Hoffman M, Monroe D M, Roberts H R
Department of Pathology, Durham Veterans Affairs Medical Center, NC 27705, USA.
Blood Coagul Fibrinolysis. 1998 Mar;9 Suppl 1:S61-5.
High levels of recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) have been found to be effective in providing haemostasis in haemophiliacs and in normal individuals with acquired inhibitors to factor VIII (FVIII) or FIX. However, the mechanism of this therapeutic effect of FVIIa is unclear. Opinion is divided over whether high-dose FVIIa therapy works primarily by a tissue factor (TF)-dependent or -independent mechanism. Our group originally favoured a TF-dependent mechanism; however, we have recently found that, at levels comparable with those attained therapeutically, FVIIa activates enough FX on activated platelets to restore platelet surface thrombin generation. These data now lead us to favour a primarily (although not necessarily exclusively) TF-independent mechanism for the haemostatic effect of high-dose FVIIa. We believe that a platelet surface localization of FVIIa activity explains both its safety and efficacy, as well as its haemostatic effect in patients with thrombocytopenia and platelet function defects. Localization on activated platelets would tend to restrict the activity of FVIIa to sites of injury. Activation of FX on the platelet surface in haemophiliacs would provide FXa in a favourable location to escape inhibition by plasma protease inhibitors and be incorporated into platelet prothrombinase complexes. Activation of FIX and FX on platelet surfaces in thrombocytopenia would result in more thrombin generation per platelet, possibly leading to formation of a stable fibrin network even in the absence of an optimal initial platelet plug.
已发现高剂量的重组活化因子VII（rFVIIa；诺其，诺和诺德公司，丹麦 Bagsvaerd）在血友病患者以及获得性VIII因子（FVIII）或IX因子抑制物的正常个体中能有效实现止血。然而，FVIIa这种治疗作用的机制尚不清楚。对于高剂量FVIIa治疗主要是通过组织因子（TF）依赖还是非依赖机制起作用，存在不同观点。我们小组最初倾向于TF依赖机制；然而，我们最近发现，在与治疗中达到的水平相当的情况下，FVIIa能在活化血小板上激活足够的FX以恢复血小板表面凝血酶生成。这些数据现在使我们倾向于认为高剂量FVIIa的止血作用主要（尽管不一定完全）是通过TF非依赖机制。我们认为FVIIa活性在血小板表面的定位解释了其安全性和有效性，以及它在血小板减少症和血小板功能缺陷患者中的止血作用。在活化血小板上的定位倾向于将FVIIa的活性限制在损伤部位。血友病患者血小板表面FX的激活将使FXa处于有利位置，从而逃避血浆蛋白酶抑制剂的抑制并被纳入血小板凝血酶原酶复合物。血小板减少症患者血小板表面FIX和FX的激活将导致每个血小板产生更多的凝血酶，即使在没有最佳初始血小板栓的情况下也可能导致形成稳定的纤维蛋白网络。
