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Thromb Haemost 2021; 121(10): 1289-1298
DOI: 10.1055/s-0041-1725009
Coagulation and Fibrinolysis

Ex Vivo Prediction of Comprehensive Coagulation Potential Using Simulated Blood Concentrations of Emicizumab in Patients with Acquired Hemophilia A

Masahiro Takeyama 
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Shoko Furukawa
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
2   The Course of Thrombosis and Hemostasis Molecular Pathology, Nara Medical University, Kashihara, Nara, Japan
,
Koji Yada
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
3   The Course of Hemophilia Education, Nara Medical University, Kashihara, Nara, Japan
,
Kenichi Ogiwara
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Naruto Shimonishi
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Yuto Nakajima
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Kuniyoshi Mizumachi
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Mariko Noguchi-Sasaki 
4   Chugai Pharmaceutical Co., Ltd., Kamakura, Kanagawa, Japan
,
Midori Shima
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
,
Keiji Nogami
1   Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan
› Author Affiliations Funding This work was partly supported by a Grant-in-Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) to K.N. (18K07885).
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Abstract

Introduction Emicizumab prophylaxis improves coagulation function in congenital hemophilia A, regardless of inhibitor presence. We recently reported that emicizumab enhanced the coagulant potentials, ex vivo, in plasmas from patients with acquired hemophilia A (PwAHAs) at diagnosis. However, coagulant effects of emicizumab in PwAHAs during the clinical course remain unclear.

Aim To assess ex vivo coagulant effects of emicizumab in PwAHAs during the clinical course.

Methods/Results Blood samples were obtained from 14 PwAHAs on (median) days 0 and 6 during a severe-bleeding phase, and days 27 and 59 during a reduced-bleeding phase with elevated endogenous factor VIII (FVIII) and decreased inhibitor titers. If administered a single dose of 3 or 6 mg/kg, or two doses at 6 mg/kg followed by 3 mg/kg, estimated plasma emicizumab concentrations (10/5/2.5, 20/10/5, and 30/15/7.5 µg/mL on days 0–7/30/60, respectively) could be used to represent potential changes, based on the half-life (T 1/2: ∼30 days). Emicizumab concentrations that covered maximum plasma concentrations of each dosage were used for spiking on day 0. Ex vivo addition of estimated emicizumab to PwAHA's plasma containing endogenous FVIII and/or inhibitor, without and with recombinant (r)FVIIa administration during immunosuppressive therapy, increased the calculated Ad|min1| values, assessed by clot waveform analysis, and their coagulant potentials were below normal levels. Rotational thromboelastometry revealed that ex vivo emicizumab addition resulted in the further improvement of coagulant potentials in whole bloods when combined with rFVIIa administration.

Conclusion Based on ex vivo and in vitro data, emicizumab has the potential to be effective in clinical situations for PwAHAs.

Keywords

bispecific - acquired hemophilia A - autoantibodies - pharmacokinetic - coagulation

Author Contributions

M.T. designed the research, provided clinical support, performed experiments, analyzed, and interpreted the data, made the figures, and wrote the paper. S.F., K.Y., K.O., N.S., Y.N., and K.M. provided clinical support. M.N.-S. prepared emicizumab and interpreted the data. M.S. supervised this study. K.N. designed the research, provided clinical support, interpreted the data, wrote the paper, edited the manuscript, and approved the final version to be published.




Publication History

Received: 03 November 2020

Accepted: 06 January 2021

Article published online:
28 February 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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