P-selectin inhibition enhances thrombus resolution and decreases vein wall fibrosis in a rat model.

Abstract

The purpose of this study was to compare the efficacy of P-selectin inhibition with standard anticoagulant and thrombolytic therapy in a rodent model of established deep vein thrombosis (DVT). Rats underwent temporary inferior vena cava (IVC) ligation for 2 days to create a stasis-induced thrombosis. On day 2, the animals had the IVC ligature removed and received either recombinant P-selectin glycoprotein ligand-Ig (rPSGL-Ig; 4 mg/kg) intravenously, low-molecular weight heparin (LMWH; 450 IU/kg) subcutaneously, tissue plasminogen activator (tPA; 0.5 mg/kg) intravenously, combination rPSGL-Ig plus tPA, or saline vehicle. IVC segments were harvested from rats at 4 (n = 8) and 7 (n = 3) days after treatment. All treatments were given as a single dose except for daily LMWH. Evaluation included contrast venography with computer image analysis, thrombus weight/length (mass), vein wall leukocyte counts, cytokine and tissue factor analysis with enzyme-linked immunosorbent assay, and (ED1) monocyte immunohistochemical staining. Collagen was estimated with a quantitative assay. Contrast venography revealed that rats with both rPSGL-Ig and tPA treatment had significantly smaller thrombi as compared with controls at day 7 (0.34 +/- 0.07 cm(2) and 0.34 +/- 0.05 cm(2) versus 0.68 +/- 0.13 cm(2); P <.05). LMWH and tPA groups had significantly decreased thrombus mass at harvest compared with controls on day 4 (0.06 +/- 0.009 g/cm and 0.08 +/- 0.01 g/cm versus 0.1 +/- 0.005 g/cm; P <.05), and rPSGL-Ig showed a similar trend (P =.072). Vein wall, but not thrombus, monocytes were more numerous in those rats receiving rPSGL-Ig versus controls at day 4 (30 +/- 4 cells/5 high power fields [HPFs] versus 19 +/- 2 cells/5 HPFs; P <.05) and at day 7 (32 +/- 2 cells/5 HPFs versus 20 +/- 3 cells/5 HPFs; P <.05). rPSGL-Ig treatment was associated with significantly reduced vein wall collagen at day 7 versus controls (1.3 +/- 0.6 pg/mg versus 3.7 +/- 0.5 pg/mg; P <.05) and a trend toward lower tissue factor levels. rPSGL-Ig, LMWH, and tPA showed equal DVT resolution efficacy over 7 days. However, only rPSGL-Ig was associated with a decrease in vein wall fibrosis, suggesting that purely accelerating DVT resolution may not decrease long-term vein scarring.