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  1. Article ; Online: High factor VIII concentrations interfere with glycoprotein VI-mediated platelet activation in vitro.

    Sekar, Rohini / Mimoun, Angelina / Bou-Jaoudeh, Melissa / Loyau, Stéphane / Delignat, Sandrine / Daventure, Victoria / Bonilla, Perrine / Bhale, Aishwarya Sudam / Venkataraman, Krishnan / Rayes, Julie / Boulaftali, Yacine / Jandrot-Perrus, Martine / Proulle, Valérie / Lacroix-Desmazes, Sébastien

    Journal of thrombosis and haemostasis : JTH

    2024  Volume 22, Issue 5, Page(s) 1489–1495

    Abstract: Background: The recruitment of activated factor VIII (FVIII) at the surface of activated platelets is a key step toward the burst of thrombin and fibrin generation during thrombus formation at the site of vascular injury. It involves binding to ... ...

    Abstract Background: The recruitment of activated factor VIII (FVIII) at the surface of activated platelets is a key step toward the burst of thrombin and fibrin generation during thrombus formation at the site of vascular injury. It involves binding to phosphatidylserine and, possibly, to fibrin-bound α
    Objectives: To characterize the effects of FVIII-platelet interaction and its potential modulation of platelet function.
    Methods: FVIII was incubated with washed platelets. The effects on platelet activation (spontaneously or triggered by collagen and thrombin) were studied by flow cytometry and light transmission aggregometry. We explored the involvement of downstream pathways by studying phosphorylation profiles (Western blot). The FVIII-glycoprotein (GP) VI interaction was investigated by ELISA, confocal microscopy, and proximity ligation assay.
    Results: FVIII bound to the surface of resting and activated platelets in a dose-dependent manner. FVIII at supraphysiological concentrations did not induce platelet activation but rather specifically inhibited collagen-induced platelet aggregation and altered glycoprotein VI (GPVI)-dependent phosphorylation. FVIII, freed of its chaperone protein von Willebrand factor (VWF), interacted in close proximity with GPVI at the platelet surface.
    Conclusion: We showed that VWF-free FVIII binding to, or close to, GPVI modulates platelet activation in vitro. This may represent an uncharacterized negative feedback loop to control overt platelet activation. Whether locally activated FVIII concentrations achieved during platelet accumulation and thrombus formation at the site of vascular injury in vivo are compatible with such a function remains to be determined.
    MeSH term(s) Humans ; Platelet Membrane Glycoproteins/metabolism ; Platelet Activation/drug effects ; Blood Platelets/metabolism ; Phosphorylation ; Factor VIII/metabolism ; Platelet Aggregation ; Collagen/metabolism ; Protein Binding ; Flow Cytometry ; Thrombin/metabolism ; Dose-Response Relationship, Drug ; Microscopy, Confocal
    Chemical Substances platelet membrane glycoprotein VI ; Platelet Membrane Glycoproteins ; Factor VIII (9001-27-8) ; Collagen (9007-34-5) ; Thrombin (EC 3.4.21.5) ; F8 protein, human (839MOZ74GK)
    Language English
    Publishing date 2024-02-05
    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.2024.01.021
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Heparin-induced thrombocytopenia in newborns: experience at a pediatric hospital and a literature review.

    Gay, Juliette / Le Beller, Christine / Asgari, Roya / Chocron, Richard / Bajolle, Fanny / Auger, Ludivine / Mimoun, Angelina / Borgel, Delphine / Lillo-Le-Louet, Agnès / Lasne, Dominique

    Research and practice in thrombosis and haemostasis

    2023  Volume 7, Issue 7, Page(s) 102214

    Abstract: Background: Heparin-induced thrombocytopenia (HIT) is a rare, difficult-to-diagnose, and potentially serious adverse drug reaction with thrombotic complications. Even though the immune system is still immature during the neonatal period, HIT has been ... ...

    Abstract Background: Heparin-induced thrombocytopenia (HIT) is a rare, difficult-to-diagnose, and potentially serious adverse drug reaction with thrombotic complications. Even though the immune system is still immature during the neonatal period, HIT has been described in newborns with reporting rates ranging from 0% to 2.3%. Therefore, it is important to clarify the risk of HIT in newborns because it can affect the management and monitoring of heparin treatment.
    Objectives: The objectives of the present study were to review the literature and determine the incidence of HIT after cardiac surgery in newborns in our pediatric hospital.
    Methods: We searched the literature from 1992 to 2021 for reports of HIT in newborns. Four raters then analyzed all the literature reports on HIT and classified them as "likely," "uncertain," or "unlikely." We also determined the incidence of HIT among newborns having undergone cardiac surgery in our pediatric hospital.
    Results: Eleven population-based studies and 12 case reports on suspected HIT in 17 newborns were reviewed. One study reported HIT in 14 out of 930 (1.5%) heparin-treated newborns, but the other studies (
    Conclusion: We conclude that the incidence of HIT in newborns has been overestimated in the literature.
    Language English
    Publishing date 2023-09-29
    Publishing country United States
    Document type Journal Article
    ISSN 2475-0379
    ISSN (online) 2475-0379
    DOI 10.1016/j.rpth.2023.102214
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  4. 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
    Database MEDical Literature Analysis and Retrieval System OnLINE

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    In stock of ZB MED Cologne/Königswinter

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  5. Article ; Online: Relevance of the Materno-Fetal Interface for the Induction of Antigen-Specific Immune Tolerance.

    Mimoun, Angelina / Delignat, Sandrine / Peyron, Ivan / Daventure, Victoria / Lecerf, Maxime / Dimitrov, Jordan D / Kaveri, Srinivas V / Bayry, Jagadeesh / Lacroix-Desmazes, Sébastien

    Frontiers in immunology

    2020  Volume 11, Page(s) 810

    Abstract: In humans, maternal IgGs are transferred to the fetus from the second trimester of pregnancy onwards. The transplacental delivery of maternal IgG is mediated by its binding to the neonatal Fc receptor (FcRn) after endocytosis by the syncytiotrophoblast. ... ...

    Abstract In humans, maternal IgGs are transferred to the fetus from the second trimester of pregnancy onwards. The transplacental delivery of maternal IgG is mediated by its binding to the neonatal Fc receptor (FcRn) after endocytosis by the syncytiotrophoblast. IgGs present in the maternal milk are also transferred to the newborn through the digestive epithelium upon binding to the FcRn. Importantly, the binding of IgGs to the FcRn is also responsible for the recycling of circulating IgGs that confers them with a long half-life. Maternally delivered IgG provides passive immunity to the newborn, for instance by conferring protective anti-flu or anti-pertussis toxin IgGs. It may, however, lead to the development of autoimmune manifestations when pathological autoantibodies from the mother cross the placenta and reach the circulation of the fetus. In recent years, strategies that exploit the transplacental delivery of antigen/IgG complexes or of Fc-fused proteins have been validated in mouse models of human diseases to impose antigen-specific tolerance, particularly in the case of Fc-fused factor VIII (FVIII) domains in hemophilia A mice or pre-pro-insulin (PPI) in the case of preclinical models of type 1 diabetes (T1D). The present review summarizes the mechanisms underlying the FcRn-mediated transcytosis of IgGs, the physiopathological relevance of this phenomenon, and the repercussion for drug delivery and shaping of the immune system during its ontogeny.
    MeSH term(s) Animals ; Antigens/immunology ; Autoantibodies/metabolism ; Female ; Fetus/immunology ; Histocompatibility Antigens Class I/metabolism ; Humans ; Immune System/embryology ; Immune System/metabolism ; Immune Tolerance ; Immunoglobulin G/metabolism ; Maternal-Fetal Exchange/immunology ; Mice ; Placenta/immunology ; Pregnancy ; Protein Transport/immunology ; Receptors, Fc/metabolism ; Transcytosis/immunology
    Chemical Substances Antigens ; Autoantibodies ; Histocompatibility Antigens Class I ; Immunoglobulin G ; Receptors, Fc ; Fc receptor, neonatal (TW3XAW0RCY)
    Language English
    Publishing date 2020-05-14
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2606827-8
    ISSN 1664-3224 ; 1664-3224
    ISSN (online) 1664-3224
    ISSN 1664-3224
    DOI 10.3389/fimmu.2020.00810
    Database MEDical Literature Analysis and Retrieval System OnLINE

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