Introduction

Tissue factor (TF) and factor (F) VII, components of the extrinsic pathway of blood coagulation, are essential for hemostatic plug formation in response to injury; less clear are their roles in propagating thrombosis, as observational data in humans with congenital FVII deficiency suggests persistent thrombotic and bleeding risk even at significantly decreased FVII levels. We aimed to define the contribution of FVII to thrombus formation and hemostasis using a non-human primate model.

Methods

We treated baboons with a FVII antisense oligonucleotide (ASO) and measured platelet and fibrin deposition inside and distal to collagen- or TF-coated vascular grafts. We assessed hemostasis by measuring bleeding time (BT) and prothrombin time (PT). Enoxaparin and vehicle treatments served as controls.

Results

FVII–ASO treatment reduced FVII levels by 95% and significantly increased both the PT and BT. Lowering FVII levels did not decrease platelet deposition in collagen- or TF-coated grafts, in thrombi distal to the grafts, or fibrin content of either collagen- and TF-coated grafts. Lowering FVII levels were associated with a modest 25% reduction in platelet deposition at 60 min in the distal thrombus tail of TF-coated grafts only.

Conclusions

FVII inhibition by way of ASO is feasible yet significantly impairs hemostasis while only exhibiting antithrombotic effects when thrombosis is initiated by vessel wall surface-associated TF exposure.

中文翻译：

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评估降低非人类灵长类动物凝血因子 VII 水平的抗止血和抗血栓作用。

介绍

组织因子 (TF) 和因子 (F) VII 是凝血外在途径的组成部分，对于损伤时止血栓的形成至关重要；它们在传播血栓形成中的作用不太清楚，因为在患有先天性 FVII 缺乏症的人类中的观察数据表明，即使在 FVII 水平显着降低的情况下，仍存在持续的血栓形成和出血风险。我们旨在使用非人类灵长类动物模型确定 FVII 对血栓形成和止血的贡献。

方法

我们用 FVII 反义寡核苷酸 (ASO) 处理狒狒，并测量了胶原蛋白或 TF 涂层血管移植物内部和远端的血小板和纤维蛋白沉积。我们通过测量出血时间 (BT) 和凝血酶原时间 (PT) 来评估止血。依诺肝素和载体治疗作为对照。

结果

FVII-ASO 处理将 FVII 水平降低了 95%，并显着增加了 PT 和 BT。降低 FVII 水平不会减少胶原或 TF 涂层移植物、移植物远端血栓中的血小板沉积或胶原蛋白和 TF 涂层移植物的纤维蛋白含量。降低 FVII 水平与仅 TF 涂层移植物远端血栓尾部 60 分钟时血小板沉积适度减少 25% 相关。

结论

通过 ASO 抑制 FVII 是可行的，但会显着削弱止血作用，而仅当血管壁表面相关的 TF 暴露引发血栓形成时才表现出抗血栓形成作用。