Administration of a small molecule tissue factor/Factor VIIa inhibitor in a non-human primate thrombosis model of venous thrombosis: effects on thrombus formation and bleeding time

• Published in: Thrombosis research Vol. 112; no. 3; pp. 167 - 174
• Main Authors: Szalony, James A, Suleymanov, Osman D, Salyers, Anita K, Panzer-Knodle, Susan G, Blom, Jason D, LaChance, Rhonda M, Case, Brenda L, Parlow, John J, South, Michael S, Wood, Rhonda S, Nicholson, Nancy S
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Ltd 2003; Elsevier Science
• Subjects: Animal models; Animals; Aspirin; Aspirin - toxicity; Biological and medical sciences; Bleeding Time; Blood and lymphatic vessels; Blood. Blood coagulation. Reticuloendothelial system; Body Weight; Cardiology. Vascular system; Cardiovascular; Disease Models, Animal; Diseases of the peripheral vessels. Diseases of the vena cava. Miscellaneous; Factor VIIa; Factor VIIa - antagonists & inhibitors; Macaca fascicularis; Male; Medical sciences; Pharmacology. Drug treatments; Platelet Aggregation Inhibitors - toxicity; Thromboplastin - antagonists & inhibitors; Thrombosis; Thrombosis - blood; Thrombosis - chemically induced; Thrombosis - physiopathology; Tissue factor; Animal models; Aspirin; aPTT; DVT; PT; Cardiovascular; Tissue factor; Thrombosis; ADP; IV; S.E.M; ASA; LMWH; ACT; BT; TF/VIIa; UFH; Factor VIIa; Prostaglandin-endoperoxide synthase; Animal model; Intravenous administration; Hemostatic; Cardiovascular disease; Thrombin; Acetylsalicylic acid; Bleeding time; Venous disease; Vascular disease; Prevention; Primates; Venous thrombosis; Salicylates; Antirheumatic agent; Vena cava; Human; Salicylic acid; Serine endopeptidases; Enzyme; Vein thrombosis; Enzyme inhibitor; Deep vein thrombosis; Antiplatelet agent; Non steroidal antiinflammatory agent; Peptidases; Vertebrata; Mammalia; Analgesic; Treatment; Antipyretic; Hydrolases; Oxidoreductases
• ISSN: 0049-3848; 1879-2472
• DOI: 10.1016/j.thromres.2003.10.017

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
50s 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 μg/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 μg/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 μg/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.