Ligands involved in the life cycle of VWF. (A) Ligands involved in VWF biosynthesis and secretion. VWF trafficking through the endoplasmic reticulum is regulated by interaction with ligands including binding-immunoglobulin protein (BiP). VWFpp plays key roles in regulating VWF multimerization and packing in WPB. Furin cleaves VWFpp from mature VWF. VWF strings can be tethered on the surface of activated ECs by ligands including integrin αvβ3, P-selectin, and syndecan-1 (SDC-1)–linked heparan sulfate (HS). This figure includes many but not all ligands involved in VWF biosynthesis and secretion. (B) Ligands involved in VWF proteolysis. ADAMTS13 and plasmin independently proteolyze VWF. FVIII and GPIbα binding to VWF promote ADAMTS13-mediated proteolysis. Conversely, binding of PF4, complement factor H, hemoglobin, human neutrophile peptides, and thrombospondin 1 (TSP1) to VWF all attenuate VWF proteolysis by ADAMTS13. This figure includes many but not all ligands involved in VWF proteolysis. (C) Ligands involved in regulating VWF clearance. Macrophage receptors implicated in regulating VWF clearance include the low-density lipoprotein receptor–related protein 1 (LRP1), macrophage galactose lectin (MGL), and scavenger receptor class A member I (SR-A1). In addition, the asialoglycoprotein receptor (ASGPR) on hepatocytes, and C-type lectin domain family 4 member M (CLEC4M) and stabilin-2 (STAB2) on sinusoidal ECs also contribute to VWF clearance. Finally, scavenger receptor class A member 5 (SCARA5) on splenic littoral ECs has also been reported to interact with VWF.