Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
Research Division, Chugai Pharmaceutical Co., Ltd, Kamakura, Japan.
J Thromb Haemost. 2019 Jan;17(1):126-137. doi: 10.1111/jth.14334. Epub 2018 Dec 10.
Essentials Emicizumab mimics factor (F)VIIIa cofactor function, augments the intrinsic tenase activity. We assessed the emicizumab-driven hemostatic function in FXI-deficient plasmas. Emicizumab improved the coagulation potentials in severe FXI-deficient plasma. Emicizumab may provide a possibility for clinical application in patients with FXI deficiency. SUMMARY: Background Patients with factor (F)XI deficiency commonly present with markedly prolonged activated partial thromboplastin times (APTT), although bleeding phenotypes are heterogeneous. Emicizumab, a bispecific monoclonal antibody to FIX/FIXa and FX/FXa, mimics FVIIIa cofactor function on phospholipid (PL) surfaces. Antibody reactions were designed, therefore, to augment mechanisms during the propagation phase of blood coagulation. Aim To assess emicizumab-driven hemostatic function in FXI-deficient plasmas. Methods and Results Standard ellagic acid (Elg)/PL-based APTTs of different FXI-deficient plasmas (n = 13; FXI activity, < 1 IU dl ) were markedly shortened dose dependently by the presence of emicizumab. To further analyze the effects of emicizumab, clot waveform analysis (CWA) in FXI-deficient plasmas with emicizumab, triggered by tissue factor (TF)/Elg demonstrated improvements in both clot times, reflecting the initiation phase, and coagulation velocity, which represents the propagation phase. Emicizumab also enhanced the TF/Elg-triggered thrombin generation in FXI-deficient plasmas dose-dependently although the degree of enhancement varied in individual cases. Thrombin generation with either FVII-deficient plasma or FIX-deficient plasma treated with anti-FXI antibody showed little or no increase by the co-presence of emicizumab, suggesting that the accelerated thrombin generation in FXI-deficient plasmas by emicizumab should depend on the FIXa-involved coagulation propagation initially triggered by FVIIa/TF. The ex vivo addition of emicizumab to whole blood from three patients with severe FXI deficiency demonstrated modest, dose-dependent improvements in Ca -triggered thromboelastograms (NATEM mode). Conclusion Emicizumab appeared to improve coagulation function in severe FXI-deficient plasma, and might provide possibilities for clinical application in patients with FXI deficiency.
依科珠单抗模拟因子 (F)VIIIa 辅因子功能，增强内在凝血酶原酶活性。我们评估了依科珠单抗在 FXI 缺乏血浆中的止血功能。依科珠单抗改善了严重 FXI 缺乏血浆的凝血潜能。依科珠单抗可能为 FXI 缺乏症患者的临床应用提供可能性。
FXI 缺乏症患者通常表现为活化部分凝血活酶时间 (APTT) 明显延长，尽管出血表型存在异质性。依科珠单抗是一种针对 FIX/FIXa 和 FX/FXa 的双特异性单克隆抗体，在磷脂 (PL) 表面模拟 FVIIIa 辅因子功能。因此，抗体反应旨在增强血液凝固的扩展阶段的机制。目的：评估依科珠单抗在 FXI 缺乏血浆中的止血功能。
不同 FXI 缺乏血浆 (n=13; FXI 活性<1 IU dl) 的标准鞣花酸 (Elg)/PL 基础 APTT 剂量依赖性地显著缩短，依科珠单抗的存在。为了进一步分析依科珠单抗的作用，用组织因子 (TF)/Elg 触发 FXI 缺乏血浆的凝块波形分析 (CWA) 显示，在起始阶段，凝块时间和凝血速度均得到改善，凝血速度代表扩展阶段。依科珠单抗还可增强 FXI 缺乏血浆中 TF/Elg 触发的凝血酶生成，呈剂量依赖性，尽管在个别情况下增强程度不同。用抗 FXI 抗体处理的 FVII 缺乏血浆或 FIX 缺乏血浆的凝血酶生成，即使存在依科珠单抗，也很少或没有增加，表明依科珠单抗在 FXI 缺乏血浆中加速的凝血酶生成应依赖于最初由 FVIIa/TF 触发的 FIXa 参与的凝血扩展。将依科珠单抗添加到来自三名严重 FXI 缺乏症患者的全血中，在 Ca 触发的血栓弹力图 (NATEM 模式) 中显示出适度的、剂量依赖性的改善。
依科珠单抗似乎改善了严重 FXI 缺乏血浆的凝血功能，可能为 FXI 缺乏症患者的临床应用提供可能性。
