Department of Medicine, Malmo University Hospital, University of Lund, Malmo, Sweden.
Thromb Res. 2010 Apr;125 Suppl 1:S4-6. doi: 10.1016/j.thromres.2010.01.021. Epub 2010 Feb 26.
Hemophilia patients with inhibitors against FVIII/FIX present with a major challenge in the clinical practice. In the 1970s such patients were treated in association with emergency situations and essential surgery using huge amounts of FVIII/FIX concentrates often preceded by extracorporal adsorption of antibodies against FVIII/FIX. However, moderate to mild bleedings were not effectively treated. A certain hemostatic effect of activated prothrombin complex concentrates (aPCC) not exceeding 65% was reported. Unfortunately, also thromboembolic events occurred, which made them less attractive to use in inhibitor patients. In a dog model the thrombogenic effects on the coagulation system was almost completely avoided by adding antithrombin and heparin, suggesting factors like IXa, Xa or XIa to be responsible. On the other hand FVIIa is not readily inactivated by antithrombin in the circulation. Furthermore, a detailed literature review revealed very high levels of FVII in the aPCC used with some success in the treatment of hemophilia patients with inhibitors. The potential possibility to use FVIIa as a hemostatic agent was investigated by the administration of pure human FVIIa to two hemophilia patients with inhibitors. In both, a hemostatic effect was recorded. The development of recombinant FVIIa was initiated by Novo Nordisk A/S, Denmark, in June 1986 resulting in NovoSeven (rFVIIa) being licensed for use in patients with inhibitors against coagulation factors in EU in 1996. By then, a hemostatic effect of rFVIIa also in non-hemophilia patients such as patients with platelet dysfunctions or suffering from profuse, heavy bleedings initiated by extensive surgery or trauma had been demonstrated. In parallel the mechanism of action of pharmacological doses of rFVIIa was investigated resulting in a revision of the hemostatic process in stressing the compartmentalization of the process to TF-bearing cells and to thrombin activated platelets at the site of injury. The initial thrombin generation is generated by the formation of the TF-FVIIa-complex formed initially on the TF-bearing cells.
患有针对 FVIII/FIX 的抑制剂的血友病患者在临床实践中面临重大挑战。在 20 世纪 70 年代，此类患者在紧急情况下和进行重要手术时接受治疗，通常需要大量 FVIII/FIX 浓缩物，且在此之前要先进行针对 FVIII/FIX 的抗体的体外吸附。然而，中度至轻度出血并不能得到有效治疗。据报道，激活的凝血酶原复合物浓缩物（aPCC）具有不超过 65%的止血作用。不幸的是，也发生了血栓栓塞事件，这使得它们在抑制剂患者中的应用吸引力降低。在犬模型中，通过添加抗凝血酶和肝素，几乎完全避免了对凝血系统的促血栓形成作用，这表明 IXa、Xa 或 XIa 等因子可能是罪魁祸首。另一方面，在循环中，凝血酶原复合物不易被抗凝血酶灭活。此外，详细的文献回顾显示，在用于治疗具有抑制剂的血友病患者的 aPCC 中，FVII 水平非常高。通过向两名患有抑制剂的血友病患者给予纯人类 FVIIa，研究了将 FVIIa 用作止血剂的可能性。在这两名患者中，均记录到了止血作用。丹麦诺和诺德公司于 1986 年 6 月启动了重组 FVIIa 的开发，导致诺和凝（rFVIIa）于 1996 年在欧盟获得批准，可用于针对凝血因子的抑制剂的患者。到那时，rFVIIa 在非血友病患者中的止血作用也得到了证明，例如血小板功能障碍患者，或广泛手术或创伤引发大量、严重出血的患者。与此同时，还研究了药理学剂量的 rFVIIa 的作用机制，结果对止血过程进行了重新审视，强调了该过程在损伤部位向 TF 携带细胞和激活的血小板的分区化。最初的凝血酶生成是由最初在 TF 携带细胞上形成的 TF-FVIIa 复合物形成的。
