title: Dose-dependent thrombus resolution due to oral plaminogen activator inhibitor (PAI)-1 inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis.
abstract: 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 and TCT) 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 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.
authors.affiliation: Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0654, USA.
authors.forename: Sanjiv
authors.initials: S
authors.lastname: Baxi
authors.forename: David L
authors.initials: DL
authors.lastname: Crandall
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Meier
authors.forename: Shirley
authors.initials: S
authors.lastname: Wrobleski
authors.forename: Angela
authors.initials: A
authors.lastname: Hawley
authors.forename: Diana
authors.initials: D
authors.lastname: Farris
authors.forename: Hassan
authors.initials: H
authors.lastname: Elokdah
authors.forename: Robert
authors.initials: R
authors.lastname: Sigler
authors.forename: Robert G
authors.initials: RG
authors.lastname: Schaub
authors.forename: Thomas
authors.initials: T
authors.lastname: Wakefield
authors.forename: Daniel
authors.initials: D
authors.lastname: Myers
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D017984:Enoxaparin / Q000037:antagonists & inhibitors; D005355:Fibrosis; D007210:Indoleacetic Acids / Q000008:administration & dosage*; D007249:Inflammation / Q000188:drug therapy / Q000473:pathology; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000097:blood*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017539:Tunica Intima / Q000473:pathology; D014682:Vena Cava, Inferior / Q000473:pathology; D020246:Venous Thrombosis / Q000097:blood* / Q000188:drug therapy* / Q000473:pathology
chemical_list: D017984:Enoxaparin; D007210:Indoleacetic Acids; D017395:Plasminogen Activator Inhibitor 1; C488103:tiplaxtinin