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• W2517163449 abstract "Essentials•Factor VIIa is cleared principally as a complex with antithrombin.•Enzyme/serpin complexes are preferred ligands for the scavenger‐receptor LRP1.•Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1.•Macrophage‐expressed LRP1 contributes to the clearance of factor VIIa/antithrombin.AcknowledgementsThe study was supported by grants from the Bayer Hemophilia Program (Early Career Investigator Award to N. Wohner) and from Fondation pour la Recherche Médicale (FRM‐SPF20130526717 to N. Wohner).Bayer Hemophilia ProgramFondation pour la Recherche MédicaleSPF20130526717Summary: BackgroundRecent findings point to activated factor VII (FVIIa) being cleared predominantly (± 65% of the injected protein) as part of a complex with the serpin antithrombin. FVIIa–antithrombin complexes are targeted to hepatocytes and liver macrophages. Both cells lines abundantly express LDL receptor‐related protein 1 (LRP1), a scavenger receptor mediating the clearance of protease–serpin complexes.ObjectivesTo investigate whether FVIIa–antithrombin is a ligand for LRP1.MethodsBinding of FVIIa and pre‐formed FVIIa–antithrombin to purified LRP1 Fc‐tagged cluster IV (rLRP1‐cIV/Fc) and to human and murine macrophages was analyzed. FVIIa clearance was determined in macrophage LRP1 (macLRP1)‐deficient mice.ResultsSolid‐phase binding assays showed that FVIIa–antithrombin bound in a specific, dose‐dependent and saturable manner to rLRP1‐cIV/Fc. Competition experiments with human THP1 macrophages indicated that binding of FVIIa but not of FVIIa–antithrombin was reduced in the presence of annexin‐V or anti‐tissue factor antibodies, whereas binding of FVIIa–antithrombin but not FVIIa was inhibited by the LRP1‐antagonist GST‐RAP. Additional experiments revealed binding of both FVIIa and FVIIa–antithrombin to murine control macrophages. In contrast, no binding of FVIIa–antithrombin to macrophages derived from macLRP1‐deficient mice could be detected. Clearance of FVIIa–antithrombin but not of active site‐blocked FVIIa was delayed 1.5‐fold (mean residence time of 3.3 ± 0.1 h versus 2.4 ± 0.2 h) in macLRP1‐deficient mice. The circulatory presence of FVIIa was prolonged to a similar extent in macLRP1‐deficient mice and in control mice.ConclusionsOur data show that FVIIa–antithrombin but not FVIIa is a ligand for LRP1, and that LRP1 contributes to the clearance of FVIIa–antithrombin in vivo. Essentials•Factor VIIa is cleared principally as a complex with antithrombin.•Enzyme/serpin complexes are preferred ligands for the scavenger‐receptor LRP1.•Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1.•Macrophage‐expressed LRP1 contributes to the clearance of factor VIIa/antithrombin.AcknowledgementsThe study was supported by grants from the Bayer Hemophilia Program (Early Career Investigator Award to N. Wohner) and from Fondation pour la Recherche Médicale (FRM‐SPF20130526717 to N. Wohner).Bayer Hemophilia ProgramFondation pour la Recherche MédicaleSPF20130526717 •Factor VIIa is cleared principally as a complex with antithrombin.•Enzyme/serpin complexes are preferred ligands for the scavenger‐receptor LRP1.•Factor VIIa/antithrombin but not factor VIIa alone is a ligand for LRP1.•Macrophage‐expressed LRP1 contributes to the clearance of factor VIIa/antithrombin. The study was supported by grants from the Bayer Hemophilia Program (Early Career Investigator Award to N. Wohner) and from Fondation pour la Recherche Médicale (FRM‐SPF20130526717 to N. Wohner).Bayer Hemophilia ProgramFondation pour la Recherche MédicaleSPF20130526717 Recent findings point to activated factor VII (FVIIa) being cleared predominantly (± 65% of the injected protein) as part of a complex with the serpin antithrombin. FVIIa–antithrombin complexes are targeted to hepatocytes and liver macrophages. Both cells lines abundantly express LDL receptor‐related protein 1 (LRP1), a scavenger receptor mediating the clearance of protease–serpin complexes. To investigate whether FVIIa–antithrombin is a ligand for LRP1. Binding of FVIIa and pre‐formed FVIIa–antithrombin to purified LRP1 Fc‐tagged cluster IV (rLRP1‐cIV/Fc) and to human and murine macrophages was analyzed. FVIIa clearance was determined in macrophage LRP1 (macLRP1)‐deficient mice. Solid‐phase binding assays showed that FVIIa–antithrombin bound in a specific, dose‐dependent and saturable manner to rLRP1‐cIV/Fc. Competition experiments with human THP1 macrophages indicated that binding of FVIIa but not of FVIIa–antithrombin was reduced in the presence of annexin‐V or anti‐tissue factor antibodies, whereas binding of FVIIa–antithrombin but not FVIIa was inhibited by the LRP1‐antagonist GST‐RAP. Additional experiments revealed binding of both FVIIa and FVIIa–antithrombin to murine control macrophages. In contrast, no binding of FVIIa–antithrombin to macrophages derived from macLRP1‐deficient mice could be detected. Clearance of FVIIa–antithrombin but not of active site‐blocked FVIIa was delayed 1.5‐fold (mean residence time of 3.3 ± 0.1 h versus 2.4 ± 0.2 h) in macLRP1‐deficient mice. The circulatory presence of FVIIa was prolonged to a similar extent in macLRP1‐deficient mice and in control mice. Our data show that FVIIa–antithrombin but not FVIIa is a ligand for LRP1, and that LRP1 contributes to the clearance of FVIIa–antithrombin in vivo." @default.
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• W2517163449 date "2016-12-01" @default.
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• W2517163449 title "LDL receptor‐related protein 1 contributes to the clearance of the activated factor VII–antithrombin complex" @default.
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• W2517163449 doi "https://doi.org/10.1111/jth.13502" @default.
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