Golino P, Ragni M, Cirillo P, D'Andrea D, Scognamiglio A, Ravera A, Buono C, Ezban M, Corcione N, Vigorito F, Condorelli M, Chiariello M
Department of Internal Medicine, 2nd School of Medicine, University of Naples, Italy.
Circ Res. 1998;82(1):39-46. doi: 10.1161/01.res.82.1.39.
The extrinsic coagulation pathway is activated when circulating factor VII (FVII) gains access to tissue factor (TF) exposed as a consequence of vascular injury. Increasing evidence indicates that this TF-dependent activation of the coagulation plays an important role in the pathophysiology of intravascular thrombus formation. In the present study, we tested the effects of recombinant human, active site-blocked activated FVII (FVIIai) in a rabbit model of carotid artery thrombosis. Cyclic flow variations (CFVs), due to recurrent thrombus formation, were obtained in stenotic rabbit carotid arteries with endothelial injury. Carotid blood flow velocity was measured by a Doppler flow probe. After 30 minutes of CFVs, the animals received FVIIai (100 microg x kg(-1) x min(-1) intracarotid infusion for 10 minutes, n=9). If CFVs were abolished, animals were followed for 30 additional minutes, after which recombinant human activated FVII (FVIIa) was infused into the carotid artery (100 microg x kg(-1) x min(-1) for 10 minutes) to determine whether FVIIai could be displaced from TF by FVIIa, thus restoring CFVs. To establish the duration of action of FVIIai, an additional group of animals received FVIIai at the same dose as above, and after CFVs were inhibited, they were followed until CFVs were restored or for up to 6 hours. To determine whether CFVs could be restored by epinephrine after their abolition with FVIIai, increasing doses of epinephrine were administered to a third group of 6 animals. FVIIai abolished CFVs in 8 of 9 rabbits (P<.01). This effect was reversible, as FVIIa administration restored CFVs in all animals. Prothrombin times and activated partial thromboplastin times did not change significantly throughout the study. One single 10-minute infusion exerted complete antithrombotic effects for at least 6 hours, despite the fact that at this time point, plasma FVIIai levels were well below threshold concentrations. Epinephrine restored CFVs in 3 of 6 animals in which CFVs were inhibited by FVIIai. FVIIai exerts potent antithrombotic effects in this model; these effects were prolonged even after FVIIai was almost completely cleared from the circulation, probably as a result of the tight binding of FVIIai to TF. Thus, FVIIai might represent an antithrombotic substance of potential interest.
当循环中的凝血因子 VII（FVII）接触到因血管损伤而暴露的组织因子（TF）时，外源性凝血途径被激活。越来越多的证据表明，这种 TF 依赖性凝血激活在血管内血栓形成的病理生理学中起重要作用。在本研究中，我们在兔颈动脉血栓形成模型中测试了重组人活性位点阻断的活化 FVII（FVIIai）的作用。通过在有内皮损伤的狭窄兔颈动脉中反复形成血栓，获得了周期性血流变化（CFV）。用多普勒血流探头测量颈动脉血流速度。在 CFV 出现 30 分钟后，动物接受 FVIIai（100μg·kg⁻¹·min⁻¹ 颈动脉内输注 10 分钟，n = 9）。如果 CFV 消失，动物再观察 30 分钟，之后将重组人活化 FVII（FVIIa）注入颈动脉（100μg·kg⁻¹·min⁻¹ 持续 10 分钟），以确定 FVIIa 是否能将 FVIIai 从 TF 上置换下来，从而恢复 CFV。为确定 FVIIai 的作用持续时间，另一组动物接受与上述相同剂量的 FVIIai，在 CFV 被抑制后，观察直到 CFV 恢复或长达 6 小时。为确定在用 FVIIai 消除 CFV 后肾上腺素是否能恢复 CFV，给第三组 6 只动物给予递增剂量的肾上腺素。FVIIai 使 9 只兔中的 8 只 CFV 消失（P<0.01）。这种作用是可逆的，因为给予 FVIIa 后所有动物的 CFV 均恢复。在整个研究过程中，凝血酶原时间和活化部分凝血活酶时间没有显著变化。尽管在该时间点血浆 FVIIai 水平远低于阈值浓度，但单次 10 分钟输注至少 6 小时都发挥了完全的抗血栓作用。肾上腺素使 6 只被 FVIIai 抑制 CFV 的动物中的 3 只恢复了 CFV。FVIIai 在该模型中发挥强大的抗血栓作用；即使 FVIIai 几乎完全从循环中清除后，这些作用仍持续存在，这可能是由于 FVIIai 与 TF 紧密结合的结果。因此，FVIIai 可能是一种具有潜在意义的抗血栓物质。
