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CME Evaluation

Oral Communication Session

Inherited Bleeding Disorders and Inhibitors

Session: Novel hemophilia treatment, clinical trials II

OC 50.4 - Assessment of global coagulation function under treatment with emicizumab concomitantly with bypassing agents in hemophilia A with inhibitor (UNEBI Study): Multicenter open-label non-randomized trial.

Tuesday, June 25, 2024
10:15 – 10:30 ICT
Room: Plenary Hall

    Presenting Author(s)

  • Kenichi Ogiwara, MD, PhD

    Associate Professor
    Department of Pediatrics, Nara Medical University
    Kashihara, Nara, Japan

    • Co-Author(s)

  • Teruhisa Fujii

    Manager of Division of Transfusion Medicine and Hemophilia Treatment Center
    Hiroshima University Hospital
    Hiroshima, Hiroshima, Japan

  • Azusa Nagao, MD, MSc, PhD

    Stuff physician
    Department of Blood Coagulation, Ogikubo Hospital
    Tokyo, Tokyo, Japan

  • HT

    Hideyuki Takedani

    Department Chair
    Department of rehabilitation, NHO Tsuruga Medical Center
    Tsuruga, Fukui, Japan

  • Kumiko Ono, MD, PhD

    project lecturer
    Division of Science for Joint Reconstruction, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
    Chiyoda-ku, Tokyo, Japan

  • CN

    Chiai Nagae

    Lecturer
    Department of Pediatrics, St. Marianna University School of Medicine
    Kawasaki, Kanagawa, Japan

  • KA

    Kagehiro Amano

    Professor
    Department of Laboratory Medicine, Tokyo Medical University
    Shinjuku, Tokyo, Japan

  • AY

    Atsuki Yamashita

    Department Chair
    Department of Pediatrics, Yokohama City Seibu Hospital, St. Marianna University School of Medicine
    Yokohama, Kanagawa, Japan

  • RS

    Rie Shirayama

    Assistant professor
    Department of Pediatrics, University of Occupational and Environmental Health
    Kitakyushu, Fukuoka, Japan

  • YH

    Yasuo Horikoshi

    Department Chair
    Division of Hematology and Oncology, Shizuoka Children’s Hospital
    Shizuoka, Shizuoka, Japan

  • SH

    Satoshi Higasa

    Lecturer
    Department of Hematology, Hyogo University of Medicine
    Nishinomiya, Hyogo, Japan

  • Tadashi Matsushita

    Professor
    Nagoya University Hospital, Nagoya, Japan
    Nagoya, Aichi, Japan

  • MT

    Masashi Taki

    Honorary professor
    Department of Pediatrics, St. Marianna University School of Medicine
    Kawasaki, Kanagawa, Japan

  • MM

    Masanori Matsumoto

    Professor
    Department of Hematology and Blood Transfusion Medicine, Nara Medical University Hospital, Kashihara, Japan
    Kashihara, Nara, Japan

  • NO

    Naoki Ozu

    Assistant professor
    Institute for Clinical and Translational Science, Nara Medical University
    Kashihara, Nara, Japan

  • MK

    Masato Kasahara

    Professor
    Institute for Clinical and Translational Science, Nara Medical University
    Kashihara, Nara, Japan

  • Midori Shima

    Director
    Thrombosis and Hemostasis Research Center, Nara Medical University
    Kashihara, Nara, Japan

  • KN

    Keiji Nogami

    Professor
    Nara Medical University, Nara, Japan
    Nara, Nara, Japan

Background: Emicizumab prophylaxis reduces bleeding in hemophilia A patients with inhibitor (HAwI). After thrombotic complications occurred in concomitant use of aPCC (bypassing agent, BPA) with high cumulative doses, a guidance was proposed for the BPAs therapy under emicizumab prophylaxis. However, a detailed investigation is required to elucidate the safe and appropriate dose of BPAs.

Aims: To evaluate global coagulation function under emicizumab prophylaxis and BPAs. To explore clues for understanding the mechanisms leading to thrombosis in these settings.

Methods: HAwI were enrolled between 2020-2023. Blood samples before/after administration of a fixed dose of BPAs at breakthrough bleeding or surgical procedures were collected. Global coagulation assays including thrombin generation assay (TGA), clot waveform analysis (CWA), and thromboelastometry were performed. The primary endpoint was the degree of improvement in the maximum coagulation rate (IMCR%) by CWA. CWA was triggered with an optimally diluted mixture of PT/aPTT reagents [Nogami, JTH2018]. The study was approved by the Japan-Certified-Review-Board (jRCTs051190119).

Results: Of 38 HAwI (median observation period 132 weeks), 29 bleeding (n=12)/surgical (n=17) events occurred in 18 HAwI (7-67 year-old). In the first events in 18 HAwI, only rFVIIa (85±5 μg/mL) was used. Mean±SD of IMCR% by CWA before/after rFVIIa were 37.6±24.9%/60.9±21.4%, respectively. ΔIMCR% was 23.3±11.7% [Figure]. Anti-emicizumab antibodies reagent could discriminate each effect of emicizumab and rFVIIa. In TF-triggered TGA (LowPPP®), peak thrombin before/after rFVIIa were 73±35/200±60 nM, respectively. ΔIMCR% of the peak was 162.2±53.5%, over the normal upper limit (100.0±61.9%). In thromboelastometry (NATEM, n=9), clot time (1607±583 seconds, reference 938±128) was improved after rFVIIa (803±331) [Table]. One case used a single dose of aPCC in the second event. No thrombotic complication occurred in all cases. VWF:Ag, VWF multimer, and ADAMTS13 activity showed no significant changes.

Conclusion(s): In emicizumab-treated HAwI, rFVIIa at a dose of ≦90 μg/kg was effective and safe. The modified CWA was useful in these settings.