However FVIII can be activated and/or inactivated by a number of

However FVIII can be activated and/or inactivated by a number of coagulation-related serine proteases, including FXa,

APC and FIXa. The physiological relevance of these reactions remains unclear, however FVIII-binding to VWF protects against cleavage by these proteases with the exception of thrombin [74–77]. This protection is mediated by two mechanisms First, VWF-bound FVIII is unable to bind to phospholipid or platelets [78,79], second, direct protease-binding sites within the FVIII light chain are hidden whilst FVIII is in complex with VWF [80,81]. This protection from proteolysis serves to increase FVIII circulatory life-span. The VWF-bound or -unbound state of FVIII modulates FVIII cellular learn more interactions and removal from the circulation. Several cellular receptors implicated in FVIII Epigenetics inhibitor clearance have been described and extensively reviewed elsewhere (see [82]). In particular, the role of the low-density lipoprotein receptor-related

protein (LRP), a member of the LDLR family and its effects on FVIII clearance, have been studied in vitro and in vivo in murine model studies. LRP is a multifunctional scavenger receptor abundant in the liver that can bind to at least 30 ligands with high affinity [83]. FVIII can bind to LRP via the A3 1811–1818 region within light chain, and 484–509 region of the A2 domain within the heavy chain [84,85]. The latter site is cryptic and exposed only on activation of FVIII, whereas the LRP-binding site within the FVIII light chain is only exposed when FVIII is not bound to VWF [86]. VWF does not bind to LRP, and because of the higher affinity of FVIII for VWF, prevents binding of bound FVIII to the receptor, suggesting that LRP-mediated clearance is of minimal importance in the FVIII life-cycle. However an LRP-knockout mouse model

has a twofold increase in FVIII levels as compared with control mice, and an increased FVIII half-life, suggesting a significant role for LRP-related clearance mechanisms of FVIII [87]. A recent hypothesis to resolve this apparent contradiction has been suggested by Lenting et al. [88]. Because of high affinity of both molecules and the molar excess of VWF as compared with FVIII, almost all circulating FVIII is bound in complex with VWF. However a small (approximately 2%), but significant proportion circulates unbound, and it is this pool of free FVIII Loperamide that is cleared by LRP-mediated mechanisms. Moreover, clearance of the free FVIII results in a shift in the balance of bound and free FVIII, and a further release of FVIII from VWF [88]. The close association of FVIII and VWF levels and half-life suggests that the remaining FVIII is cleared as part of the VWF complex. Clearance of the VWF complex from the circulation remains an enigma, however very recent data has thrown some light on possible mechanisms. Studies of cell types within the liver and spleen demonstrate that isolated FVIII, VWF and FVIII–VWF complex can be endocytosed by macrophages within these organs [89].

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