Hedner Ulla
Department of Medicine, Malmo University Hospital, University of Lund, Malmo, Sweden.
Front Biosci (Elite Ed). 2012 Jan 1;4(4):1210-23. doi: 10.2741/e452.
Around 20 % of the patients with severe hemophilia develop inhibitory antibodies against the factor they lack. In these patients the administration of FVIII/FIX-concentrates are not hemostatically effective. Since FVIIa is not enzymatically active unless complexed with tissue factor (TF) exposed following an injury to the vessel wall, it was considered an attractive candidate for improved treatment of patients with inhibitors. Plasma-derived FVIIa was purified and shown to induce hemostasis in two hemophilia A patients with inhibitors. Later recombinant FVIIa (rFVIIa) was developed and pharmacological doses have an efficacy rate of around 90 % in serious bleedings and permit major orthopaedic surgery. These findings were a breakthrough in understanding the FVII-TF pathway in hemostasis. The initially formed FVIIa-TF complexes provide a limited amount of thrombin, activating FVIII, FV, FXI as well as platelets. On the activated platelet surface the full burst of thrombin necessary for generating a firm fibrin hemostatic plug occurs. In case of impaired thrombin generation, loose fibrin plugs easily dissolved are formed. Extra rFVIIa enhances thrombin generation and generates tight fibrin plugs.
约20%的重度血友病患者会产生针对其缺乏的凝血因子的抑制性抗体。在这些患者中，输注FVIII/FIX浓缩物无法有效止血。由于FVIIa只有在与血管壁损伤后暴露的组织因子（TF）结合形成复合物时才具有酶活性，因此它被认为是改善抑制性抗体患者治疗效果的理想选择。血浆源性FVIIa被纯化出来，并在两名患有抑制性抗体的甲型血友病患者中显示出诱导止血的作用。后来，重组FVIIa（rFVIIa）被研发出来，其药理剂量在严重出血的治疗中有效率约为90%，并可用于大型骨科手术。这些发现是在理解止血过程中FVII-TF途径方面的一个突破。最初形成的FVIIa-TF复合物会产生有限量的凝血酶，激活FVIII、FV、FXI以及血小板。在活化的血小板表面会产生生成牢固纤维蛋白止血栓所需的全部凝血酶。在凝血酶生成受损的情况下，会形成容易溶解的松散纤维蛋白栓。额外的rFVIIa可增强凝血酶生成并产生紧密的纤维蛋白栓。
