J Thromb Haemost. 2024 Apr 5:S1538-7836(24)00181-8. doi: 10.1016/j.jtha.2024.03.022. Online ahead of print.
ABSTRACT
BACKGROUND: Emicizumab has been approved for the prophylaxis of patients with hemophilia A with or without inhibitors. However, spontaneous and trauma-induced breakthrough bleeds have been reported in patients on emicizumab prophylaxis and no laboratory assay is validated to evaluate the hemostatic activity of emicizumab .
OBJECTIVES: The thrombin generation assay (TGA) could be a surrogate marker of the hemostatic efficacy of emicizumab. The correlation between TGA and the methods used to measure emicizumab blood concentration was evaluated in this study.
METHODS: TGA was modified by the use of a trigger reagent combining a very low concentration of tissue factor (TF) and activated factor XI (FXIa). Emicizumab quantification was performed by three methods, the modified one-step factor VIII (FVIII) assay, and two methods based on liquid chromatography and mass spectrometry (LC-MS).
RESULTS: Using TF/FXIa-triggered TGA and platelet-poor plasma, a relationship was observed between the area under the thrombin generation curve (ETP) and the clinical response of patients to emicizumab. The ultrastructure of fibrin clots was consistent with ETP results and showed that emicizumab had a hemostatic activity equivalent to 20-30 IU/dL of factor VIII. Finally, pharmacokinetic/pharmacodynamic analyses showed no correlation between ETP and LC-MS nor with modified one-stage FVIII assay, but a statistically significant correlation between the LC-MS methods and the time to peak results of TGA.
CONCLUSION: Using a modified TGA, this study showed that patients who experienced breakthrough bleeds while on emicizumab had a lower thrombin generating capacity compared to others with good clinical response to emicizumab.
PMID:38583717 | DOI:10.1016/j.jtha.2024.03.022
