title: 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.
  
  
  
  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: FeCl3injury-induced and laser injury-induced thrombosis. Results In a 10% FeCl3injury-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 FeCl3injury 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.
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: P
authors.identifier: 0000-0001-9501-0065
authors.initials: P
authors.lastname: Prakash
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: M K
authors.initials: MK
authors.lastname: Nayak
authors.affiliation: Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
authors.forename: A K
authors.initials: AK
authors.lastname: Chauhan
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology; D001792:Blood Platelets / Q000378:metabolism; D002712:Chlorides / Q000737:chemistry; D004195:Disease Models, Animal; D005290:Ferric Compounds / Q000737:chemistry; D007074:Immunoglobulin G / Q000378:metabolism; D007834:Lasers; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019007:P-Selectin / Q000378:metabolism*; D015539:Platelet Activation; D010973:Platelet Adhesiveness / Q000187:drug effects; D011485:Protein Binding; D013927:Thrombosis / Q000378:metabolism*; D019700:Thrombospondin 1 / Q000378:metabolism*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; D002712:Chlorides; D005290:Ferric Compounds; D007074:Immunoglobulin G; D019007:P-Selectin; D019700:Thrombospondin 1; D014841:von Willebrand Factor; C024555:ferric chloride
keywords: P-selectin; arterial thrombosis; platelets; thrombospondin-1; von Willebrand factor