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Thromb Haemost 2023; 123(10): 955-965
DOI: 10.1055/s-0043-1769788
New Technologies, Diagnostic Tools and Drugs

Pharmacodynamics Monitoring of Emicizumab in Patients with Hemophilia A

Debora Bertaggia Calderara    *
1   Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
,
Rita Marchi Cappelletti    *
2   Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
,
Ana Patricia Batista Mesquita Sauvage 
1   Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
,
Stéphane Durual 
3   Biomaterials Laboratory, University Clinics of Dental Medicine, University of Geneva, Switzerland
,
Francisco J. Gomez 
1   Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
,
Maxime G. Zermatten 
1   Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
,
Alessandro Aliotta 
1   Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
,
Alessandro Casini    **
4   Department of Medicine, University of Geneva, Geneva, Switzerland
5   Division of Angiology and Hemostasis, University Hospitals of Geneva, Geneva, Switzerland
,
Lorenzo Alberio    **
1   Division of Hematology and Central Hematology Laboratory, Lausanne University Hospital (CHUV) and University of Lausanne (UNIL), Lausanne, Switzerland
› Author Affiliations Funding This study was supported by the 2021 annual research grants of Swiss Hemophilia Network (Switzerland). L.A. is supported by a grant from the Swiss National Science Foundation (SNF 320030–197392).
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Abstract

Background Emicizumab is a bispecific antibody mimicking coagulation factor VIII (FVIII) employed to treat patients with hemophilia A (PwHA) regardless of FVIII inhibitor status. The identification of biological markers reflecting the hemostatic competence of patients under emicizumab therapy would have a great clinical value. Unfortunately, emicizumab over-corrects standard coagulation assays, precluding their use for evaluating the hemostatic correction achieved in vivo. Here, we investigated whether global coagulation assays (GCA) would allow monitoring the biological response to non-factor replacement therapy with emicizumab.

Materials and Methods Six adults PwHA received a weekly dose of emicizumab of 3 mg/kg during weeks (W) 1 4 and 1.5 mg/kg from W5 onwards. Response to treatment was monitored weekly by emicizumab plasma concentration, thrombin generation (TG), and fibrin clot formation (FCF) and structure. TG and FCF results were compared to patient baseline, FVIII replacement, and healthy donors.

Results TG and FCF significantly increased in PwHA after the loading period, reaching a plateau that lasted until the end of monitoring. Similarly, fibrin clot network became denser with thinner fibrin fibers. However, TG contrary to FCF remained at the lower limits of reference values. Remarkably, despite having similar plateau concentrations of emicizumab some patients showed markedly different degrees of TG and FCF improvement.

Conclusion Our study enriches the knowledge on the use of GCA to monitor non-factor replacement therapy, indicating that TG and FCF could act as direct markers of emicizumab biological activity. GCA allow to capture and visualize the individually variable response to emicizumab, leading a step forward to the personalization of patient treatment.

Keywords

emicizumab pharmacodynamics - global coagulation assays - non-factor replacement - thrombin generation - fibrin clot formation - fibrin clot structure

Authors' Contribution

D.B.C. and R.M.C. contributed to study design, performed research, collected laboratory data and analyzed results, wrote and critically revised the manuscript; M.G.Z. and A.A. critically revised the manuscript; A.P.B.M.S. coordinated sample and patient data collections and revised critically the manuscript; F.J.G. performed routine laboratory analyses including emicizumab measurements; A.C. contributed to study design, supervised fibrin clot structure and fibrinolytic assays, and critically revised the manuscript; L.A. designed the study, supervised patient treatment, laboratory assays, data analysis, and manuscript writing and revision.


* D.B.C and R.M.C. share first authorship.


** A.C. and L.A. share senior authorship.


Supplementary Material



Publication History

Received: 20 October 2022

Accepted: 01 May 2023

Article published online:
19 June 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
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