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, David L. Crandall, Thomas R. Meier, Shirley Wrobleski, Angela Hawley, Diana Farris, Hassan Elokdah, Robert Sigler, Robert G. Schaub, Thomas Wakefield, Daniel D. Myers

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23 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)749-758
Number of pages10
JournalThrombosis and Haemostasis
Volume99
Issue number4
DOIs
StatePublished - Apr 1 2008

Keywords

  • Animal models
  • Deep vein thrombosis
  • Plasminogen activator inhibitors
  • Stenosis
  • Venous thrombosis

ASJC Scopus subject areas

  • Hematology

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    Baxi, S., Crandall, D. L., Meier, T. R., Wrobleski, S., Hawley, A., Farris, D., Elokdah, H., Sigler, R., Schaub, R. G., Wakefield, T., & Myers, D. D. (2008). Dose-dependent thrombus resolution due to oral plasminogen activator inhibitor (PAI)-1 inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis. Thrombosis and Haemostasis, 99(4), 749-758. https://doi.org/10.1160/TH07-11-0669