Department of Pediatrics, Nara Medical University, Kashihara, Japan.
Sysmex Corporation, Kobe, Japan.
Haemophilia. 2020 May;26(3):e97-e105. doi: 10.1111/hae.13961. Epub 2020 Mar 11.
Emicizumab is an antifactor (F)IXa/FX bispecific antibody, mimicking FVIIIa cofactor function. Emi prophylaxis effectively reduces bleeding events in patients with haemophilia A. The physical properties of emicizumab-induced fibrin clots remain to be investigated, however.
We have investigated the stability and structure of emicizumab-induced fibrin clots.
Coagulation was initiated by activated partial thromboplastin time (aPTT) trigger and prothrombin time (PT)/aPTT-mixed trigger in FVIII-deficient plasma with various concentrations of emicizumab or recombinant FVIII. The turbidity and stability of fibrin clots were assessed by clot waveform and clot-fibrinolysis waveform analyses, respectively. The resulting fibrin was analysed by scanning electron microscopy (SEM).
Using an aPTT trigger, the turbidity was decreased and the fibrinolysis times were prolonged in the presence of emicizumab dose-dependently. Scanning electron microscopy imaging demonstrated that emicizumab improved the structure of fibrin network with thinner fibres than in its absence. Although emicizumab shortened the aPTT dramatically, the nature of emicizumab-induced fibrin clots did not reflect the hypercoagulable state. Similarly, using a PT/aPTT-mixed trigger that could evaluate potential emicizumab activity, emicizumab improved the stability and structure of fibrin clot in a series of experiments. In this circumstance, fibrin clot properties with emicizumab at 50 and 100 µg/mL appeared to be comparable to those with FVIII at ~12 and ~24-32 IU/dL, respectively.
Emicizumab effectively improved fibrin clot stability and structure in FVIII-deficient plasma, and the physical properties of emicizumab-induced fibrin clots were similar to those with FVIII.
依库珠单抗是一种抗因子 (F)IXa/FX 双特异性抗体，模拟 FVIIIa 辅助因子功能。依库珠单抗预防治疗可有效减少血友病 A 患者的出血事件。然而，依库珠单抗诱导的纤维蛋白凝块的物理性质仍有待研究。
我们研究了依库珠单抗诱导的纤维蛋白凝块的稳定性和结构。
在缺乏 FVIII 的血浆中，使用活化部分凝血活酶时间 (aPTT) 触发和凝血酶原时间 (PT)/aPTT 混合触发，用不同浓度的依库珠单抗或重组 FVIII 启动凝血。通过凝块浊度和凝块纤维蛋白溶解波形分析分别评估纤维蛋白凝块的浊度和稳定性。通过扫描电子显微镜 (SEM) 分析所得纤维蛋白。
使用 aPTT 触发时，依库珠单抗剂量依赖性地降低浊度并延长纤维蛋白溶解时间。扫描电子显微镜成像显示，依库珠单抗改善了纤维蛋白网络的结构，纤维比没有依库珠单抗时更细。尽管依库珠单抗显著缩短 aPTT，但依库珠单抗诱导的纤维蛋白凝块的性质并不反映高凝状态。同样，使用可评估潜在依库珠单抗活性的 PT/aPTT 混合触发，依库珠单抗在一系列实验中改善了纤维蛋白凝块的稳定性和结构。在这种情况下，依库珠单抗在 50 和 100 μg/mL 时的纤维蛋白凝块特性似乎与 FVIII 在 12 左右和 24-32 IU/dL 左右时的特性相当。
依库珠单抗可有效改善缺乏 FVIII 的血浆中的纤维蛋白凝块稳定性和结构，并且依库珠单抗诱导的纤维蛋白凝块的物理性质与 FVIII 相似。
