Potential clearance pathways for VWF. VWF circulates as a globular protein, with the majority of its glycan structures being well sialylated. In this form, VWF is recognized by 2 different receptors that could mediate the removal of VWF from the circulation: CLEC4M on endothelial cells and Siglec-5 on macrophages. Shear stress-induced unfolding of VWF is associated with the exposure of interactive site(s) for LRP1. Indeed, in vitro and in vivo experiments have confirmed the involvement of LRP1 in the uptake of VWF in macrophages. Certain VWD-related mutations (eg, the VWD-type 1 Vicenza mutation p.R1205H and the VWD-type 2B mutations p.R1306Q and p.V1316M) provoke exposure of LRP1-interactive sites in the absence of shear stress, which could perhaps explain the accelerated clearance of these mutants. It is unknown whether binding of mutant VWF is limited to macrophage LRP1 (as seems to be the case for wt-VWF) or whether interactions also include LRP1 on other cell types, like hepatocytes or even other as-yet-unidentified receptors. Desialylation of VWF exposes terminal galactose residues, allowing efficient interaction with the ASGPR on macrophages and hepatocytes. Of note, the clearance receptors responsible for the discordant clearance of blood group O and non-O VWF have not been identified yet. ASGPR, asialoglycoprotein receptor. Reprinted from Casari et al⁸⁷  with permission.