Dose-dependent thrombus resolution due to oral plasminogen activator inhibitor (PAI)-1 inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis
Sanjiv Baxi 1, David L. Crandall 3, Thomas R. Meier*,1,2, Shirley Wrobleski 1, Angela Hawley 1, Diana Farris 1, Hassan Elokdah4†, Robert Sigler 5, Robert G. Schaub**, 3, Thomas Wakefield 1, Daniel Myers 1, 2
1 Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA; 2 Unit for Laboratory Animal Medicine, University of Michigan Medical Center, Ann Arbor, Michigan, USA; 3 Cardiovascular and Metabolic Diseases Research, Wyeth Research, Cambridge, Massachussetts, USA; 4 Chemical & Screening Sciences Research, Wyeth Research, Collegeville, Pennsylvania, USA; 5 Walker Downey & Associates, Inc., Verona, Wisconsin, USA
Stenosis, Plasminogen activator inhibitors, Deep vein thrombosis, Venous thrombosis, Animal models
This study aimed to evaluate a small-molecule PAI-1 inhibitor (PAI-039; tiplaxtinin) in a rodent stenosis model of venous thrombosis in a two-phase experiment. Phase 1 determined the efficacy of tiplaxtinin against Lovenox (LOV), while phase 2 determined the dose-dependent efficacy. For both phases, drug treatment began 24 hours after surgically induced venous thrombosis and continued for four days.Phase 1 animals (n = 24) receiving low-dose (LD; 1 mg/kg oral gavage) PAI-1 inhibitor demonstrated a 52% decrease in thrombus weight (TW) versus controls (p < 0.05) with significant reductions in active plasma PAI-1, while the high-dose (HD; 10 mg/kg oral gavage) group demonstrated a 23% reduction in TW versus controls.Animals treated subcutaneously with LOV (3 mg/kg) showed a 39% decrease in TW versus controls (p < 0.05). Coagulation tests (aPTT andTCT) were significantly different in LOV compared to PAI-1 inhibitor groups. PAI-039 treatment was also associated with significantly increased return of inferior vena cava blood flow four days post-thrombosis versus controls (p < 0.05). In phase 2 (n = 30),TW was reduced from the 0.5 mg/kg to 5 mg/ kg experimental groups,with the 10 mg/kg group demonstrating a paradoxical increase. The 5 mg/kg group showed statistically significant decreases inTW versus controls after four treatment days (p < 0.05).This is the first study to demonstrate dose related effects of PAI-039 on increasing thrombus resolution and inferior vena cava blood flow without adverse effects on anti-coagulation in a rat stenosis model of venous thrombosis.