Dose-dependent thrombus resolution due to oral plaminogen activator inhibitor (PAI)-I inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis

This study aimed to evaluate a small-molecule PAI-I inhibitor (PAI-039; tiplaxtinin) in a rodent stenosis model of venous thrombosis in a two-phase experiment. Phase I 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 I animals (n = 24) receiving low-dose (LD; 1 mg/kg oral gavage) PAI-I inhibitor demonstrated a 52% decrease in thrombus weight (TW) versus controls (p < 0.05) with significant reductions in active plasma PAI-I, 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 and TCT) were significantly different in LOV compared to PAI-I 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 in TW 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.