Decreased venous thrombosis with an oral inhibitor of P selectin

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Decreased venous thrombosis with an oral inhibitor of P selectin Daniel D. Myers, DVM, MPH, John E. Rectenwald, MD, Patricia W. Bedard, BS, Neelu Kaila, PhD, Gray D. Shaw, BS, Robert G. Schaub, PhD, Diana M. Farris, LVT, Angela E. Hawley, MS, Shirley K. Wrobleski, BS, Peter K. Henke, MD, Thomas W. Wakefield, MD Journal of Vascular Surgery Volume 42, Issue 2, Pages 329-336 (August 2005) DOI: 10.1016/j.jvs.2005.04.045 Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 1 A. Small molecule inhibition of P selectin (PSI-697) significantly decreased thrombus weight in the wild-type (WT) and Delta Cytoplasmic Tail (^CT) groups at day 2. CTR, Control without drug; EPKO, mice gene-deleted for both E and P selectin. B, Only the ^CT mouse group with drug therapy showed a significant decrease in thrombosis at day 6. Journal of Vascular Surgery 2005 42, 329-336DOI: (10.1016/j.jvs.2005.04.045) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 2 A. Drug treatment at day 2 significantly increased vein wall inflammatory cell extravasation in wild-type (WT) and Delta Cytoplasmic Tail (^CT) animals, with increased thrombus burden. Animals deficient in selectins had significantly decreased vein wall inflammatory cell extravasation at day 2. NEUT, Neutrophils; MONO, mononuclear cells; TC, total inflammatory cells; CTR, control without drug; PSI, with PSI-697; EPKO, mice gene-deleted for both E and P selectin; HPF, high-power field. B, Only the ^CT group with PSI-697 therapy showed significant increases in vein wall inflammatory cells at day 6. Journal of Vascular Surgery 2005 42, 329-336DOI: (10.1016/j.jvs.2005.04.045) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 3 Hematoxylin and eosin staining showed decreased inflammatory cells in vein wall endothelium and adventitial layers 2 days after thrombosis in a Delta Cytoplasmic Tail (^CT) mouse without drug. Note that this animal had prominent inflammatory cells aligned at the vein wall/thrombus interface. (A) With drug treatment, a significant increase in vein wall inflammatory cells was noted in the ^CT mouse at day 2 (original magnification, ×80; short arrows depict mononuclear cells; long arrows depict neutrophils). (B) CTR, Control without drug; PSI, with PSI-697. Journal of Vascular Surgery 2005 42, 329-336DOI: (10.1016/j.jvs.2005.04.045) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions

Fig 4 A. The anti-inflammatory cytokine IL-10 was significantly upregulated in wild-type (WT) and Delta Cytoplasmic Tail (^CT) animals at day 2 treated with the small molecule inhibitor of P selectin vs animals without drug. P selectin (Psel), monocyte chemotactic protein 1 (MCP-1), and interleukin 10 (IL-10) were measured from vein wall homogenates at 2 and 6 days after thrombosis. CTR, Control without drug; PSI, with PSI-697; EPKO, mice gene-deleted for both E and P selectin; ELISA, enzyme-linked immunosorbent assay. B, Significant decreases in protein expression were noted between the groups at day 6. Psel, MCP-1, and IL-10 were measured from vein wall homogenates at 2 and 6 days after thrombosis. Journal of Vascular Surgery 2005 42, 329-336DOI: (10.1016/j.jvs.2005.04.045) Copyright © 2005 The Society for Vascular Surgery Terms and Conditions