A novel pathophysiology underlying low VWF levels: reduced N-linked sialylation leads to increased galactose (Gal) exposure, which in turn triggers enhanced VWF clearance. In normal human plasma, the N-linked glycans of VWF exist predominantly as bi-antennary complex-type chains that are capped by terminal sialic acid residues (purple diamonds), which play an important role in protecting against clearance. In a subgroup of patients with low VWF, a quantitative reduction in N-linked sialylation results in enhanced exposure of subterminal Gal residues (yellow circles). These exposed Gal residues trigger enhanced VWF clearance through a number of different pathways including the asialoglycoprotein receptor (ASGPR; also known as Ashwell-Morell receptor) on hepatocytes and macrophage galactose lectin receptor (MGL) on macrophages.