INTRODUCTION: Pharmacological treatment of deep vein thrombosis (DVT) in the future may target inhibitors of specific procoagulant proteins. This study used a non-human primate model to test the effect of PHA-798, a specific inhibitor of the tissue factor/Factor VIIa complex (TF/VIIa), on venous thrombus formation. MATERIALS AND METHODS: PHA inhibits the TF/VIIa complex with an IC(50) of 13.5 nM (K(i) 9 nM) and is more than 2000-fold selective for the TF/VIIa complex with respect to IC(50)s for factor Xa and thrombin. In the model, a thrombogenic surface was introduced into the vena cava of a primate, and the amount of thrombus accumulated after 30 min was determined. RESULTS: PHA-798 reduced thrombus formation on the thrombogenic surface in a dose-dependent manner (56+/-1.9% and 85+/-0.3% inhibition with 100 and 200 microg/kg/min PHA-798, respectively) indicating that the model is sensitive to TF/VIIa inhibition. Treatment with 1 mg/kg intravenous (IV) acetyl salicylic acid (ASA) resulted in only a slight (4-12%), non-significant inhibition of thrombus formation. However, the combination of 100 microg/kg/min PHA-798 and 1 mg/kg ASA resulted in an 89% inhibition of thrombus formation. Additionally, while ASA alone increased bleeding time (BT) from 3.3 min at baseline to 4.6 min following treatment, addition of PHA-798 (100 microg/kg/min) to ASA did not significantly increase the BT further (4.7 min). CONCLUSIONS: The results of this study indicate that inhibition of TF/VIIa may be safe and effective for the prevention of the proprogation of venous thrombosis and that the combination of ASA and PHA may provide increased efficacy with little change in safety.
INTRODUCTION: Pharmacological treatment of deep vein thrombosis (DVT) in the future may target inhibitors of specific procoagulant proteins. This study used a non-human primate model to test the effect of PHA-798, a specific inhibitor of the tissue factor/Factor VIIa complex (TF/VIIa), on venous thrombus formation. MATERIALS AND METHODS: PHA inhibits the TF/VIIa complex with an IC(50) of 13.5 nM (K(i) 9 nM) and is more than 2000-fold selective for the TF/VIIa complex with respect to IC(50)s for factor Xa and thrombin. In the model, a thrombogenic surface was introduced into the vena cava of a primate, and the amount of thrombus accumulated after 30 min was determined. RESULTS: PHA-798 reduced thrombus formation on the thrombogenic surface in a dose-dependent manner (56+/-1.9% and 85+/-0.3% inhibition with 100 and 200 microg/kg/min PHA-798, respectively) indicating that the model is sensitive to TF/VIIa inhibition. Treatment with 1 mg/kg intravenous (IV) acetyl salicylic acid (ASA) resulted in only a slight (4-12%), non-significant inhibition of thrombus formation. However, the combination of 100 microg/kg/min PHA-798 and 1 mg/kg ASA resulted in an 89% inhibition of thrombus formation. Additionally, while ASA alone increased bleeding time (BT) from 3.3 min at baseline to 4.6 min following treatment, addition of PHA-798 (100 microg/kg/min) to ASA did not significantly increase the BT further (4.7 min). CONCLUSIONS: The results of this study indicate that inhibition of TF/VIIa may be safe and effective for the prevention of the proprogation of venous thrombosis and that the combination of ASA and PHA may provide increased efficacy with little change in safety.
Authors: Xiaojun Zhang; Wen Jiang; Swanee Jacutin-Porte; Peter W Glunz; Yan Zou; Xuhong Cheng; Alexandra H Nirschl; Nicholas R Wurtz; Joseph M Luettgen; Alan R Rendina; Gang Luo; Timothy M Harper; Anzhi Wei; Rushith Anumula; Daniel L Cheney; Robert M Knabb; Pancras C Wong; Ruth R Wexler; E Scott Priestley Journal: ACS Med Chem Lett Date: 2013-12-26 Impact factor: 4.345
Authors: Jeremy M Richter; Daniel L Cheney; J Alex Bates; Anzhi Wei; Joseph M Luettgen; Alan R Rendina; Timothy M Harper; Rangaraj Narayanan; Pancras C Wong; Dietmar Seiffert; Ruth R Wexler; E Scott Priestley Journal: ACS Med Chem Lett Date: 2016-11-01 Impact factor: 4.345