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

Research output: Contribution to journalArticle

21 Citations (Scopus)

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 2008

Fingerprint

Plasminogen Activator Inhibitor 1
Venous Thrombosis
Pathologic Constriction
Thrombosis
Enoxaparin
Plasminogen Inactivators
Weights and Measures
Inferior Vena Cava
tiplaxtinin
Rodentia
Pharmaceutical Preparations

Keywords

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

ASJC Scopus subject areas

  • Hematology

Cite this

Dose-dependent thrombus resolution due to oral plasminogen activator inhibitor (PAI)-1 inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis. / Baxi, Sanjiv; Crandall, David L.; Meier, Thomas D; Wrobleski, Shirley; Hawley, Angela; Farris, Diana; Elokdah, Hassan; Sigler, Robert; Schaub, Robert G.; Wakefield, Thomas; Myers, Daniel D.

In: Thrombosis and Haemostasis, Vol. 99, No. 4, 04.2008, p. 749-758.

Research output: Contribution to journalArticle

Baxi, S, Crandall, DL, Meier, TD, Wrobleski, S, Hawley, A, Farris, D, Elokdah, H, Sigler, R, Schaub, RG, Wakefield, T & Myers, DD 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, vol. 99, no. 4, pp. 749-758. https://doi.org/10.1160/TH07-11-0669
Baxi, Sanjiv ; Crandall, David L. ; Meier, Thomas D ; Wrobleski, Shirley ; Hawley, Angela ; Farris, Diana ; Elokdah, Hassan ; Sigler, Robert ; Schaub, Robert G. ; Wakefield, Thomas ; Myers, Daniel D. / Dose-dependent thrombus resolution due to oral plasminogen activator inhibitor (PAI)-1 inhibition with tiplaxtinin in a rat stenosis model of venous thrombosis. In: Thrombosis and Haemostasis. 2008 ; Vol. 99, No. 4. pp. 749-758.
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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.",
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AU - Wrobleski, Shirley

AU - Hawley, Angela

AU - Farris, Diana

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