Monroe D M, Hoffman M, Oliver J A, Roberts H R
Center for Thrombosis and Hemostasis, and Hematology/Oncology, Department of Medicine, University of North Carolina, Chapel Hill, USA.
Br J Haematol. 1997 Dec;99(3):542-7. doi: 10.1046/j.1365-2141.1997.4463256.x.
High-dose recombinant factor VIIa has been successfully used as therapy for haemophiliacs with inhibitors. The mechanism by which high-dose factor VIIa supports haemostasis is the subject of some controversy. Postulating a mechanism in which activity is dependent on tissue factor at the site of injury explains the localization of activity but not the requirement for high doses. Postulating a mechanism in which factor VIIa acts on available lipid independently of tissue factor explains the requirement for high doses but not the lack of systemic procoagulant activity. We report that factor VIIa bound weakly to activated platelets (Kd approximately 90 nM). This factor VIIa was functionally active and could initiate thrombin generation in the presence of plasma concentrations of prothrombin, factor X, factor V, antithrombin III and tissue factor pathway inhibitor. The activity was not dependent on tissue factor. The concentration of factor VIIa required for detectable thrombin generation agreed well with the lowest concentration of factor VIIa required for efficacy in patients. High-dose factor VIIa may function on the activated platelets that form the initial haemostatic plug in haemophilic patients. These observations are in agreement with clinical trials which have shown that high-dose factor VIIa was haemostatically effective without causing systemic activation of coagulation.
高剂量重组凝血因子VIIa已成功用于治疗有抑制剂的血友病患者。高剂量凝血因子VIIa支持止血的机制存在一些争议。假设一种机制，即活性依赖于损伤部位的组织因子，这解释了活性的定位，但无法解释高剂量的必要性。假设一种机制，即凝血因子VIIa独立于组织因子作用于可用脂质，这解释了高剂量的必要性，但无法解释缺乏全身促凝血活性的原因。我们报告凝血因子VIIa与活化血小板的结合较弱（解离常数约为90 nM）。这种凝血因子VIIa具有功能活性，在血浆浓度的凝血酶原、因子X、因子V、抗凝血酶III和组织因子途径抑制剂存在的情况下能够启动凝血酶生成。该活性不依赖于组织因子。可检测到凝血酶生成所需的凝血因子VIIa浓度与患者有效所需的最低凝血因子VIIa浓度非常吻合。高剂量凝血因子VIIa可能作用于血友病患者形成初始止血栓的活化血小板上。这些观察结果与临床试验一致，临床试验表明高剂量凝血因子VIIa在止血方面有效且不会引起全身凝血激活。
