Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation

Daniel D. Myers Jr.; Shirley K. Wrobleski; Chris Longo; Patricia W. Bedard; Neelu Kaila; George D. Shaw; Frank J. Londy; Suzan E. Rohrer; Beverly A. Fex; Paul J. Zajkowski; Thomas R. Meier; Angela E. Hawley; Diana M. Farris; Nicole E. Ballard; Peter K. Henke; Robert G. Schaub; Thomas W. Wakefield

doi:10.1160/TH06-11-0658

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2007; 97(03): 400-407
DOI: 10.1160/TH06-11-0658

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation

Daniel D. Myers Jr.

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

²Unit for Laboratory Animal Medicine

,

Shirley K. Wrobleski

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Chris Longo

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Patricia W. Bedard

⁴Wyeth Research, Cambridge, Massachussetts, USA

,

Neelu Kaila

⁴Wyeth Research, Cambridge, Massachussetts, USA

,

George D. Shaw

⁴Wyeth Research, Cambridge, Massachussetts, USA

,

Frank J. Londy

³Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA

,

Suzan E. Rohrer

³Department of Radiology, University of Michigan Medical Center, Ann Arbor, Michigan, USA

,

Beverly A. Fex

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Paul J. Zajkowski

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Thomas R. Meier

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

²Unit for Laboratory Animal Medicine

,

Angela E. Hawley

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Diana M. Farris

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Nicole E. Ballard

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Peter K. Henke

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

,

Robert G. Schaub

⁴Wyeth Research, Cambridge, Massachussetts, USA

,

Thomas W. Wakefield

¹Jobst Vascular Research Laboratories, Section of Vascular Surgery

› Author Affiliations

Abstract

Summary

P-selectin inhibition has been shown to decrease thrombogenesis in multiple animal species. In this study, we show that a novel oral small-molecule inhibitor of P-selectin, PSI-697, promotes thrombus resolution and decreases inflammation in a baboon model of venous thrombosis. Experimental groups consisted of the following: 1) primates receiving a single oral dose of PSI-697 (30 mg/kg) daily starting three days pre-iliac vein balloon occlusion, and continued for six days; 2) primates receiving a single treatment dose of a low-molecular-weight-heparin (LMVVH) (1.5 mg/kg) daily starting one day pre-iliac balloon occlusion, and continued for six days; and 3) primates receiving a single oral dose of a vehicle control daily starting three days pre-iliac vein balloon occlusion, and continued for six days. Animals receiving PSI-697, although thrombosed after balloon deflation, demonstrated greater than 80% vein lumen opening over time, with no opening (0%) for vehicle control (p<0.01). LMVVH opening evident after balloon deflation slightly deteriorated overtime compared to PSI-697. PSI-697 therapy also significantly decreased vein wall inflammation determined by magnetic resonance venography (MRV). Importantly, this beneficial opening occurred without measured anticoagulation. Animals receiving PSI-697 demonstrated significantly increased plasma D-dimer levels versus LMVVH and control animals six hours post thrombus induction (p<0.01). This study is the first to demonstrate the effectiveness of oral P-selectin inhibition to modify venous thrombogenesis, increase vein lumen opening, and decrease inflammation in a large animal model.

Keywords

Deep venous thrombosis - thrombus resolution - small-molecule inhibitor of p-selectin - inflammation - animal models

Full Text

References

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