Himber J, Kirchhofer D, Riederer M, Tschopp T B, Steiner B, Roux S P
F. Hoffmann-La Roche Ltd, Pharma Division, Preclinical Research Basel, Switzerland.
Thromb Haemost. 1997 Sep;78(3):1142-9.
Inhibition of the tissue factor/factor VIIa (TF/F.VIIa) complex attenuates thrombosis in different animal models of arterial thrombosis. However, it remains unclear to what extent the antithrombotic effects are associated with changes in hemostatic functions and how this compares with inhibition of thrombin, an enzyme acting at a later stage in the coagulation cascade. The antithrombotic and the antihemostatic effects of a monoclonal anti-TF antibody (AP-1) were compared in a model of arterial thrombosis to those of a direct thrombin inhibitor (napsagatran) and heparin. In anesthetized rabbits transient arterial thrombi were induced by mechanical damage to the subendothelium of a moderately stenosed carotid artery. Recurrent formation and dislodgement of thrombi resulted in cyclic flow variations (CFVs) which were monitored over 2 hours. Rabbits received intravenously either a placebo (control), a monoclonal anti-rabbit TF antibody (AP-1, 0.05 mg/kg as an i.v. bolus repeated every 15 min, a specific low molecular weight thrombin inhibitor (napsagatran, 3 microg/kg/min) or heparin (3 and 13 microg/kg/min). The effect of the inhibitors on the hemostatic system was studied in a separate set of rabbits by measuring template bleeding times (BT) in the ear arterioles, marginal ear vein and the nail cuticle of the foreleg. AP-1 and napsagatran showed a similar antithrombotic activity (78% and 80% abolition of the CFVs, respectively), whereas either low or high dose heparin was poorly effective (43% and 40% inhibition of CFVs, respectively). At these antithrombotic doses and even at 4-fold higher dosage, AP-1 did not significantly alter the BT, whereas napsagatran and heparin prolonged the ear vessels and cuticle BT in a dose-dependent manner. These results suggest that in contrast to direct thrombin inhibition, the blockade of the TF/F. VIIa function did not result in a concomitant prolongation of the bleeding time. Thus, dissociation of antithrombotic and antihemostatic effects indicates that inhibition of the coagulation system at its initial stage represents a promising approach for the development of new anticoagulants.
抑制组织因子/因子VIIa（TF/F.VIIa）复合物可减轻不同动脉血栓形成动物模型中的血栓形成。然而，尚不清楚抗血栓作用在多大程度上与止血功能的变化相关，以及这与抑制凝血酶（一种在凝血级联反应后期起作用的酶）相比如何。在动脉血栓形成模型中，将单克隆抗TF抗体（AP-1）的抗血栓和抗止血作用与直接凝血酶抑制剂（那沙加群）和肝素的作用进行了比较。在麻醉的兔中，通过对中度狭窄的颈动脉内膜下进行机械损伤诱导短暂性动脉血栓形成。血栓的反复形成和脱落导致周期性血流变化（CFV），对其进行2小时的监测。兔静脉内给予安慰剂（对照）、单克隆抗兔TF抗体（AP-1，0.05mg/kg静脉推注，每15分钟重复一次）、特异性低分子量凝血酶抑制剂（那沙加群，3μg/kg/min）或肝素（3和13μg/kg/min）。通过测量耳小动脉、耳缘静脉和前肢甲襞的模板出血时间（BT），在另一组兔中研究抑制剂对止血系统的作用。AP-1和那沙加群显示出相似的抗血栓活性（分别消除78%和80%的CFV），而低剂量或高剂量肝素的效果较差（分别抑制43%和40%的CFV）。在这些抗血栓剂量下，甚至在4倍更高剂量时，AP-1并未显著改变BT，而那沙加群和肝素以剂量依赖的方式延长耳血管和甲襞BT。这些结果表明，与直接抑制凝血酶相反，阻断TF/F.VIIa功能并未导致出血时间同时延长。因此，抗血栓和抗止血作用的分离表明，在凝血系统的初始阶段进行抑制是开发新型抗凝剂的一种有前景的方法。
