A modified thrombin generation assay to evaluate the plasma coagulation potential in the presence of emicizumab, the bis
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ORIGINAL ARTICLE
A modified thrombin generation assay to evaluate the plasma coagulation potential in the presence of emicizumab, the bispecific antibody to factors IXa/X Kenichi Ogiwara1 · Keiji Nogami1 · Naoki Matsumoto2 · Mariko Noguchi‑Sasaki2 · Michinori Hirata2 · Tetsuhiro Soeda2 · Midori Shima1 Received: 3 April 2020 / Revised: 18 June 2020 / Accepted: 21 July 2020 © Japanese Society of Hematology 2020
Abstract Emicizumab shortens activated partial thromboplastin time (aPTT) greater than Factor (F)VIII. Clot waveform analysis triggered by ellagic acid and tissue factor trigger (Elg/TF) provided a useful means of assessing emicizumab activity. Thrombin generation assays (TGA) using this trigger reagent might also overcome the difficulties associated with aPTT by emicizumab. To compare TGA triggered by Elg/TF and other reagents (FXIa, TF) for evaluating emicizumab activity. Emicizumab, FVIII, or FVIII-bypassing agents (BPAs) were incubated with FVIII-deficient plasmas prior to TGA initiated by Elg/TF (0.2 μM/0.5 pM), FXIa (5.21 pM), or TF (PPP-Reagent LOW®). Emicizumab, FVIII, or BPAs increased peak thrombin generation (peak-Th) dose-dependently using Elg/TF-trigger and the other triggers. Low responses were evident with FXIa-trigger and the enhanced effects remained below normal levels with Elg/TF-trigger. Experiments using FVIII with emicizumab demonstrated an additive effect on peak-Th using Elg/TF-trigger, and this effect appeared to be less at FVIII ≥ 40 IU/dl. BPAs with emicizumab appeared to mediate additive effects, although its effects were variable. Parameters of thrombin generation from BPAs and emicizumab with Elg/TF-trigger were improved to normal level compared to low TF-trigger. Elg/TF-TGA could evaluate global coagulation potential during emicizumab prophylaxis including concomitant therapy with FVIII or BPAs. Keywords Bispecific antibodies · Blood coagulation tests · Treatment · Hemophilia A · Factor VIII
Introduction Hemophilia A (HA) results from a deficiency or defect of factor (F)VIII, and is the most common of the severe hemorrhagic disorders. The development of regular prophylaxis Statement of prior presentation: An account of this work was presented at the 60th annual meeting of the American Society of Hematology, 2018, San Diego, LA, USA. Electronic supplementary material The online version of this article (https://doi.org/10.1007/s12185-020-02959-x) contains supplementary material, which is available to authorized users. * Keiji Nogami roc‑noga@naramed‑u.ac.jp 1
Department of Pediatrics, Nara Medical University, 840 Shijo‑cho, Kashihara, Nara 634‑8522, Japan
Chugai Pharmaceutical Co., Ltd, Kamakura, Kanagawa, Japan
2
using FVIII products has dramatically improved the quality of life of patients with HA (PwHA) [1]. Extended half-life products have been recently devised [2], although frequent intravenous infusions of FVIII products may pose a mental and physical burden [3]. In addition, the development of anti-FVIII antibodies (inhibitors) can render standard FVIII
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