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Haemophilic animals (F8(-/-) mice) fed a high fat/fructose diet are highly prone to hepatic steatosis and thrombocytopenia.
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CD32 blockade suppresses the FVIII-specific recall response by two ways: i) increasing apoptosis of FVIII-specific memory B-cells and ii) disturbing FVIII-specific T cell response by modulating presentation of rhFVIII to CD4(+) T cells.
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Type 2N von Willebrand disease variants were associated with decreased VWF secretion and impaired factor VIII binding/stability.
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Cytokine release was quantified from FVIII(-/-) splenocytes restimulated with FVIII in the absence or presence of different anti-FcgammaRIIB (CD32) Antibodies (anti-CD32 mAbs) over 6 days.
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results revealed localized vascular expression of FVIII and von Willebrand factor and identified lymphatic endothelial cell as a major cellular source of FVIII in extrahepatic tissues.
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the results indicate that residues in the C1 and/or C2 domains of factor VIII are implicated in immunogenic factor VIII uptake, at least in vitro Conversely, in vivo, the binding to endogenous von Willebrand factor masks the reducing effect of mutations in the C domains on factor VIII immunogenicity.
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Describe a genetically engineered mouse model of hemophilia A with complete deletion of the F8 gene.
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data demonstrate that infusion of platelets containing FVIII triggers neither primary nor memory anti-FVIII immune response in FVIII(null) mice
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Both platelet-VWF and plasma-VWF are required for optimal platelet-derived FVIII gene therapy for hemophilia A in the presence of inhibitors.
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These data support the investigation of FVIII orthologs as treatment modalities in both the congenital and acquired FVIII inhibitor settings.
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Extrahepatic sources of factor VIII potentially contribute to the coagulation cascade correcting the bleeding phenotype of mice with hemophilia A.
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Activatable bioengineered FIX molecules with FVIII-independent activity might be a promising tool for improving hemophilia A treatment, especially for patients with inhibitors.
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This study demonstrated that FVIIIa interacts with Low-density lipoprotein receptor-related protein 1 cluster III.
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a fragment containing only approximately 20% of the VWF sequence is sufficient to support FVIII stability in vivo
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Endothelial cells from multiple, but not all, tissues contribute to the plasma FVIII pool in the mouse.
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Endothelial cells are the predominant, and possibly exclusive, source of plasma FVIII.
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Micro-computed tomography analysis of distal tibia metaphyses also revealed for the first time a major impact of the FVIII/thrombin/PAR1 axis on the dynamic bone structure, showing reduced bone.
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Findings indicate that improving protein trans-splicing by inter-chain disulfide bonding is a promising approach for increasing the efficacy of dual-vector based FVIII gene transfer.
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Acute elevations in FVIII levels result in a non-linear thrombogenic effect, with non-significant increases in thrombogenic risk. Prolonged elevation of plasma FVIII did not further increase the thrombogenic potential of elevated FVIII levels.
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Transient B cell depletion and even more so use of a codon-optimized FVIII sequence in hepatic gene transfer represent promising strategies to avoid inhibitor formation and promote tolerance in gene therapy for hemophilia A.
