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

Daniel D. Myers, 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

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38 Scopus citations

Abstract

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 (LMWH) (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). LMWH opening evident after balloon deflation slightly deteriorated over time 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 LMWH and control animals six hours post thrombus induction (p<0.0 1). 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.

Original languageEnglish (US)
Pages (from-to)400-407
Number of pages8
JournalThrombosis and Haemostasis
Volume97
Issue number3
DOIs
StatePublished - Mar 1 2007

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Keywords

  • Animal models
  • Deep venous thrombosis
  • Inflammation
  • Small-molecule inhibitor of p-selectin
  • Thrombus resolution

ASJC Scopus subject areas

  • Hematology

Cite this

Myers, D. D., Wrobleski, S. K., Longo, C., Bedard, P. W., Kaila, N., Shaw, G. D., Londy, F. J., Rohrer, S. E., Fex, B. A., Zajkowski, P. J., Meier, T. R., Hawley, A. E., Farris, D. M., Ballard, N. E., Henke, P. K., Schaub, R. G., & Wakefield, T. W. (2007). Resolution of venous thrombosis using a novel oral small-molecule inhibitor of P-selectin (PSI-697) without anticoagulation. Thrombosis and Haemostasis, 97(3), 400-407. https://doi.org/10.1160/TH06-11-0658