P-selectin can promote thrombus propagation independently of both von Willebrand factor and thrombospondin-1 in mice

Abstract

Essentials The main receptor for platelet glycoprotein (GP) Ibα is von Willebrand factor (VWF). P-selectin and thrombospondin-1 (TSP1) have been suggested as counter receptors for GPIbα. In a laser injury model, P-selectin promotes thrombus propagation independently of VWF and TSP1. In a laser injury model, thrombus persists in interleukin-4 receptor α/GPIbα-transgenic mice. Summary: Background P-selectin and thrombospondin-1 (TSP1) have been suggested as counter ligands that may mediate GPIbα-dependent thrombus growth independently of von Willebrand factor (VWF) in vitro. However, residual thrombus formation still persists in Vwf −/−Tsp1−/− mice, suggesting existence of other mechanisms that modulate thrombus propagation. Objective We determined whether P-selectin modulates thrombus propagation in injured arterioles independently of TSP1 and VWF. Methods CD-62P blocking antibody in Vwf −/−Tsp1−/− mice was used to inhibit P-selectin. We determined thrombus growth kinetics in two models of thrombosis: FeCl3 injury-induced and laser injury-induced thrombosis. Results In a 10% FeCl3 injury-induced thrombosis model, the initial platelet adhesion, time to form first thrombus, and non-occlusive residual thrombus growth kinetics were comparable between P-selectin-blocking antibody-treated Vwf −/−Tsp1−/− mice and control IgG-treated Vwf −/−Tsp1−/− mice. On the other hand, in a laser injury-induced thrombosis model, residual thrombus growth kinetics were significantly decreased in P-selectin-blocking antibody-treated Vwf −/−Tsp1−/− mice vs. control IgG-treated Vwf −/−Tsp1−/− mice. Because P-selectin has been suggested as a counter ligand for platelet GPIbα, we determined the role of GPIbα in a laser injury-induced thrombosis model. Surprisingly, in a laser injury model, unlike in a FeCl3 injury model, thrombus formation was not completely inhibited in IL4Rα/GPIbα-tg mice. Residual thrombus growth kinetics were comparable between P-selectin-blocking antibody-treated IL4Rα/GPIbα-tg mice and control IgG-treated IL4Rα/GPIbα-tg mice. Comparison of slopes over time showed that residual thrombus growth kinetics were comparable in P-selectin-blocking antibody-treated Vwf −/−Tsp1−/− and control IgG-treated IL4Rα/GPIbα-tg mice. Conclusion In a laser injury-induced thrombosis model, P-selectin modulates thrombus propagation independently of VWF and TSP1.