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Article ; Online: Angiopoietin-2 binds to multiple interactive sites within von Willebrand factor.

Texier, Alexis / Lenting, Peter J / Denis, Cécile V / Roullet, Stéphanie / Christophe, Olivier D

Research and practice in thrombosis and haemostasis

2023 Volume 7, Issue 7, Page(s) 102204

Abstract: Background: Biosynthesis of von Willebrand factor (VWF) in endothelial cells drives the formation of storage-organelles known as Weibel-Palade bodies (WPBs). WPBs also contain several other proteins, including angiopoietin-2 (Ang-2).: Objectives: At ... ...

Abstract	Background: Biosynthesis of von Willebrand factor (VWF) in endothelial cells drives the formation of storage-organelles known as Weibel-Palade bodies (WPBs). WPBs also contain several other proteins, including angiopoietin-2 (Ang-2). Objectives: At present, the molecular basis of the VWF-Ang-2 interaction is poorly understood. Here, we used immunosorbent-binding assays and specific recombinant VWF fragments to analyze VWF-Ang-2 interactions. Results: We found that VWF bound to immobilized Ang-2 most efficiently (half-maximal binding at 0.5 ± 0.1 μg/mL) under conditions of high CaCl Conclusion: Our data show that both Ang-1 and Ang-2 bind to VWF, seemingly using different interactive sites. Ang-2 modulates the binding of VWF to Ang-1, the (patho)-physiological consequences of which remain to be investigated.
Language	English
Publishing date	2023-09-19
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1016/j.rpth.2023.102204
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Article ; Online: Thrombin generation on vascular cells in the presence of factor VIII and/or emicizumab.

Atsou, Sénadé / Schellenberg, Célia / Lagrange, Jeremy / Lacolley, Patrick / Lenting, Peter J / Denis, Cécile V / Christophe, Olivier D / Regnault, Véronique

Journal of thrombosis and haemostasis : JTH

2023 Volume 22, Issue 1, Page(s) 112–125

Abstract: Background: The effect of factor VIII (FVIII) or emicizumab on thrombin generation is usually assessed in assays using synthetic phospholipids. Here, we assessed thrombin generation at the surface of human arterial cells (aortic endothelial cells [hAECs] ...

Abstract	Background: The effect of factor VIII (FVIII) or emicizumab on thrombin generation is usually assessed in assays using synthetic phospholipids. Here, we assessed thrombin generation at the surface of human arterial cells (aortic endothelial cells [hAECs] and aortic vascular smooth muscle cells [hVSMCs]). Objectives: To explore the capacity of hAECs (resting or stimulated) and hVSMCs to support thrombin generation by FVIII or emicizumab. Methods: Primary hVSMCs and hAECs were analyzed for tissue factor (TF)-activity and antigen, phosphatidylserine (PS)-exposure, tissue factor pathway inhibitor (TFPI)-content and thrombomodulin expression. Cells were incubated with FVIII-deficient plasma spiked with FVIII, emicizumab, activated prothrombin complex concentrate (APCC) or combinations thereof. Results: TF activity and PS-exposure were present on both hVSMCs and hAECs. In contrast, thrombomodulin and TFPI were expressed on hAECs, while virtually lacking on hVSMCs, confirming the procoagulant nature of hVSMCs. Tumor necrosis factor α-mediated stimulation of hAECs increased not only TF antigen, TF activity, and PS-exposure but also TFPI and thrombomodulin expression. As expected, FVIII and emicizumab promoted thrombin generation on nonstimulated hAECs and hVSMCs, with more thrombin being generated on hVSMCs. Unexpectedly, FVIII and emicizumab increased thrombin generation to a lesser extent on stimulated hAECs compared with nonstimulated hAECs. Finally, adding emicizumab to FVIII did not further increase thrombin generation, whereas the addition of emicizumab to APCC resulted in exaggerated thrombin generation. Conclusion: Tumor necrosis factor stimulation of hAECs increases both pro- and anticoagulant activity. Unexpectedly, the increased anticoagulant activity is sufficient to limit both FVIII- and emicizumab-induced thrombin generation. This protective effect disappears when emicizumab is combined with APCC.
MeSH term(s)	Humans ; Factor VIII/metabolism ; Thrombin/metabolism ; Thrombomodulin ; Endothelial Cells/metabolism ; Hemostatics ; Antibodies, Bispecific/pharmacology ; Factor VIIa ; Factor IX ; Anticoagulants ; Hemophilia A
Chemical Substances	Factor VIII (9001-27-8) ; Thrombin (EC 3.4.21.5) ; emicizumab (7NL2E3F6K3) ; Thrombomodulin ; Hemostatics ; Antibodies, Bispecific ; Factor VIIa (EC 3.4.21.21) ; Factor IX (9001-28-9) ; Anticoagulants
Language	English
Publishing date	2023-09-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.09.017
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Article ; Online: Fitusiran reduces bleeding in Factor X-deficient mice.

Verhenne, Sebastien / McCluskey, Genevieve / Maynadié, Hortense / Adam, Frédéric / Casari, Caterina / Panicot-Dubois, Laurence / Crescence, Lydie / Dubois, Christophe / Denis, Cecile V / Lenting, Peter J / Christophe, Olivier D

Blood

2024

Abstract: Factor X (FX)-deficiency is a rare bleeding disorder manifesting a bleeding tendency caused by low FX activity levels. We aimed to explore the use of fitusiran (an investigational siRNA that silences antithrombin expression) to increase thrombin ... ...

Abstract	Factor X (FX)-deficiency is a rare bleeding disorder manifesting a bleeding tendency caused by low FX activity levels. We aimed to explore the use of fitusiran (an investigational siRNA that silences antithrombin expression) to increase thrombin generation and the in vivo hemostatic potential under conditions of FX-deficiency. We therefore developed a novel model of inducible FX-deficiency, generating mice expressing <1% FX activity and antigen (f10low-mice). Compared to control f10WT-mice, f10low-mice had 6- and 4-fold prolonged clotting times in Prothrombin Time- and activated Partial Prothrombin Time-assays, respectively (p<0.001). Thrombin generation was severely reduced, irrespective whether tissue factor or factor XIa was used as initiator. In vivo analysis revealed near-absent thrombus formation in a laser-induced vessel injury-model. Furthermore, in two distinct bleeding models, f10low-mice displayed an increased bleeding tendency compared to f10WT-mice. In the tail-clip assay blood loss was increased from 12±16 microliter to 590±335 microliter (p<0.0001). In the saphenous vein puncture (SVP)-model, the number of clots generated was reduced from 19±5 clots/30 min for f10WT-mice to 2±2 clots/30 min (p<0.0001) for f10low-mice. In both models, bleeding was corrected upon infusion of purified FX. Treatment of f10low-mice with fitusiran (2x10 mg/kg at one-week interval) resulted in 17±6% residual antithrombin activity and increased thrombin generation (4-fold and 2-3-fold increase in endogenous thrombin potential and thrombin peak, respectively). In the SVP-model, the number of clots was increased to 8±6 clots/30 min (p=0.0029). Altogether, we demonstrate that reduction of antithrombin levels is associated with improved hemostatic activity under conditions of FX-deficiency.
Language	English
Publishing date	2024-04-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023023404
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Article ; Online: Differences in venous clot structures between hemophilic mice treated with emicizumab versus factor VIII or factor VIIIFc.

Sefiane, Thibaud / Maynadié, Hortense / Ettingshausen, Carmen Escurola / Muczynski, Vincent / Heiligenstein, Xavier / Dumont, Julien / Christophe, Olivier D / Denis, Cécile V / Casari, Caterina / Lenting, Peter J

Haematologica

2023

Abstract: Recombinant factor VIII (rFVIII), rFVIIIFc and emicizumab are established treatment options in the management of hemophilia A. Each has its unique mode of action, which can influence thrombin generation kinetics and therefore also the kinetics of ... ...

Abstract	Recombinant factor VIII (rFVIII), rFVIIIFc and emicizumab are established treatment options in the management of hemophilia A. Each has its unique mode of action, which can influence thrombin generation kinetics and therefore also the kinetics of thrombin substrates. Such differences may potentially result in clots with different structural and physical properties. A starting observation of incomplete wound closure in a patient on emicizumab-prophylaxis led us employ a relevant mouse model in which we noticed that emicizumab-induced clots appeared less stable compared to FVIII-induced clots. We thus analyzed fibrin formation in vitro and in vivo. In vitro fibrin formation was faster and more abundant in the presence of emicizumab compared to rFVIII/rFVIIIFc. Furthermore, the time-interval between the initiation of fibrin formation and factor XIII activation was twice as long for emicizumab compared to rFVIII/rFVIIIFc. Scanning-electron microscopy and immunofluorescent spinning-disk confocal-microscopy of in vivo generated clots confirmed increased fibrin formation in the presence of emicizumab. Unexpectedly, we also detected a different morphology between rFVIII/rFVIIIFc- and emicizumab-induced clots. Contrary to the regular fibrin-mesh obtained with rFVIII/rFVIIIFc, fibrin-fibers appeared to be fused into large patches upon emicizumabtreatment. Moreover, fewer red blood cells were detected in regions where these fibrin patches were present. The presence of highly-dense fibrin-structures associated with a diffuse fiber-structure in emicizumab-induced clots was also observed when using superresolution imaging. We hypothesize that the modified kinetics of thrombin, fibrin and factor XIIIa generation contribute to differences in structural and physical properties between clots formed in the presence of FVIII or emicizumab.
Language	English
Publishing date	2023-12-07
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.284142
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Article ; Online: Emicizumab, a bispecific antibody recognizing coagulation factors IX and X: how does it actually compare to factor VIII?

Lenting, Peter J / Denis, Cécile V / Christophe, Olivier D

Blood

2017 Volume 130, Issue 23, Page(s) 2463–2468

Abstract: During the last decade, the development of improved and novel approaches for the treatment of hemophilia A has expanded tremendously. These approaches include factor VIII (FVIII) with extended half-life (eg, FVIII-Fc and PEGylated FVIII), monoclonal ... ...

Abstract	During the last decade, the development of improved and novel approaches for the treatment of hemophilia A has expanded tremendously. These approaches include factor VIII (FVIII) with extended half-life (eg, FVIII-Fc and PEGylated FVIII), monoclonal antibodies targeting tissue factor pathway inhibitor, small interfering RNA to reduce antithrombin expression and the bispecific antibody ACE910/emicizumab. Emicizumab is a bispecific antibody recognizing both the enzyme factor IXa and the substrate factor X. By simultaneously binding enzyme and substrate, emicizumab mimics some part of the function exerted by the original cofactor, FVIII, in that it promotes colocalization of the enzyme-substrate complex. However, FVIII and the bispecific antibody are fundamentally different proteins and subject to different modes of regulation. Here, we will provide an overview of the similarities and dissimilarities between FVIII and emicizumab from a biochemical and mechanistical perspective. Such insight might be useful in the clinical decision making for those who apply emicizumab in their practice now or in the future, particularly in view of the thrombotic complications that have been reported when emicizumab is used in combination with FVIII-bypassing agents.
MeSH term(s)	Animals ; Antibodies, Bispecific/chemistry ; Antibodies, Bispecific/metabolism ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; Antibodies, Monoclonal, Humanized/chemistry ; Antibodies, Monoclonal, Humanized/metabolism ; Antibodies, Monoclonal, Humanized/pharmacology ; Antibodies, Monoclonal, Humanized/therapeutic use ; Blood Coagulation/drug effects ; Drug Discovery ; Enzyme Activation ; Factor IX/chemistry ; Factor IX/metabolism ; Factor VIII/chemistry ; Factor VIII/metabolism ; Factor VIII/pharmacology ; Factor VIII/therapeutic use ; Factor X/chemistry ; Factor X/metabolism ; Factor XIIIa/metabolism ; Hemophilia A/blood ; Hemophilia A/drug therapy ; Humans ; Multiprotein Complexes/metabolism ; Protein Binding ; Substrate Specificity
Chemical Substances	Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized ; Multiprotein Complexes ; emicizumab (7NL2E3F6K3) ; Factor VIII (9001-27-8) ; Factor IX (9001-28-9) ; Factor X (9001-29-0) ; Factor XIIIa (EC 2.3.2.13)
Language	English
Publishing date	2017-10-17
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood-2017-08-801662
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Article ; Online: Imlifidase, a new option to optimize the management of patients with hemophilia A on emicizumab.

Bou-Jaoudeh, Melissa / Mimoun, Angelina / Delignat, Sandrine / Peyron, Ivan / Capdevila, Ladislas / Daventure, Victoria / Deligne, Claire / Dimitrov, Jordan D / Christophe, Olivier D / Denis, Cécile V / Lenting, Peter J / Proulle, Valérie / Lacroix-Desmazes, Sébastien

Journal of thrombosis and haemostasis : JTH

2023 Volume 21, Issue 10, Page(s) 2776–2783

Abstract: Background: Emicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating ... ...

Abstract	Background: Emicizumab is a bispecific, chimeric, humanized immunoglobulin G (IgG)4 that mimics the procoagulant activity of factor (F) VIII (FVIII). Its long half-life and subcutaneous route of administration have been life-changing in treating patients with hemophilia A (HA) with or without FVIII inhibitors. However, emicizumab only partially mimics FVIII activity; it prevents but does not treat acute bleeds. Emergency management is particularly complicated in patients with FVIII inhibitors receiving emicizumab prophylaxis in whom exogenous FVIII is inefficient. We have shown recently that Imlifidase (IdeS), a bacterial IgG-degrading enzyme, efficiently eliminates human anti-FVIII IgG in a mouse model of severe HA with inhibitors and opens a therapeutic window for the administration of exogenous FVIII. Objectives: To investigate the impact of IdeS treatment in inhibitor-positive HA mice injected with emicizumab. Methods: IdeS was injected to HA mice reconstituted with human neutralizing anti-FVIII IgG and treated with emicizumab. Results: IdeS hydrolyzed emicizumab in vitro and in vivo, albeit, at slower rates than another recombinant human monoclonal IgG4. While F(ab') Conclusion: Our results suggest that IdeS could be administered to inhibitor-positive patients with HA receiving emicizumab prophylaxis to improve and ease the management of breakthrough bleeds or programmed major surgeries.
MeSH term(s)	Humans ; Animals ; Mice ; Hemophilia A/drug therapy ; Factor VIII/therapeutic use ; Antibodies, Bispecific/therapeutic use ; Hemorrhage/drug therapy ; Immunosuppressive Agents/therapeutic use ; Immunoglobulin G
Chemical Substances	Factor VIII (9001-27-8) ; emicizumab (7NL2E3F6K3) ; Antibodies, Bispecific ; Immunosuppressive Agents ; Immunoglobulin G
Language	English
Publishing date	2023-07-18
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.06.038
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Article ; Online: Toll-like receptor 4 and macrophage scavenger receptor 1 crosstalk regulates phagocytosis of a fungal pathogen.

Onyishi, Chinaemerem U / Desanti, Guillaume E / Wilkinson, Alex L / Lara-Reyna, Samuel / Frickel, Eva-Maria / Fejer, Gyorgy / Christophe, Olivier D / Bryant, Clare E / Mukhopadhyay, Subhankar / Gordon, Siamon / May, Robin C

Nature communications

2023 Volume 14, Issue 1, Page(s) 4895

Abstract: The opportunistic fungal pathogen Cryptococcus neoformans causes lethal infections in immunocompromised patients. Macrophages are central to the host response to cryptococci; however, it is unclear how C. neoformans is recognised and phagocytosed by ... ...

Abstract	The opportunistic fungal pathogen Cryptococcus neoformans causes lethal infections in immunocompromised patients. Macrophages are central to the host response to cryptococci; however, it is unclear how C. neoformans is recognised and phagocytosed by macrophages. Here we investigate the role of TLR4 in the non-opsonic phagocytosis of C. neoformans. We find that loss of TLR4 function unexpectedly increases phagocytosis of non-opsonised cryptococci by murine and human macrophages. The increased phagocytosis observed in Tlr4
MeSH term(s)	Animals ; Humans ; Mice ; Cryptococcosis ; Cryptococcus neoformans ; Macrophages/microbiology ; Phagocytosis ; Toll-Like Receptor 4/genetics ; Scavenger Receptors, Class A/metabolism
Chemical Substances	Toll-Like Receptor 4 ; TLR4 protein, human ; Tlr4 protein, mouse ; MSR1 protein, human ; Msr1 protein, mouse ; Scavenger Receptors, Class A
Language	English
Publishing date	2023-08-14
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-40635-w
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Article ; Online: Emerging Therapeutic Strategies in the Treatment of Hemophilia A.

Muczynski, Vincent / Christophe, Olivier D / Denis, Cécile V / Lenting, Peter J

Seminars in thrombosis and hemostasis

2017 Volume 43, Issue 6, Page(s) 581–590

MeSH term(s)	Antibodies, Bispecific/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Antithrombin III/genetics ; Factor VIII/therapeutic use ; Hemophilia A/genetics ; Hemophilia A/therapy ; Hemostasis/drug effects ; Humans ; RNA Interference
Chemical Substances	Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized ; SERPINC1 protein, human ; emicizumab ; Antithrombin III (9000-94-6) ; Factor VIII (9001-27-8)
Language	English
Publishing date	2017-07-27
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	196901-8
ISSN	1098-9064 ; 0094-6176
ISSN (online)	1098-9064
ISSN	0094-6176
DOI	10.1055/s-0037-1604053
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Article ; Online: Transplacental delivery of therapeutic proteins by engineered immunoglobulin G: a step toward perinatal replacement therapy.

Mimoun, Angelina / Bou-Jaoudeh, Melissa / Delignat, Sandrine / Daventure, Victoria / Reyes Ruiz, Alejandra / Lecerf, Maxime / Azam, Aurélien / Noe, Remi / Peyron, Ivan / Christophe, Olivier D / Lenting, Peter J / Proulle, Valérie / McIntosh, Jenny / Nathwani, Amit C / Dimitrov, Jordan D / Denis, Cécile V / Lacroix-Desmazes, Sébastien

Journal of thrombosis and haemostasis : JTH

2023 Volume 21, Issue 9, Page(s) 2405–2417

Abstract: Background: Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to ... ...

Abstract	Background: Transplacental delivery of maternal immunoglobulin G (IgG) provides humoral protection during the first months of life until the newborn's immune system reaches maturity. The maternofetal interface has been exploited therapeutically to replace missing enzymes in the fetus, as shown in experimental mucopolysaccharidoses, or to shape adaptive immune repertoires during fetal development and induce tolerance to self-antigens or immunogenic therapeutic molecules. Objectives: To investigate whether proteins that are administered to pregnant mice or endogenously present in their circulation may be delivered through the placenta. Methods: We engineered monovalent immunoglobulin G (FabFc) specific for different domains of human factor VIII (FVIII), a therapeutically relevant model antigen. FabFc was injected with exogenous FVIII into pregnant severe hemophilia A mice or pregnant mice expressing human FVIII following AAV8-mediated gene therapy. FabFc and FVIII were detected in the pregnant mice and/or fetuses by enzyme-linked immunosorbent assay and immunohistochemistry. Results: Administration of FabFc to pregnant mice allowed the maternofetal delivery of FVIII in a FcRn-dependent manner. FVIII antigen levels achieved in the fetuses represented 10% of normal plasma levels in the human. We identified antigen/FabFc complex stability, antigen size, and shielding of promiscuous protein patches as key parameters to foster optimal antigen delivery. Conclusion: Our results pave the way toward the development of novel strategies for the in utero delivery of endogenous maternal proteins to replace genetically deficient fetal proteins or to educate the immune system and favor active immune tolerance upon protein encounter later in life.
MeSH term(s)	Pregnancy ; Female ; Mice ; Humans ; Animals ; Immunoglobulin G ; Factor VIII ; Hemophilia A/genetics ; Hemophilia A/therapy ; Placenta ; Genetic Therapy ; Immune Tolerance
Chemical Substances	Immunoglobulin G ; Factor VIII (9001-27-8)
Language	English
Publishing date	2023-06-02
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.05.021
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Article ; Online: Efficacy of platelet-inspired hemostatic nanoparticles on bleeding in von Willebrand disease murine models.

Roullet, Stéphanie / Luc, Norman / Rayes, Julie / Solarz, Jean / Disharoon, Dante / Ditto, Andrew / Gahagan, Emily / Pawlowski, Christa / Sefiane, Thibaud / Adam, Frédéric / Casari, Caterina / Christophe, Olivier D / Bruckman, Michael / Lenting, Peter J / Sen Gupta, Anirban / Denis, Cécile V

Blood

2023 Volume 141, Issue 23, Page(s) 2891–2900

Abstract: The lack of innovation in von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by patients with VWD. ... ...

Abstract	The lack of innovation in von Willebrand disease (VWD) originates from many factors including the complexity and heterogeneity of the disease but also from a lack of recognition of the impact of the bleeding symptoms experienced by patients with VWD. Recently, a few research initiatives aiming to move past replacement therapies using plasma-derived or recombinant von Willebrand factor (VWF) concentrates have started to emerge. Here, we report an original approach using synthetic platelet (SP) nanoparticles for the treatment of VWD type 2B (VWD-2B) and severe VWD (type 3 VWD). SP are liposomal nanoparticles decorated with peptides enabling them to concomitantly bind to collagen, VWF, and activated platelets. In vitro, using various microfluidic assays, we show the efficacy of SPs to improve thrombus formation in VWF-deficient condition (with human platelets) or using blood from mice with VWD-2B and deficient VWF (VWF-KO, ie, type 3 VWD). In vivo, using a tail-clip assay, SP treatment reduced blood loss by 35% in mice with VWD-2B and 68% in mice with VWF-KO. Additional studies using nanoparticles decorated with various combinations of peptides demonstrated that the collagen-binding peptide, although not sufficient by itself, was crucial for SP efficacy in VWD-2B; whereas all 3 peptides appeared necessary for mice with VWF-KO. Clot imaging by immunofluorescence and scanning electron microscopy revealed that SP treatment of mice with VWF-KO led to a strong clot, similar to those obtained in wild-type mice. Altogether, our results show that SP could represent an attractive therapeutic alternative for VWD, especially considering their long half-life and stability.
MeSH term(s)	Humans ; Animals ; Mice ; von Willebrand Diseases/complications ; von Willebrand Diseases/therapy ; von Willebrand Factor/metabolism ; Blood Platelets/metabolism ; Hemostatics/therapeutic use ; von Willebrand Disease, Type 3/metabolism ; Disease Models, Animal ; Hemorrhage/metabolism
Chemical Substances	von Willebrand Factor ; Hemostatics
Language	English
Publishing date	2023-03-01
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2022018956
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