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

Abstract

Purpose: 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). Methods: 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. Results: 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 cm2 and 0.34 ± 0.05 cm2 versus 0.68 ± 0.13 cm2; P < .05) and a trend toward lower tissue factor levels. Conclusion: 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.