In addition, cells that were deficient for LRP1 proved approximately 50% less efficient than their LRP1-expressing counterparts in the uptake and

degradation of FVIII [33,53,54]. Similar results were obtained by blocking cellular LRP1 with its universal inhibitor receptor-associated protein (RAP). Thus, it became apparent that LRP1 participates in the uptake and transport of FVIII to intracellular degradation pathways. However, a message that could easily be overlooked from these experiments is that the absence of LRP1 resulted in but a partial inhibition of FVIII degradation, strongly indicating that alternative pathways contributing to FVIII catabolism should exist. Nevertheless, a vast amount of data has been produced showing that the contribution of LRP1 to FVIII catabolism is of in vivo relevance. These include experiments using Fostamatinib mice with a

conditional induced deletion of the LRP1 gene, which resulted in increased plasma levels of FVIII in these mice [55]. In addition, the mean residence time of intravenously administered FVIII was prolonged 1.5-fold, from 2.5 to 4 h. A number of epidemiological studies revealed that LRP1 this website modulates FVIII plasma levels also in humans [56–59]. So far, two distinct LRP1 polymorphisms (LRP1/D2080N and LRP1/A217V) have been suggested to be associated with up to 20% higher FVIII plasma levels [57,58]. The underlying mechanism of how these polymorphisms affect FVIII levels remains to be elucidated. Despite the

Obatoclax Mesylate (GX15-070) proven physiological relevance of LRP1 in FVIII clearance, a number of issues still remain unclear. For instance, LRP1 is known for its large spectrum of structurally and functionally unrelated ligands, with more than 50 ligands currently being identified [60]. It is unknown however, if and how these other ligands affect LRP1-dependent clearance of FVIII. Another point relates to the fact that LRP is able to assemble into heterologous receptor complexes. Examples hereof include platelet-derived growth factor (PDGF) receptor in smooth muscle cells, N-methyl-d-aspartate (NMDA) receptor in neurons and β2-integrins on leukocytes [61–63]. It cannot be excluded therefore that part of the LRP-mediated effects are indirect, in that LRP1 affects the function of other receptors. Direct evidence for this possibility is currently lacking. However, it has been shown that LRP1 is able to modulate FVIII catabolism in concert with other receptors. For instance, Bovenschen et al. [64] demonstrated that LRP1 regulates FVIII levels in a coordinated fashion with LDL receptor, illustrated by a synergistic increase in plasma levels and survival of FVIII in mice with a combined LRP1/LDL receptor deficiency [64]. Of note, also other members of the LDL receptor family are able to recognize FVIII, such as vLDL receptor and megalin [65–67].