Another example relates to heparan-sulphate proteoglycans (HSPG). For several LRP1-ligands, it has been proposed that HSPG are needed to increase local concentrations of the ligand at the cellular surface, allowing lateral diffusion to LRP1 [68,69]. Sarafanov et al. [70] showed that this may also be true for FVIII,

as blocking HSPG in vitro and in vivo reduces the capacity of LRP1 to endocytose FVIII. Whether or not other members of the LDL receptor family Fulvestrant need assistance of HSPG in their interaction with FVIII is likely, but requires additional studies. What complicates the assessment of the coordinated actions of LRP1 with LDL receptor and/or HSPG, is that LDL receptor and HSPG themselves have the intrinsic capacity of binding and transporting RO4929097 ic50 FVIII to intracellular pathways. It remains possible therefore

that LDL receptor and HSPG function as scavenger receptors for FVIII independent of LRP1. Alternatively, these heterologous receptor complexes (i.e. LRP1/LDL receptor or LRP1/HSPG complexes) may function more efficiently than the individual constituents. It is of interest to mention that recently it has been reported that a similar co-receptor role for LRP1 has been described with regard to the homologous cofactor FV [71]. It appears that LRP1 in combination with a so far unidentified receptor mediates the uptake of FV into megakaryocytes. Probably this unidentified receptor is able to distinguish between FV and FVIII, as otherwise one would expect also to find FVIII in platelets. As mentioned before, FVIII B-domain is heavily glycosylated, thereby allowing interactions with

carbohydrate-recognizing receptors. The commonly known asialoglycoprotein receptor (ASGPR) has indeed been found to recognize FVIII [72]. This receptor has already been identified three decades ago to mediate the uptake of proteins exposing β-d-galactose or N-acetyl-d-galectosamine residues [73]. In a system using purified proteins, Bovenschen et al. [72] found that full-length but not B-domainless FVIII binds to ASGPR. This indicates that solely the glycans present within the B-domain mediate binding to this receptor. It should be noted that various studies have GPX6 established that full-length and B-domainless FVIII have a similar survival when applied to haemophiliacs [74,75]. The physiological relevance of ASGPR in the clearance of FVIII remains therefore to be determined. In addition, it is unclear whether the interaction with ASGPR is solely mediated by N-linked glycans, or if insufficiently sialylated O-linked glycans contribute to this interaction as well. As for the glycans that are present outside the heavily glycosylated B-domain, it was recently reported by Dasgupta et al.