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P-Selectin-dependent inhibition of thrombosis during venous stasis
1Wyeth/Genetics Institute, Discovery Research, Andover, Massachusetts, USA.
Insights
Recombinant soluble P-selectin glycoprotein ligand-1 (rPSGL-Ig) prevented thrombus formation in feline jugular veins during venous stasis. This suggests rPSGL-Ig has an antithrombotic effect, independent of leukocyte adhesion or endothelial injury.
Area of Science:
- Vascular Biology
- Thrombosis Research
- Immunology
Background:
- Leukocyte adhesion and migration are key in deep vein thrombosis (DVT) pathogenesis.
- P-selectin glycoprotein ligand-1 (PSGL-1) interactions mediate leukocyte adhesion.
- Understanding DVT mechanisms can inform new antithrombotic strategies.
Purpose of the Study:
- To investigate the antithrombotic potential of targeting P-selectin glycoprotein ligand-1 (PSGL-1).
- To evaluate the effect of recombinant soluble PSGL-1 (rPSGL-Ig) on thrombus formation during venous stasis.
- To assess the impact of rPSGL-Ig and an E/L-selectin antibody on leukocyte adhesion and endothelial injury.
Main Methods:
- Anesthetized cats underwent jugular vein occlusion.
- Treatment groups received saline, rPSGL-Ig, or an E/L-selectin antibody (EL-246).
- Jugular veins were analyzed by scanning electron microscopy after 2 or 6 hours of occlusion.
Main Results:
- Saline-treated cats showed moderate leukocyte/platelet adhesion and endothelial injury.
- rPSGL-Ig and EL-246 treatments did not alter cell adhesion or endothelial injury.
- rPSGL-Ig significantly prevented mural thrombus formation after 6 hours of venous stasis.
Conclusions:
- rPSGL-Ig exhibits antithrombotic properties by inhibiting thrombus formation during venous stasis.
- The antithrombotic effect of rPSGL-Ig is independent of its impact on leukocyte adhesion or endothelial injury.
- Targeting PSGL-1 interactions may offer a novel therapeutic approach for preventing deep vein thrombosis.
Abstract:
Leukocyte adhesion, transendothelial migration, and stasis are important components in the pathogenesis of deep vein thrombosis. Anesthetized cats were treated with saline, a recombinant soluble form of P-selectin glycoprotein ligand-1 (rPSGL-Ig), or an E- and L-selectin antibody (EL-246) before exposure and occlusion of a jugular vein. After 2 or 6 hours of occlusion, jugular veins were perfused with buffer, fixed, and prepared for scanning electron microscopy. In cats receiving saline, 2 and 6 hours of occlusion produced moderate levels of leukocyte and platelet adhesion and endothelial cell injury. Treatment of cats with rPSGL-Ig or EL-246 had no apparent effect on the magnitude of cell adhesion and endothelial cell injury compared with no treatment. After 6 hours of occlusion, the presence of a mural thrombus in untreated veins was observed and confirmed by scanning electron microscopy. Pretreatment of cats with rPSGL-Ig completely (4.0 mg/kg) or partially (1.0 mg/kg) prevented the occurrence of thrombi in the jugular veins. The reduction in thrombosis by rPSGL-Ig treatment after 6 hours of venous stasis, in the absence of any effect on leukocyte-mediated endothelial cell injury, suggests an antithrombotic mechanism of action for this protein.