Shear stress-independent binding of von Willebrand factor-type 2B mutants p.R1306Q & p.V1316M to LRP1 explains their increased clearance

Journal of Thrombosis and Haemostasis : JTH
N WohnerC V Denis

Abstract

von Willebrand factor (VWF) is cleared in a shear stress- and macrophage-dependent manner by LRP1. von Willebrand disease (VWD)-type 2B mutants are endocytosed more efficiently than wild-type (wt)-VWF by macrophages. To investigate if VWD-type 2B mutations in the VWF A1-domain affect LRP1 binding and LRP1-dependent clearance. Recombinant Fc-tagged A1 domain (A1-Fc, A2-Fc, A3-Fc) and full-length VWF (wt or mutants thereof) were tested for binding to LRP1 or a recombinant fragment thereof in a static immunosorbent assay. Mutant and wt-VWF were also compared for clearance in mice lacking macrophage LRP1 (macLRP1(-) ) and control mice (macLRP1(+) ). We found that A1-Fc but not A2-Fc or A3-Fc binds dose-dependently to LRP1. Binding of A1-Fc to LRP1 was markedly enhanced by the VWD-type 2B mutation p.V1316M. As expected, full-length wt-VWF was unable to bind LRP1 under static conditions unless ristocetin was added. In contrast, the presence of the p.V1316M or p.R1306Q mutation induced spontaneous binding to LRP1 without the need for ristocetin or shear stress. Both mutants were cleared more rapidly than wt-VWF in control macLRP1(+) mice. Surprisingly, deletion of macrophage LRP1 abrogated the increased clearance of the VWF/p.R1306Q a...Continue Reading

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Citations

Sep 5, 2015·Biomicrofluidics·Karthiga PanneerselvamBrigitte Städler
Oct 13, 2016·Journal of Thrombosis and Haemostasis : JTH·J M O'SullivanJ S O'Donnell
Jan 7, 2017·Journal of Pediatric Hematology/oncology·Seth J RotzRussell E Ware
Dec 19, 2018·Journal of Thrombosis and Haemostasis : JTH·D Mezzano, T Quiroga
Dec 30, 2015·Journal of Thrombosis and Haemostasis : JTH·A de Jong, J Eikenboom
May 28, 2019·Journal of Thrombosis and Haemostasis : JTH·Laura L SwystunDavid Lillicrap
Sep 4, 2019·Journal of Thrombosis and Haemostasis : JTH·Alexander TischerMatthew Auton
Dec 4, 2016·Hematology·Michelle Lavin, James S O'Donnell
Nov 1, 2018·British Journal of Haematology·Jamie M O'SullivanJames S O'Donnell
Feb 24, 2018·Blood·Cécile V Denis, Peter J Lenting

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