Factor Xa Inhibitor Suppresses the Release of Phosphorylated HSP27 from Collagen-Stimulated Human Platelets: Inhibition of HSP27 Phosphorylation via p44/p42 MAP Kinase.

Masanori Tsujimoto,Rie Matsushima-Nishiwaki,Toru Iwama,Takanobu Otsuka,Yuko Kito,Haruhiko Tokuda,Hiroki Iida,Gen Kuroyanagi,Shinji Ogura,Yukiko Enomoto,Osamu Kozawa,Ingo Ahrens

doi:10.1371/journal.pone.0149077

Masanori Tsujimoto, Rie Matsushima-Nishiwaki + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0149077

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Journal: PloS one	Publication Date: Feb 11, 2016
Citations: 4	License type: CC BY 4.0

Affiliation: Gifu University, Nagoya City University

Abstract

Selective inhibitors of factor Xa (FXa) are widely recognized as useful therapeutic tools for stroke prevention in non-valvular atrial fibrillation or venous thrombosis. Thrombin, which is rapidly generated from pro-thrombin through the activation of factor X to FXa, acts as a potent activator of human platelets. Thus, the reduction of thrombin generation by FXa inhibitor eventually causes a suppressive effect on platelet aggregation. However, little is known whether FXa inhibitors directly affect the function of human platelets. We have previously reported that collagen induces the phosphorylation of heat shock protein 27 (HSP27), a low-molecular weight heat shock protein via Rac-dependent activation of p44/p42 mitogen-activated protein (MAP) kinase in human platelets, eventually resulting in the release of HSP27. In the present study, we investigated the direct effect of FXa inhibitor on the collagen-induced human platelet activation. Rivaroxaban as well as edoxaban significantly reduced the collagen-induced phosphorylation of both HSP27 and p44/p42 MAP kinase without affecting the platelet aggregation. Rivaroxaban significantly inhibited the release of phosphorylated HSP27 from collagen-stimulated platelets but not the secretion of platelet derived growth factor-AB. In patients administrated with rivaroxaban, the collagen-induced levels of phosphorylated HSP27 were markedly diminished after 2 days of administration, which failed to affect the platelet aggregation. These results strongly suggest that FXa inhibitor reduces the collagen-stimulated release of phosphorylated HSP27 from human platelets due to the inhibition of HSP27 phosphorylation via p44/p42 MAP kinase.

Highlights

Human platelets play pivotal roles in primary haemostasis and repairs of vascular injury [1]
We first examined the effects of factor Xa (FXa) inhibitors, rivaroxaban on platelet aggregation induced by 1.0 μg/ml of collagen
In order to investigate whether FXa inhibitor could affect the activation of p44/p42 mitogen-activated protein (MAP) kinase induced by collagen or not, we examined the effects of FXa inhibitors on the collageninduced phosphorylation of p44/p42 MAP kinase in human platelets

Summary

Introduction

Human platelets play pivotal roles in primary haemostasis and repairs of vascular injury [1]. Collagen is well known as a potent coagulant for human platelets via GPVI and integrin α2β1 on the plasma membrane of platelets [3,4]. Thrombin is rapidly generated from pro-thrombin through the activation of factor X to factor Xa (FXa) on human platelets adhering to injured vessel walls, and leads to the conversion of fibrinogen to fibrin [2,6]. Thrombin is a potent activator of human platelets via specific receptors, protease-activated receptor (PAR)-1 and PAR-4, and plays a crucial role in the initial phase of coagulation cascade [2]. Regarding FXa inhibitor-effect on platelet functions, it has been reported that FXa inhibitors reduce the tissue factor-induced platelet aggregation [10,11], whereas the collagen-induced platelet aggregation is hardly affected by FXa inhibitors [12,13]. Little is known about the direct effect of FXa inhibitors on platelet function

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