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Thrombin-dependent intravascular leukocyte trafficking regulated by fibrin and the platelet receptors GPIb and PAR4

Academic Article
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Overview

authors

  • Kaplan, Z. S.
  • Zarpellon, A.
  • Alwis, I.
  • Yuan, Y.
  • McFadyen, J.
  • Ghasemzadeh, M.
  • Schoenwaelder, S. M.
  • Ruggeri, Zaverio
  • Jackson, Shaun

publication date

  • July 2015

journal

  • Nature Communications  Journal

abstract

  • Thrombin is a central regulator of leukocyte recruitment and inflammation at sites of vascular injury, a function thought to involve primarily endothelial PAR cleavage. Here we demonstrate the existence of a distinct leukocyte-trafficking mechanism regulated by components of the haemostatic system, including platelet PAR4, GPIbα and fibrin. Utilizing a mouse endothelial injury model we show that thrombin cleavage of platelet PAR4 promotes leukocyte recruitment to sites of vascular injury. This process is negatively regulated by GPIbα, as seen in mice with abrogated thrombin-platelet GPIbα binding (hGPIbα(D277N)). In addition, we demonstrate that fibrin limits leukocyte trafficking by forming a physical barrier to intravascular leukocyte migration. These studies demonstrate a distinct 'checkpoint' mechanism of leukocyte trafficking involving balanced thrombin interactions with PAR4, GPIbα and fibrin. Dysregulation of this checkpoint mechanism is likely to contribute to the development of thromboinflammatory disorders.

subject areas

  • Animals
  • Cell Movement
  • Endothelial Cells
  • Fibrinolysis
  • Humans
  • Leukocytes
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Platelet Activation
  • Platelet Glycoprotein GPIb-IX Complex
  • Receptors, Thrombin
  • Thrombin
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Identity

International Standard Serial Number (ISSN)

  • 2041-1723

Digital Object Identifier (DOI)

  • 10.1038/ncomms8835

PubMed ID

  • 26204458
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Additional Document Info

start page

  • 7835

volume

  • 6

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