Life cycle of FVIII under physiologic conditions. Following secretion by liver sinusoidal endothelial cells (LSECs) or hepatocytes, the heterodimeric FVIII binds to circulating von Willebrand factor (VWF). VWF transports FVIII to the bleeding site, where FVIII is cleaved and activated by thrombin (FIIa). Activated FVIII binds to phospholipids (shown as triangles) on the membrane of activated cells and platelets and forms a complex with activated factor IX (FIXa) and factor X (FX), which results in activation of FX. The complex disassembles and FVIII is inactivated by spontaneous dissociation of its subunits, or cleavage by activated protein C (APC). Native, activated, or inactivated FVIII may be eliminated by binding to catabolic receptors on scavenger cells: the asialoglycoprotein receptors (ASGPRs) binds to galactose-ending glycans on the B domain of the FVIII, and receptors of the LDL receptor (LDLR) family bind to protein moieties on the heavy and/or light chain of the molecule. A role for the macrophage mannose receptors (MMRs) in FVIII catabolism is being investigated. VWF prevents the early elimination of FVIII by blocking its binding to the scavenger receptors.