THROMBOSIS AND HEMOSTASIS Macrophage LRP1 contributes to the clearance of von Willebrand factor

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/cm2, 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)