FVIIa as used pharmacologically is not TF dependent in hemophilia B mice
FVIIa as used pharmacologically is not TF dependent in hemophilia B mice
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DOI：
10.1182/blood-2013-08-522987
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发表时间：
2014-03-13
期刊：
影响因子：
20.3
通讯作者：
Stafford, Darrel W.
中科院分区：
文献类型：
--
作者：
Feng, Dengmin;Whinna, Herbert;Stafford, Darrel W.
激活的凝血因子VII被批准用于治疗对凝血因子IX或FVIII产生自身抗体的血友病患者；然而，其作用机制仍存在争议。一些研究表明，FVIIa需要组织因子(TF)才能发挥作用，而高剂量要求的原因是它必须与内源性FVII竞争组织因子。其他人认为，FVIIa直接激活FX的地方与血小板结合；所需的高浓度可能是因为FVIIa对磷脂的亲和力较弱。我们通过将带有FVIIa(EGF2和催化结构域)的嵌合体(GLA和EGF1)注入血友病B鼠来解决这个问题。这个突变体没有Tf依赖的活性，因为它不能在生理浓度下功能性地结合Tf。在体内，该突变体在控制血友病B小鼠出血方面与小鼠FVIIa一样有效。我们的结果表明，药理剂量的FVIIa止血作用不依赖于Tf。
Activated factor VII is approved for treating hemophilia patients with autoantibodies to their factor IX or FVIII; however, its mechanism of action remains controversial. Some studies suggest that FVIIa requires tissue factor (TF) for function and that the reason for the high dose requirement is that it must compete with endogenous FVII for tissue factor. Others suggest that FVIIa binds platelets where it activates FX directly; the high concentration required would result from FVIIa's weak affinity for phospholipids. We address this question by infusing a chimera of mouse FIX (Gla and EGF1) with FVIIa (EGF2 and catalytic domain) into hemophilia B mice. This mutant has no TF-dependent activity because it cannot functionally bind TF at physiologically relevant concentrations. In vivo, this mutant is as effective as mouse FVIIa in controlling bleeding in hemophilia B mice. Our results suggest that the hemostatic effect of pharmacologic doses of FVIIa is TF independent.