Department of Pediatrics, Nara Medical University, Kashihara, Japan.
Research Division, Chugai Pharmaceutical Co, Gotemba, Japan.
Haemophilia. 2021 Mar;27(2):e194-e203. doi: 10.1111/hae.14272. Epub 2021 Feb 8.
Type 2A von Willebrand disease (VWD) is common in type-2 group caused by qualitative deficiency of von Willebrand factor (VWF). Emicizumab is a bispecific antibody that mimics activated factor VIII (FVIIIa) cofactor function, and emicizumab prophylaxis substantially reduces bleeding in patients with haemophilia A. It is unknown whether emicizumab affects thrombus formation in type 2A VWD characterized by not only low FVIII levels but also the impaired platelet adhesion and aggregation.
To examine the coagulant potential of emicizumab in type 2A VWD.
PATIENTS/METHODS: Perfusion chamber experiments combined with immunostaining were performed using whole blood from 5 patients with type 2A VWD under high shear condition (2500 s ).
The addition of FVIII to type 2A VWD whole blood did not augment thrombus formation, whilst supplementation with VWF or FVIII/VWF enhanced. FVIII appeared to contribute to thrombus height rather than surface coverage. The addition of emicizumab enhanced thrombus formation in type 2A VWD compared with FVIII, but this potency was less than the presence of VWF. The effect on thrombus formation mediated by emicizumab appeared to be more rapid than that by FVIII for non-requirement of activation step of FVIII, whilst that by FVIII showed more impact on thrombus formation at the late phase.
Emicizumab-induced enhancing effects of thrombus formation, independent on VWF, may be useful as an alternative therapy for type 2A VWD patients. These results supported a critical role for the FVIII-VWF complex facilitating thrombus formation under high shear.
2A 型血管性血友病（VWD）是由血管性血友病因子（VWF）质量缺陷引起的 2 型 VWD 中的常见类型。依库珠单抗是一种双特异性抗体，可模拟激活的因子 VIII（FVIIIa）辅因子功能，依库珠单抗预防治疗可显著减少血友病 A 患者的出血。目前尚不清楚依库珠单抗是否会影响以 FVIII 水平降低和血小板黏附及聚集受损为特征的 2A 型 VWD 中的血栓形成。
研究依库珠单抗在 2A 型 VWD 中的促凝作用。
患者/方法：在 2500s 高切变条件下，使用 5 例 2A 型 VWD 患者的全血进行灌注室实验并结合免疫染色。
向 2A 型 VWD 全血中添加 FVIII 并不能增强血栓形成，而添加 VWF 或 FVIII/VWF 则会增强。FVIII 似乎主要影响血栓高度，而不是表面覆盖。与添加 FVIII 相比，依库珠单抗可增强 2A 型 VWD 中的血栓形成，但这种作用强度不及 VWF 的作用强度。与 FVIII 相比，依库珠单抗介导的血栓形成作用似乎更快，这是因为依库珠单抗不需要 FVIII 的激活步骤，而 FVIII 在后期对血栓形成的影响更大。
依库珠单抗诱导的血栓形成增强作用独立于 VWF，可能对 2A 型 VWD 患者的治疗有帮助。这些结果支持 FVIII-VWF 复合物在高切变条件下促进血栓形成的关键作用。
