Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
The Course of Hemophilia Education, Nara Medical University, Nara, Japan.
Thromb Haemost. 2020 Jun;120(6):968-976. doi: 10.1055/s-0040-1710315. Epub 2020 May 8.
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.
We evaluated coagulant effects of emicizumabin PwMHA.
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.
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.
Emicizumab enhances coagulation potential in PwMHA. Assessment of coagulant activity of emicizumab could be helpful for predicting coagulant potentials prior to treatment in these patients.
依库珠单抗预防疗法是一种很有前景的治疗方法，可减少重度血友病 A 患者（PwHA）的出血事件。尽管尚未对此进行研究，但预计依库珠单抗在轻度/中度血友病 A 患者（PwMHA）中也同样有效。
我们评估了依库珠单抗在 PwMHA 中的凝血效果。
利用凝血酶原时间/活化部分凝血活酶时间混合试剂触发的凝血波分析（CWA），检测依库珠单抗在 FVIII 缺乏的血浆与重组 FVIII（rFVIII）混合以及 16 例 PwMHA 天然血浆中的凝血效果。使用调整的|min1|（Ad|min1|）参数。通过在 rFVIII 存在下计算回归直线斜率来计算依库珠单抗介导的 Ad|min1|（ΔAd|min1|）增加量。
FVIII 缺乏的血浆中，随着 rFVIII 浓度的增加，Ad|min1|呈负相关，添加依库珠单抗后，ΔAd|min1|也呈负相关，这些数据被定义为标准参考值。16 例 PwMHA 的 Ad|min1|（4.57±0.50）分别增加至 5.05±0.54 和 5.37±0.60，添加 50 和 100μg/mL 的依库珠单抗，但仍低于正常范围（7.22±0.21）。与 rFVIII 确定的参考值相比，5 例患者的ΔAd|min1|水平高 1.5 至 2 倍，4 例患者的ΔAd|min1|水平低 0.4 至 0.6 倍。在某些情况下，基因分析表明特定的点突变可能导致了这些发现。然而，使用 rFVIII 突变体的进一步研究表明，ΔAd|min1|的差异与 FVIII 基因缺陷无关。
依库珠单抗增强了 PwMHA 的凝血潜能。评估依库珠单抗的凝血活性可能有助于预测这些患者治疗前的凝血潜能。
