Figure 4: Inactivation and clearance of Factor VIII: Inactivation of FVIII comprises two distinct pathways: proteolytic degradation and spontaneous dissociation. Activated FVIII is intrinsically unstable, attributed to the weak interaction between the A2 domain and the metal ion-linked A1/A3-C1-C2 dimer [52] and therefore spontaneous dissociation occurs as the equilibrium is in favor of the inactive, dissociated state of FVIIIa at a physiological pH. Proteolytic degradation of FVIIIa involves cleavages in the heavy chain at positions 336 and 562 by various enzymes, such as FIXa, FXa, and activated protein C (APC) [51]. Cleavage at position 336 in FVIIIa releases a acidic sequence that interconnects the A1 and A2 domain. Because of this release, the A2 domain dissociates more rapidly from the FVIIIa heterotrimer. Arg562, which is part of the A2 domain sequence that comprises a FIXa interactive site, is exclusively cleaved by APC [147]. The relative contribution of each of these mechanisms to FVIII inactivation is not fully understood. FVIII catabolism is mediated by low-density lipoprotein receptor-related protein (LRP), a multiligand hepatic receptor, which belongs to low-density lipoprotein (LDL) receptor superfamily of endocytic receptors [53]. LRP-mediated clearance of FVIII from its complex with VWF is facilitated by cell-surface heparin sulphate proteoglycans (HSPGs), one of the major glycoprotein components of the extracellular matrix [148,149]. These HSPGs provide primary binding sites for FVIII, thus concentrating it on the cell surface and presenting it to LRP. Interaction of FVIII with LRP involves multiple, at least three, FVIII binding sites: within the A2 domain of the heavy chain and the C2 and A3 domains of the light chain [54].