Different factor VIII neutralizing effects on anti-factor VIII inhibitor antibodies associated with epitope specificity and von Willebrand factor.
Different factor VIII neutralizing effects on anti-factor VIII inhibitor antibodies associated with epitope specificity and von Willebrand factor.
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与表位特异性和冯维勒布兰德因子相关的抗因子 VIII 抑制剂抗体的不同因子 VIII 中和作用。
DOI：
10.1111/bjh.12473
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发表时间：
2013
影响因子：
6.5
通讯作者：
Shima M.
中科院分区：
文献类型：
--
作者：
Yada K;Nogami K;Shima M.
基于因子(F)VIII替代的抑制剂中和疗法用于低反应型血友病A患者的止血治疗，但效果似乎取决于抑制剂的各种性质。我们通过将FVIII(1单位/毫升)与含有不同表位的抗FVIII同种异体抗体(2·5贝塞斯达单位/毫升)混合后在计时反应中评估整体凝血功能来研究这一性质。凝血酶生成分析显示，抗C2 1型抑制剂对凝血酶峰值和平均峰值凝血酶速度的抑制程度明显大于抗A2 1型和抗C2 2型(分别为2~6倍和10~20倍)。在FVIII-von Willebrand因子(VWF)复合体存在下，抗C2-1介导的凝血酶生成减少20-40%，反映了VWF的保护作用。但对抗A2-1型抗体活性影响不大，对抗C2-2型抗体活性有较强的促进作用。2·5倍，相对于FVIII。血栓波形分析也显示出类似的模式。具有明确特征的抗FVIII单抗表现出与多克隆抑制剂相似的反应。总之，依赖于表位的FVIII(-VWF)的中和作用可能具有重要的治疗意义，确定抑制剂的性质以预测输注FVIII在中和治疗中的效果可能是重要的。
Inhibitor neutralization therapy based on factor (F)VIII replacement is used for haemostatic treatment in haemophilia A patients with inhibitors on low responder, but effects appear to depend on various properties of inhibitors. We investigated this nature by evaluating the global coagulation function in timed‐reactions after mixing FVIII (1 U/ml) with anti‐FVIII alloantibodies containing distinct epitopes (2·5 Bethesda units/ml). Thrombin generation assays showed that peak thrombin and mean velocity to peak thrombin were depressed by anti‐C2 type 1 inhibitors to significantly greater extents than by anti‐A2 type 1 and anti‐C2 type 2 (2‐ to 6‐fold and 10‐ to 20‐fold, respectively). In the presence of FVIII‐von Willebrand Factor (VWF) complex, the anti‐C2 type 1‐mediated decreased thrombin generation was reduced by 20–40%, reflecting the protective function of VWF. However, the activities of anti‐A2 type 1 were little affected, and that of anti‐C2 type 2 was rather enhanced byc. 2·5‐fold, relative to FVIII. Clot waveform analysis also showed similar patterns. Anti‐FVIII monoclonal antibodies with well‐defined characteristics demonstrated similar reactions to those with polyclonal inhibitors. In conclusion, the neutralizing effects of FVIII(‐VWF) depending on epitopes could have significant therapeutic implications, and it could be important to determine inhibitor properties in order to predict the effects of infused FVIII in neutralization therapy.