Scandella Dorothea
Holland Laboratory, American Red Cross, Rockville, Maryland.
Semin Thromb Hemost. 2002 Jun;28(3):291-6. doi: 10.1055/s-2002-32665.
Treatment of individuals with severe hemophilia A by plasma-derived or recombinant factor VIII leads to the production of anti-factor VIII antibodies in approximately 30% of such patients. Because some of these antibodies inactivate factor VIII, they are considered a major factor in preventing optimal therapeutic treatment. Factor VIII is a cofactor that must bind to factors IX and X and phospholipids in order for normal blood coagulation to occur. The inhibition of factor VIII activity is due to binding by anti- factor VIII antibodies in the patient plasma to the same sites required for factors IX and X and phospholipid binding. Previously, inhibitor epitopes were localized to the A2, A3, and C2 domains and to a region of acidic amino acids between the A1 and A2 domains. Inhibitor binding to these domains prevented factor VIII binding to factor IXa (A2, A3), factor Xa (C2), and phospholipids (C2), and binding to the acidic region interfered with factor X binding. Antibody binding to a minor C2 domain epitope slowed activated factor VIII release from von Willebrand factor (vWF) and interfered with factor Xa binding to factor VIII.
通过血浆源性或重组凝血因子 VIII 治疗重度甲型血友病患者，约 30% 的此类患者会产生抗凝血因子 VIII 抗体。由于其中一些抗体可使凝血因子 VIII 失活，它们被视为妨碍实现最佳治疗效果的主要因素。凝血因子 VIII 是一种辅助因子，必须与凝血因子 IX 和 X 以及磷脂结合，正常的血液凝固过程才能发生。凝血因子 VIII 活性受到抑制是因为患者血浆中的抗凝血因子 VIII 抗体与凝血因子 IX 和 X 以及磷脂结合所需的相同位点结合。此前，抑制剂表位定位于 A2、A3 和 C2 结构域以及 A1 和 A2 结构域之间的酸性氨基酸区域。抑制剂与这些结构域的结合阻止了凝血因子 VIII 与凝血因子 IXa（A2、A3）、凝血因子 Xa（C2）和磷脂（C2）的结合，而与酸性区域的结合则干扰了凝血因子 X 的结合。抗体与一个较小的 C2 结构域表位的结合减缓了活化凝血因子 VIII 从血管性血友病因子（vWF）的释放，并干扰了凝血因子 Xa 与凝血因子 VIII 的结合。
