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Usefulness of the human-factor based chromogenic substrate assay for evaluating coagulability of Emicizumab

1Tokyo Medical University, Shinjukuku, Tokyo, Japan, 2Tokyo Medical University, Tokyo, Tokyo, Japan, 3Tokyo Medical University, Shinjukuku Nishishinjuku, Tokyo, Japan, 4Tokyo Medical University Hospital, Tokyo, Tokyo, Japan, 5The Institute of Medical Science, The University of Tokyo, Minatoku, Tokyo, Japan

Abstract Number: VPB0209

Meeting: ISTH 2022 Congress

Theme: Hemophilia and Rare Bleeding Disorders » Hemophilia - Basic

Background: Emicizumab is a bispecific antibody mimicking activated factor VIII (FVIII) and increasingly used because of its practicality. In patients receiving emicizumab, since activated partial thromboplastin time (aPTT) is excessively shortened, it is an urgent issue to establish an appropriate and easy-to-access coagulation assay.

Aims: The aim of this study is to assess the usefulness of the human factor-based chromogenic substrate assay (hCSA) with reference to the thrombin generation assay (TGA), the established coagulation assay for emicizumab.

Methods: The coagulability of spiked emicizumab and recombinant FVIII (rFVIII) were measured and compared among TGA using extrinsic and intrinsic pathway triggers, hCSA, one-stage clotting assay (OSA), and clot waveform analysis (CWA). We also investigated the additive effect of 340 nM emicizumab in combination with rFVIII by measuring in the same assays.

Results: Both the peak thrombin by TGA and FXa generation by hCSA consistently showed a linear relationship between emicizumab and rFVIII concentration in wide range of emicizumab concentration (10-2000 nM). While TGA showed a plateau in higher emicizumab concentration, hCSA did not at any concentration. FVIII-equivalent activity of emicizumab in hCSA can be approximated by halving to that in TGA triggered by the extrinsic pathway reagent (27.3 IU/dL vs. 13.9 IU/dL) in steady state (340 nM) of emicizumab. The additive effect in combination of 340 nM of emicizumab plus rFVIII gradually diminished at higher range of rFVIII in TGA, hCSA and CWA.

Conclusion(s): Reported FVIII activity of emicizumab in hCSA can be easily approximated to TGA, and the additive effect of FVIII on emicizumab is diminished in higher doses of FVIII. For clinical applicability of hCSA, further investigation is needed.

This research was supported by Chugai Pharmaceutical Co., Ltd, and emicizumab used in this study was provided by Chugai Pharmaceutical.

Figure 1

The left panel shows the peak thrombin of thrombin generation assay -TGA- triggered by extrinsic pathway reagent in recombinant factor VIII -rFVIII- -1-600 IU/dL- or emicizumab -10-10000 nM- spiked hemophilia A pooled plasma. The right shows the activated factor X -FXa- generation of human factor-based chromogenic substrate assay -hCSA- in the same plasma samples. Bars represent standard errors of the mean -SEM-.

Table 1

Comparison of the equivalent factor VIII -FVIII- activity to emicizumab calculated by the results of each measuring methods.

To cite this abstract in AMA style:

Yamaguchi T, Shinozawa K, Hiroshi I, Mitsuhashi A, Harada Y, Miyashita R, Kamikubo Y, Ichiki A, Chikasawa Y, Bingo M, Sekiya R, Muramatsu T, Yotsumoto M, Hagiwara T, Amano K, Nagatoishi S, Tsumoto K, Kinai E. Usefulness of the human-factor based chromogenic substrate assay for evaluating coagulability of Emicizumab [abstract]. https://abstracts.isth.org/abstract/usefulness-of-the-human-factor-based-chromogenic-substrate-assay-for-evaluating-coagulability-of-emicizumab/. Accessed September 29, 2023.

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