Department of Pediatrics, Nara Medical University, Kashihara, Nara, Japan.
Research Division, Chugai Pharmaceutical Co., Gotemba, Shizuoka, Japan.
Haemophilia. 2022 Sep;28(5):694-701. doi: 10.1111/hae.14581. Epub 2022 Apr 27.
Type 1 and type 3 von Willebrand disease (VWD) are caused by partial and complete, quantitative deficiency of von Willebrand factor (VWF), respectively, and factor (F)VIII/VWF complex concentrates are used for haemostatic treatment. Emicizumab, mimics activated FVIII, reduces bleeding in haemophilia A patients. The effects of emicizumab on haemostasis in both types of VWD remain to be fully established, however.
To examine the effects of emicizumab on thrombogenesis in type 1 and type 3 VWD.
PATIENTS/METHODS: Perfusion chamber experiments under high shear conditions (2500 s ) combined with immunostaining were performed using whole blood samples from patients with type 1 (VWF:Ag 25 U/dl) and type 3 VWD (<1.0 U/dl).
The addition of FVIII (1 U/ml) to type 1 blood did not affect thrombus formation, whilst supplementation with VWF (1.6 U/ml) or FVIII/VWF (1 U/ml/1.6 U/ml) enhanced thrombogenesis to a similar extent. FVIII/VWF promoted thrombus formation significantly more than VWF alone, however, in type 3 blood. Emicizumab (100 μg/ml) augmented thrombus formation in type 3 blood compared to FVIII, and this potency seemed to be somewhat greater than that of VWF. Surface coverage of formed thrombus in type 3 VWD was less than that in type 1 VWD, but thrombus height was comparable in both. The addition of emicizumab to type 3 blood enhanced thrombin generation and fibrin formation compared to control IgG.
Emicizumab promoted mechanisms of thrombus formation in vitro in type 3 and type 1 VWD, suggesting the possibility of alternative therapeutic protocols in these patients.
1 型和 3 型血管性血友病（VWD）分别由血管性血友病因子（VWF）部分和完全、定量缺乏引起，因子（F）VIII/VWF 复合物浓缩物用于止血治疗。依库珠单抗模拟激活的 FVIII，减少血友病 A 患者的出血。然而，依库珠单抗对 1 型和 3 型 VWD 的止血作用仍有待充分确立。
研究依库珠单抗对 1 型和 3 型 VWD 血栓形成的影响。
患者/方法：使用来自 1 型（VWF：Ag 25 U/dl）和 3 型 VWD（<1.0 U/dl）患者的全血样本，在高剪切条件（2500 s）下进行灌注室实验，并结合免疫染色。
向 1 型血液中添加 FVIII（1 U/ml）不会影响血栓形成，而补充 VWF（1.6 U/ml）或 FVIII/VWF（1 U/ml/1.6 U/ml）则以相似的程度增强血栓形成。然而，在 3 型血液中，FVIII/VWF 促进血栓形成的作用明显大于 VWF 单独使用。与 FVIII 相比，依库珠单抗（100 μg/ml）增强了 3 型血液中的血栓形成，而且这种效力似乎比 VWF 略大。3 型 VWD 形成的血栓表面覆盖率小于 1 型 VWD，但血栓高度在两者之间相当。与对照 IgG 相比，向 3 型血液中添加依库珠单抗增强了凝血酶生成和纤维蛋白形成。
依库珠单抗在 3 型和 1 型 VWD 中体外促进血栓形成机制，提示这些患者可能有替代治疗方案。
