Skip to main content
ISTH 2023 Main banner
Back

    Poster Networking

    Coagulation and Natural Anticoagulants

    Poster Networking Session

    PB1071 - A single-domain antibody enhancing protein S activity reduces vaso-occlusion in a murine model of sickle cell disease

    Tuesday, June 27, 2023
    18:30 – 19:30 ET
    Room: Exhibition

      Presenting Author(s)

    • Claire Auditeau, PharmD

      PhD Student
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      LE KREMLIN BICETRE, Ile-de-France, France

      • Co-Author(s)

    • TM

      Thiago T. Maciel

      Principal investigator
      Institut Imagine, INSERM U1163, Université Paris Cité, Laboratory of Excellence GR-Ex, Paris, France
      Paris, Ile-de-France, France

    • Josepha C. Sedzro, PhD (she/her/hers)

      Postdoctoral Research Fellow
      Department of Biological Chemistry, University of Michigan Medical School, Ann Arbor, MI, USA
      Ann Arbor, Michigan, United States

    • CR

      Camille Roussel

      Principal investigator
      Biologie Intégrée du Globule Rouge, Université de Paris Cité, Paris, France
      Paris, Ile-de-France, France

    • AF

      Aurélie Fricot-Montsinjon

      Engineer
      Biologie Intégrée du Globule Rouge, Université de Paris Cité, Paris, France
      Paris, Ile-de-France, France

    • MK

      Mariem Khamari

      Laboratory technician
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Paris, Ile-de-France, France

    • Ivan Peyron, PhD (he/him/his)

      Post-doctoral fellow
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Le Kremlin-Bicêtre, Ile-de-France, France

    • OC

      Olivier D. Christophe

      Principal Investigator, Director of research
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Paris, Ile-de-France, France

    • Peter J. Lenting, PhD

      Principal Investigator, Director of research
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Paris, Ile-de-France, France

    • Cécile V. Denis, PhD

      Principal investigator, Director of Research
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Le Kremlin-Bicêtre, Ile-de-France, France

    • DB

      Delphine Borgel

      Professor, Director of research
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Paris, Ile-de-France, France

    • FS

      François Saller

      Assistant Professor
      Laboratory for Hemostasis, Inflammation and Thrombosis, Unité Mixte de Recherche S1176, Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay, Le Kremlin-Bicêtre, France
      Paris, Ile-de-France, France

    Background: Ongoing coagulation activation is involved in sickle cell disease (SCD). Moreover, SCD patients have lower Protein S (PS) levels than healthy volunteers, with a further reduction during vaso-occlusive crises (VOC). PS003biv is the dimeric form of a recently described anti-PS single-domain antibody (sdAb) enhancing the activated protein C-cofactor activity of PS and exerting an antithrombotic effect in vivo, which makes it potentially relevant in SCD.

    Aims: To assess if PS003biv can enhance PS activity in SCD patients and limit VOC in SCD mice.

    Methods: PS003biv effect on PS activity in SCD patients was assessed with a clotting-based assay in plasma. We tested PS003biv effect on VOC in SCD Townes mice by intravenously injecting PS003biv at 10 mg/kg before triggering VOC with a hypoxia/reoxygenation injury model. Vaso-occlusion was quantified by Ter-119 immunofluorescence staining of red blood cells (RBC) congesting vessels in the liver and spleen. Bilirubin, heme, and thrombin-antithrombin complexes (TAT) were measured in plasma.

    Results: PS003biv increased PS activity in SCD patients (control sdAb 65.5±2.3% versus PS003biv 93.5±4.5%, p< 0.0001). PS003biv decreased RBC accumulation and vaso-occlusion, as evidenced by a reduced Ter-119 staining in the liver and spleen (liver control: 13.6±1.5x10^6 versus PS003biv 7.3±0.4x10^6AU p< 0.05; spleen control 5.6±0.2x10^7 versus PS003biv 5.0±0.1x10^7AU, p< 0.05). PS003biv-treated mice displayed lower levels of hemolysis biomarkers (bilirubin control 6.9±0.2 versus PS003biv 4.9±0.6mg/dL p< 0.05; heme control 133.0±10.4 versus PS003biv 77.5±5.3µM p< 0.05); and reduced coagulation activation (TAT control: 10.1±0.7 versus PS003biv 7.5±0.3ng/mL, p< 0.05).

    Conclusion(s): PS003biv significantly enhanced the activated protein C-cofactor activity of PS in SCD patients and reduced vaso-occlusion, hemolysis, as well as coagulation activation in a hypoxia/reoxygenation injury model of VOC in SCD mice. The precise mechanism of action of PS003biv remains to be determined.