Takeyama Masahiro, Nogami Keiji, Matsumoto Tomoko, Noguchi-Sasaki Mariko, Kitazawa Takehisa, Shima Midori
Department of Pediatrics, Nara Medical University, Kashihara, Japan.
Tenri School of Medical Technology, Tenri, Japan.
J Thromb Haemost. 2020 Apr;18(4):825-833. doi: 10.1111/jth.14746. Epub 2020 Feb 26.
Acquired hemophilia A (AHA) is caused by autoantibodies against factor (F)VIII, and is characterized by severe, spontaneous bleeding, which can be life-threatening. Emicizumab, an anti-FIXa/FX bispecific antibody, significantly reduces bleeding events in congenital hemophilia A (HA) with and without inhibitors. The known pathophysiological mechanisms and current preclinical data in HA suggest that emicizumab could provide effective treatment for AHA, but the coagulation activities of emicizumab in these patients remain unknown.
To evaluate the coagulant effects of emicizumab in plasma from AHA patients.
Tissue factor-triggered thrombin generation assays using normal plasma preincubated with anti-FVIII monoclonal antibodies recognizing different epitopes demonstrated that 20 µg/mL emicizumab recovered the depressed peak levels of thrombin generation to 46% to 72%. Further studies were devised, therefore, to simulate the clinical course in AHA patients, including during the acute phase for severe bleeding requiring FVIII-bypassing therapy, and during the subacute/chronic phase with less bleeding. Various concentrations of emicizumab were used to represent the potential changes in plasma levels based on the half-life of the antibody (~30 days). The ex vivo addition of emicizumab to plasma samples from AHA patients (n = 16) increased peak thrombin in all cases, irrespective of the inhibitor epitope specificity. Thrombin generation at 20 and 100 µg/mL emicizumab was restored to (median) 43.9% and 92.2%, respectively. Differences were evident in some cases, however, and recovery rates appeared likely to be greater in patients with type 2 inhibitor than those with type 1.
Emicizumab improved ex vivo coagulation potential in plasma from AHA patients.
获得性血友病A（AHA）由抗凝血因子（F）VIII自身抗体引起，其特征为严重的自发性出血，可危及生命。艾美赛珠单抗是一种抗FIXa/FX双特异性抗体，可显著减少先天性血友病A（HA）患者（无论有无抑制剂）的出血事件。HA中已知的病理生理机制和当前临床前数据表明，艾美赛珠单抗可为AHA提供有效治疗，但该药物在这些患者中的凝血活性仍不清楚。
评估艾美赛珠单抗对AHA患者血浆的凝血作用。
使用与识别不同表位的抗FVIII单克隆抗体预孵育的正常血浆进行组织因子触发的凝血酶生成试验，结果表明，20μg/mL艾美赛珠单抗可将凝血酶生成的降低峰值水平恢复至46%至72%。因此，进一步开展研究以模拟AHA患者的临床病程，包括在需要FVIII旁路治疗的严重出血急性期，以及出血较少的亚急性/慢性期。基于抗体的半衰期（约30天），使用不同浓度的艾美赛珠单抗来代表血浆水平的潜在变化。对16例AHA患者的血浆样本进行体外添加艾美赛珠单抗处理，结果显示，无论抑制剂表位特异性如何，所有情况下峰值凝血酶均增加。20μg/mL和100μg/mL艾美赛珠单抗处理后的凝血酶生成分别恢复至（中位数）43.9%和92.2%。不过，某些情况下差异明显，2型抑制剂患者的恢复率似乎高于1型抑制剂患者。
艾美赛珠单抗可改善AHA患者血浆的体外凝血潜能。
