Hoffman M, Monroe D M
Duke University, and Durham Veterans Affairs Medical Centers, NC 27705, USA.
Semin Hematol. 2001 Oct;38(4 Suppl 12):6-9. doi: 10.1016/s0037-1963(01)90140-4.
We have developed a cell-based model of hemostasis. This model suggests that the defect in hemophilia is specifically a failure of platelet-surface factor Xa (FXa) generation, leading to a failure of platelet surface thrombin generation. Activation of FX by FVIIa/tissue factor (TF) does not compensate for a lack of FXa activation on the platelet surface by the FVIIIa/FIXa complex. This is because plasma protease inhibitors prevent FXa from moving through the fluid phase from the TF-bearing cell to the platelet surface. We have previously proposed a platelet-dependent mechanism of action for high-dose factor VIIa (FVIIa; Novoseven, Novo Nordisk, Copenhagen, Denmark). Our data suggest that, when present at high levels, FVIIa binds to activated platelets and activates small amounts of FX independent of TF. This platelet-surface FXa can partially restore platelet-surface thrombin generation in hemophilia. Recently, van't Veer and colleagues reported results from an in vitro model in which coagulation reactions were initiated by relipidated TF. The authors concluded that high-dose FVIIa may exert a hemostatic effect in hemophilia by overcoming inhibition of FVIIa/TF activity by zymogen FVII. By contrast, we found that plasma levels of FVII did not slow thrombin generation in a model system initiated with cell-associated TF. This discrepancy highlights the potential differences between the studies of the coagulation reactions assembled on living cells compared to phospholipid vesicles. Our data suggest that in a cellular system high-dose FVIIa acts primarily by enhancing the rate of thrombin generation on platelet surfaces and not by overcoming inhibition by zymogen FVII of TF-dependent activation of FX.
我们开发了一种基于细胞的止血模型。该模型表明，血友病的缺陷具体表现为血小板表面因子Xa（FXa）生成失败，进而导致血小板表面凝血酶生成失败。FVIIa/组织因子（TF）对FX的激活并不能弥补FVIIIa/FIXa复合物在血小板表面激活FXa的不足。这是因为血浆蛋白酶抑制剂会阻止FXa从含TF的细胞通过液相转移至血小板表面。我们之前曾提出高剂量因子VIIa（FVIIa；诺其，诺和诺德公司，丹麦哥本哈根）的血小板依赖性作用机制。我们的数据表明，当FVIIa水平较高时，它会与活化的血小板结合，并独立于TF激活少量的FX。这种血小板表面的FXa可部分恢复血友病患者血小板表面凝血酶的生成。最近，范特·维尔及其同事报道了一个体外模型的结果，该模型中通过重新添加脂质的TF启动凝血反应。作者得出结论，高剂量FVIIa可能通过克服FVII酶原对FVIIa/TF活性的抑制作用，从而在血友病中发挥止血作用。相比之下，我们发现在以细胞相关TF启动的模型系统中，FVII的血浆水平并不会减缓凝血酶的生成。这种差异凸显了在活细胞上组装的凝血反应研究与磷脂囊泡研究之间的潜在差异。我们的数据表明，在细胞系统中，高剂量FVIIa主要通过提高血小板表面凝血酶的生成速率发挥作用，而不是通过克服FVII酶原对TF依赖性FX激活的抑制作用。
