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. 2020 Apr;18(4):825-833.
doi: 10.1111/jth.14746. Epub 2020 Feb 26.

An anti-factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A

Masahiro Takeyama  1 , Keiji Nogami  1 , Tomoko Matsumoto  1   2 , Mariko Noguchi-Sasaki  3 , Takehisa Kitazawa  3 , Midori Shima  1
Affiliations
Free article

An anti-factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A

Masahiro Takeyama et al. J Thromb Haemost. 2020 Apr.
Free article

Abstract

Introduction: Acquired hemophilia A (AHA) is caused by autoantibodies against factor (F)VIII, and is characterized by severe, spontaneous bleeding, which can be life-threatening. Emicizumab, an anti-FIXa/FX bispecific antibody, significantly reduces bleeding events in congenital hemophilia A (HA) with and without inhibitors. The known pathophysiological mechanisms and current preclinical data in HA suggest that emicizumab could provide effective treatment for AHA, but the coagulation activities of emicizumab in these patients remain unknown.

Aim: To evaluate the coagulant effects of emicizumab in plasma from AHA patients.

Methods and results: Tissue factor-triggered thrombin generation assays using normal plasma preincubated with anti-FVIII monoclonal antibodies recognizing different epitopes demonstrated that 20 µg/mL emicizumab recovered the depressed peak levels of thrombin generation to 46% to 72%. Further studies were devised, therefore, to simulate the clinical course in AHA patients, including during the acute phase for severe bleeding requiring FVIII-bypassing therapy, and during the subacute/chronic phase with less bleeding. Various concentrations of emicizumab were used to represent the potential changes in plasma levels based on the half-life of the antibody (~30 days). The ex vivo addition of emicizumab to plasma samples from AHA patients (n = 16) increased peak thrombin in all cases, irrespective of the inhibitor epitope specificity. Thrombin generation at 20 and 100 µg/mL emicizumab was restored to (median) 43.9% and 92.2%, respectively. Differences were evident in some cases, however, and recovery rates appeared likely to be greater in patients with type 2 inhibitor than those with type 1.

Conclusion: Emicizumab improved ex vivo coagulation potential in plasma from AHA patients.

Keywords: autoantibodies; bispecific antibodies; blood coagulation; hemophilia A; pharmacokinetics.

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