Prakash P, Nayak M K, Chauhan A K
Department of Internal Medicine, University of Iowa, Iowa City, IA, USA.
J Thromb Haemost. 2017 Feb;15(2):388-394. doi: 10.1111/jth.13586. Epub 2017 Feb 3.
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: FeCl injury-induced and laser injury-induced thrombosis. Results In a 10% FeCl 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 FeCl 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.
要点 血小板糖蛋白（GP）Ibα的主要受体是血管性血友病因子（VWF）。P-选择素和血小板反应蛋白-1（TSP1）被认为是GPIbα的反受体。在激光损伤模型中，P-选择素独立于VWF和TSP1促进血栓形成。在激光损伤模型中，血栓在白细胞介素-4受体α/GPIbα转基因小鼠中持续存在。
背景 P-选择素和血小板反应蛋白-1（TSP1）被认为是反配体，可能在体外独立于血管性血友病因子（VWF）介导依赖GPIbα的血栓生长。然而，Vwf Tsp1小鼠中仍存在残余血栓形成，提示存在其他调节血栓形成的机制。目的 我们确定P-选择素是否独立于TSP1和VWF调节受损小动脉中的血栓形成。方法 使用Vwf Tsp1小鼠中的CD-62P阻断抗体抑制P-选择素。我们在两种血栓形成模型中确定血栓生长动力学：FeCl损伤诱导的和激光损伤诱导的血栓形成。结果 在10%FeCl损伤诱导的血栓形成模型中，P-选择素阻断抗体处理的Vwf Tsp1小鼠和对照IgG处理的Vwf Tsp1小鼠之间，初始血小板黏附、形成第一个血栓的时间以及非闭塞性残余血栓生长动力学相当。另一方面，在激光损伤诱导的血栓形成模型中，P-选择素阻断抗体处理的Vwf Tsp1小鼠与对照IgG处理的Vwf Tsp1小鼠相比，残余血栓生长动力学显著降低。由于P-选择素被认为是血小板GPIbα的反配体，我们确定了GPIbα在激光损伤诱导的血栓形成模型中的作用。令人惊讶的是，在激光损伤模型中，与FeCl损伤模型不同，IL4Rα/GPIbα转基因小鼠中的血栓形成并未完全被抑制。P-选择素阻断抗体处理的IL4Rα/GPIbα转基因小鼠和对照IgG处理的IL4Rα/GPIbα转基因小鼠之间的残余血栓生长动力学相当。随时间变化的斜率比较显示，P-选择素阻断抗体处理的Vwf Tsp1小鼠和对照IgG处理的IL4Rα/GPIbα转基因小鼠中的残余血栓生长动力学相当。结论 在激光损伤诱导的血栓形成模型中，P-选择素独立于VWF和TSP1调节血栓形成。
