Clearance of von Willebrand factor

Denis, Cécile V.; Olivier, Christophe; Oortwijn, Beatrijs; Lenting, Peter J.

doi:10.1160/th07-10-0629

Cited by 39 publications

(13 citation statements)

References 113 publications

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“…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.…”

Section: Introductionmentioning

confidence: 99%

“…[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.…”

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confidence: 99%

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Macrophage LRP1 contributes to the clearance of von Willebrand factor

Rastegarlari

Pegon

Casari

et al. 2012

Blood

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103

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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...

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Section: Introductionmentioning

confidence: 99%

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confidence: 99%

Macrophage LRP1 contributes to the clearance of von Willebrand factor

Rastegarlari

Pegon

Casari

et al. 2012

Blood

Self Cite

103

130

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“…1,2 It plays a key role in hemostasis, because it recruits circulating platelets to damaged vessels through binding of the VWF A1-domain to the GpIb-IX-V platelet receptors. It also acts as a carrier for factor VIII (FVIII), thereby preventing its proteolytic degradation while inactive.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of efficacy and safety of the anti-VWF Nanobody ALX-0681 in a preclinical baboon model of acquired thrombotic thrombocytopenic purpura

Callewaert

Roodt

Ulrichts

et al. 2012

Blood

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“…However, VWFpp is cleared much more rapidly than VWF, resulting in distinct VWFpp/ VWF antigen (VWF:Ag) ratio under steady state conditions. 13 Hence, the VWFpp/VWF:Ag ratio can reflect either VWF clearance 14 or endothelial cell disorders. 15 Multiple pathogenic mechanisms are described in AVWS, including selective VWF adsorption on tumoral cells, increased VWF proteolysis, and presence of both neutralizing or nonneutralizing anti-VWF antibodies.…”

Section: Introductionmentioning

confidence: 99%