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Thromb Haemost 2008; 99(04): 749-758
DOI: 10.1160/TH07-11-0669
Animal Models
Schattauer GmbH

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   Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
,
David L. Crandall
3   Cardiovascular and Metabolic Diseases Research, Wyeth Research, Cambridge, Massachussetts, USA
,
Thomas R. Meier   *
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
,
Shirley Wrobleski
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
,
Angela Hawley
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
,
Diana Farris
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
,
Hassan Elokdah   †
4   Chemical & Screening Sciences Research, Wyeth Research, Collegeville, Pennsylvania, USA
,
Robert Sigler
5   Walker Downey & Associates, Inc., Verona, Wisconsin, USA
,
Robert G. Schaub   **
3   Cardiovascular and Metabolic Diseases Research, Wyeth Research, Cambridge, Massachussetts, USA
,
Thomas Wakefield
1   Jobst Vascular Research Laboratories, Section of Vascular Surgery, University of Michigan Medical Center, Ann Arbor, Michigan, USA
,
Daniel Myers
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
› Author AffiliationsFinancial support: This work was supported by Wyeth Research, Cambridge, MA, USA.
Further Information

Publication History

Received: 09 November 2007

Accepted after major revision: 12 February 2008

Publication Date:
25 November 2017 (online)

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Summary

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.

Keywords

Venous thrombosis - plasminogen activator inhibitors - animal models - stenosis - deep vein thrombosis

* Dr. Thomas R. Meier is currently affiliated with the Mayo Clinic, Rochester, MN, USA.


** Dr. Robert G. Schaub is currently affiliated with the Archemix Corp., Cambridge, MA, USA.


† Deceased January 13, 2008.


 

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