Emicizumab Improves Ex Vivo Clotting Function in Patients with Mild/Moderate Hemophilia AFunding 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).
20 January 2020
01 April 2020
08 May 2020 (online)
Background Emicizumab prophylaxis is a promising treatment that reduces bleeding events in severely affected patients with hemophilia A (PwHA). It is anticipated that emicizumab could be similarly effective in mild/moderate PwHA (PwMHA) although this effect has not been investigated.
Aim We evaluated ex vivo coagulant effects of emicizumabin PwMHA.
Methods Clot waveform analysis (CWA) triggered by prothrombin time/activated partial prothrombin time-mixed reagents was utilized to examine coagulant effects of emicizumabin factor (F)VIII-deficient plasma mixed with recombinant (r)FVIIIand in native plasmas from 16 PwMHA. The CWA parameter, adjusted-|min1| (Ad|min1|), was used. Increases in Ad|min1| (ΔAd|min1|) mediated by emicizumab were calculated from the slopes of regression lines in the presence of rFVIII.
Results Ad|min1| in FVIII-deficient plasma with various concentrations of rFVIII negatively correlated with ΔAd|min1|by adding emicizumab, and these data were defined as standard reference values. Ad|min1| (4.57 ± 0.50) in 16 PwMHA increased to 5.05 ± 0.54 and 5.37 ± 0.60 by adding emicizumab at 50 and 100 μg/mL, respectively, but remained lower than the normal range (7.22 ± 0.21). ΔAd|min1| levels were 1.5 to 2-fold higher in five cases and 0.4 to 0.6-fold lower in four cases, compared with reference values determined by rFVIII. In some cases, genetic analyses suggested that specific point mutations could have contributed to these findings. Further studies using rFVIII mutants indicated, however, that the differences in ΔAd|min1| were not related to individual FVIII gene defects.
Conclusion Emicizumab enhances coagulation potential in PwMHA. Assessment of ex vivo coagulant activity of emicizumab could be helpful for predicting coagulant potentials prior to treatment in these patients.
Y.N. performed experiments and prepared the FVIII mutants, analyzed the data, prepared figures, and wrote the manuscript. K.N. designed all experiments, interpreted the data, prepared figures, wrote and edited the manuscript, and approved the final version to be published. K.Y. performed gene analyses and interpreted the data. S.F. performed gene analyses and prepared the FVIII mutants. M.N.S. and M.H. supervised this study and prepared emicizumab. M.S. supervised this study.
An account of this work was presented at the ISTH 2019 Congress, Melbourne, Australia.
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