The relationship between low-density lipoprotein receptor-related protein-1 (LRP1) and von Willebrand factor (VWF) has remained elusive for years. Indeed, despite a reported absence of interaction between both proteins, liver-specific deletion of LRP1 results in increased VWF levels. To investigate this discrepancy, we used mice with a macrophagespecific deficiency of LRP1 (macLRP1 ؊ ) because we previously found that macrophages dominate VWF clearance. Basal VWF levels were increased in macLRP1 ؊ mice compared with control mice (1.6 ؎ 0.4 vs 1.0 ؎ 0.4 U/mL). Clearance experiments revealed that half-life of human VWF was significantly increased in macLRP1 ؊ mice. Ubiquitous blocking of LRP1 or additional lipoprotein receptors by overexpressing receptor-associated protein in macLRP1 ؊ mice did not result in further rise of VWF levels (0.1 ؎ 0.2 U/mL), in contrast to macLRP1 ؉ mice (rise in VWF, 0.8 ؎ 0.4 U/mL). This points to macLRP1 being the only lipoprotein receptor regulating VWF levels. When testing the mechanism(s) involved, we observed that VWFcoated beads adhered efficiently to LRP1 but only when exposed to shear forces exceeding 2.5 dyne/cm 2 , implying the existence of shear stress-dependent interactions. Furthermore, a mechanism involving ␤2-integrins that binds both VWF and LRP1 also is implicated because inhibition of ␤2-integrins led to increased VWF levels in control (rise, 0.19 ؎ 0.16 U/mL) but not in macLRP1 ؊ mice (0.08 ؎ 0.15 U/mL). (Blood. 2012; 119(9):2126-2134) Introductionvon Willebrand factor (VWF) is a hemostatic protein, the physiologic relevance of which is illustrated by the severe bleeding tendency associated with its functional deficiency. The contribution of VWF to hemostasis is 2-fold: (1) VWF is essential for the recruitment of platelets to the damaged vessel wall, particularly under conditions of arterial shear; and (2) VWF functions as a carrier protein for factor VIII (FVIII), a protein cofactor critical to the coagulation system.Whereas biosynthesis and secretion of VWF have been subject of study for more than 35 years, it is only in the last decade that clearance mechanisms of VWF have gained attention. 1,2 This has led to the discovery that increased clearance of VWF may explain part of the reduced VWF levels in von Willebrand disease (VWD). [3][4][5][6] This seems to be most prominent in case of VWDtype 1, although VWD-type 2 variants also are associated with reduced survival of the mutated VWF molecules. 2,7,8 The increased attention is further related to the development of novel therapeutic FVIII concentrates that are used in the treatment of hemophilia A. Given that FVIII circulates in a tight complex with VWF, it is already known that VWF is a major determinant of FVIII clearance. Indeed, the half-life of FVIII is considerably reduced in patients lacking VWF antigen or in those in which VWF is unable to bind FVIII correctly (VWD-type 2N). 9,10 Moreover, preinfusion VWF levels are positively correlated with FVIII half-life. 11,12 To this end, we have recently demonstrate...

Summary Recent landmark studies show that it is now possible to convert somatic cells, such as skin fibroblasts and B lymphocytes, into pluripotent stem cells that closely resemble embryonic stem cells. These induced pluripotent stem (iPS) cells can be generated without using human embryos or oocytes, thus bypassing some of the ethical issues that have limited the use of human embryonic stems (hES) cells. Additionally, they can be derived from the patient to be treated, thereby overcoming problems of immunological rejection associated with the use of allogeneic hES cell derived progenitors. Whilst these patient‐specific iPS cells have great clinical potential, their immediate utility is likely to be in drug screening and for understanding the disease process. This review discusses the promise of iPS cells as well as the challenges to their use in the clinic.