VWF-free FVIII are incompletely uncharacterized. The human liver-expressed endothelial lectin CLEC4M has been previously characterized as a clearance receptor for VWF, although its influence on FVIII is unknown. Objective The interaction between FVIII and CLEC4M was characterized in the presence or absence of VWF. Methods FVIII interactions with CLEC4M were evaluated by in vitro cell-based and solid phase binding assays. Interactions between FVIII and CLEC4M or liver sinusoidal endothelial cells were evaluated in vivo by immunohistochemistry. Results CLEC4M-expressing HEK 293 cells bound and internalized recombinant and plasma-derived FVIII through VWF-dependent and independent mechanisms. CLEC4M binding to recombinant FVIII was dependent on mannose-exposed N-linked glycans. CLEC4M mediated FVIII internalization via a clathrin-coated pit-dependent mechanism, resulting in transport of FVIII from early and late endosomes for catabolism by lysosomes. In vivo hepatic expression of CLEC4M after hydrodynamic liver transfer was associated with a decrease in plasma levels of endogenous murine FVIII:C in normal mice, whereas infused recombinant human FVIII was associated with sinusoidal endothelial cells in the presence or absence of VWF. Conclusions These findings suggest that CLEC4M is a novel clearance receptor that interacts with mannose-exposed glycans on FVIII in the presence or absence of VWF.en
dc.description.sponsorshipD.L. receives grant support from Bayer, Bioverativ, CSL and Octapharmaen
dc.description.sponsorshipP.D.J. receives research funding from CSL Behring and honoraria from CSL Behring, Bayer and Baxter for educational presentations.en
dc.subjectendocytosisen
dc.subjectendothelial cellen
dc.subjectFactor VIIIen
dc.subjectglycanen
dc.subjectlectin receptoren
dc.subjectvon Willebrand factoren
dc.titleThe endothelial lectin clearance receptor CLEC4M binds and internalizes factor VIII in a VWF-dependent and independent manneren
dc.typejournal articleen
dc.identifier.doihttps://doi.org/10.1111/jth.14404


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