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CME Evaluation

Oral Communication Session

Inherited Bleeding Disorders and Inhibitors

Session: Novel hemophilia treatments, pre-clinical

OC 21.4 - Genetic Ablation of Anticoagulant Protein S Promotes Joint Health in Hemophilia A

Sunday, June 23, 2024
15:30 – 15:45 ICT
Room: Ballroom B1

    Presenting Author(s)

  • RP

    Raja Prince-Eladnani

    Senior Scientist
    Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Switzerland; Department for BioMedical Research, University of Bern, Switzerland
    Bern, Bern, Switzerland

    • Co-Author(s)

  • SC

    Sara Calzavarini

    Dr
    Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland. Department for BioMedical Research, University of Bern, Murtenstrasse 40, CH-3010 Bern, Switzerland
    Bern, Bern, Switzerland

  • MR

    Maria Desiré Reina Caro

    Technician
    Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland. Department for BioMedical Research, University of Bern, Murtenstrasse 40, CH-3010 Bern, Switzerland
    Bern, Bern, Switzerland

  • BH

    Beat Haenni

    Technician
    Institute of Anatomy, University of Bern, Baltzerstrasse 2, 3012 Bern
    Bern, Bern, Switzerland

  • Anne Angelillo-Scherrer, MD

    Head of Department
    Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, CH-3010 Bern, Switzerland. Department for BioMedical Research, University of Bern, Murtenstrasse 40, CH-3010 Bern, Switzerland
    Bern, Bern, Switzerland

Background: Hemophilia-related joint damage stems from recurrent intra-articular bleeds (IAB). With no treatment available to reduce blood-induced synovitis, bleeding prevention is crucial to maintain joint health, but a more targeted therapy is needed. Our prior research revealed that genetic ablation (GA) of anticoagulant protein S (PS) in mice with hemophilia A (HA) reduces IAB. PS reduction was shown to enhance thrombin generation in persons with HA ex vivo

Aims: The impact of PS GA on joint health was studied using a chronic hemarthrosis (CH) model in HA mice (F8-/-).

Methods: HA (F8-/-), HA with GA of PS (F8-/-Pros1-/-) and WT mice underwent CH with three 7-day interval joint bleeds. Histology, immunostaining, transmission electron microscopy (TEM), joint lavages cytokines, and synovium RNA sequencing were conducted in both steady-state (SS) and CH conditions.

Results: CH led to increased joint diameters, intraarticular bleeding and synovitis in F8-/-, not in F8-/-Pros1-/- or WT mice (Fig.1A,B). F8-/-Pros1-/- mice showed no bleeding or iron deposition, minimal cartilage erosion, and maintained lining layer (LL) integrity, even with CH as shown by histology and TEM (Fig.1E). Macrophages were found in the LL and subLL of F8-/-Pros1-/- and WT mice during CH (Fig.1C,D). F8-/-Pros1-/- had lower inflammatory cytokines than F8-/- in joint lavage (Fig.1F). In SS, mRNA coding for proteins involved in bone resorption were decreased while those coding for cell communication and bone formation were increased in F8-/-Pros1-/- versus F8-/-mice. Post-CH, F8-/-Pros1-/- mice displayed a positive regulation of genes involved in macrophage activation, bone regeneration and tissue remodeling, angiogenesis, and fibroblast growth. Unlike F8-/-, F8-/-Pros1-/- mice's synovium had higher expression of pleiotrophin (PTN) expression, a factor involved in bone development and tissue repair (Fig.1H). PTN was strongly expressed in synovium LL of F8-/-Pros1-/- mice (Fig.1G)

Conclusion(s): These findings highlight PS as a key modifier of joint health in HA, partly through PTN