Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy.
Section of Internal and Cardiovascular Medicine, Department of Medicine, University of Perugia, Perugia, Italy.
Haemophilia. 2020 Jul;26(4):e151-e160. doi: 10.1111/hae.14008. Epub 2020 Apr 23.
Plasma-derived FVIII/VWF complex was reported to be less sensitive to inhibitors than FVIII preparations devoid of VWF.
To compare the efficacy of FVIII/VWF complex (Fanhdi) and five different VWF-free FVIII preparations in restoring thrombin generation and activation of thrombin-activatable fibrinolysis inhibitor (TAFI) in haemophilic plasma, with and without inhibitor, and in cell-based models.
Experiments were performed in haemophilic plasma supplemented with inhibitory IgG or in plasma samples obtained from haemophilia A patients without (n = 11) and with inhibitor (n = 12). Thrombin generation was evaluated by calibrated automated thrombography (CAT) under standard conditions, in the presence of activated protein C (APC) or thrombomodulin (TM), and in cell-based models including endothelial cells, either alone or in combination with platelets or tissue factor-expressing blood mononuclear cells. The kinetics of TAFI activation was determined by a two-stage functional assay in the absence and in the presence of APC.
In haemophilic plasma without inhibitor, Fanhdi enhanced thrombin generation and TAFI activation as well as recombinant (2nd-4th generation) and plasma-derived FVIII preparations devoid of VWF. On the contrary, in plasma with inhibitor, Fanhdi displayed a greater ability to restore thrombin generation and TAFI activation under all tested conditions. Notably, in cell-based models including endothelial cells, Fanhdi proved more efficient than all other preparations in improving thrombin generation even in the absence of inhibitor.
The greater pro-haemostatic activity of FVIII/VWF complex, either in haemophilic plasma with inhibitor or in the presence of endothelial cells, may offer therapeutic advantages.
与不含 VWF 的 FVIII 制剂相比，血浆来源的 FVIII/VWF 复合物对抑制剂的敏感性较低。
比较 FVIII/VWF 复合物（Fanhdi）和五种不同的无 VWF 的 FVIII 制剂在有或无抑制剂的情况下，在血友病血浆中和细胞模型中恢复凝血酶生成和激活凝血酶激活的纤溶抑制物（TAFI）的功效。
在补充有抑制性 IgG 的血友病血浆或从无抑制剂（n=11）和有抑制剂（n=12）的血友病 A 患者的血浆样本中进行实验。在标准条件下，通过校准自动血栓形成分析（CAT）评估凝血酶生成，同时存在激活蛋白 C（APC）或血栓调节蛋白（TM），并在包括内皮细胞的细胞模型中进行，这些模型单独或与血小板或表达组织因子的血液单核细胞组合。通过无 APC 和有 APC 的两阶段功能测定来确定 TAFI 激活的动力学。
在无抑制剂的血友病血浆中，Fanhdi 增强了凝血酶生成和 TAFI 激活，以及无 VWF 的重组（第 2-4 代）和血浆衍生的 FVIII 制剂。相反，在有抑制剂的血浆中，Fanhdi 在所有测试条件下都显示出更强的恢复凝血酶生成和 TAFI 激活的能力。值得注意的是，在包括内皮细胞的细胞模型中，Fanhdi 比所有其他制剂在改善凝血酶生成方面更有效，即使在没有抑制剂的情况下也是如此。
FVIII/VWF 复合物在有抑制剂的血友病血浆或存在内皮细胞的情况下，其更强的促止血活性可能提供治疗优势。
