GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice

Audrey Le Behot, Maxime Gauberti, Sara Martinez De Lizarrondo, Axel Montagne, Eloïse Lemarchand, Yohann Repesse, Sylvain Guillou, Cécile V Denis, Eric Maubert, Cyrille Orset, Denis Vivien

Research output: Contribution to journalArticlepeer-review

Abstract

Interactions between platelet glycoprotein (Gp) IIb/IIIa and plasma proteins mediate platelet cross-linking in arterial thrombi. However, GpIIb/IIIa inhibitors fail to disperse platelet aggregates after myocardial infarction or ischemic stroke. These results suggest that stability of occlusive thrombi involves additional and as-yet-unidentified mechanisms. In the present study, we investigated the mechanisms driving platelet cross-linking during occlusive thrombus formation. Using computational fluid dynamic simulations and in vivo thrombosis models, we demonstrated that the inner structure of occlusive thrombi is heterogeneous and primarily determined by the rheological conditions that prevailed during thrombus growth. Unlike the first steps of thrombus formation, which are GpIIb/IIIa-dependent, our findings reveal that closure of the arterial lumen is mediated by GpIbα-von Willebrand Factor (VWF) interactions. Accordingly, disruption of platelet cross-linking using GpIbα-VWF inhibitors restored vessel patency and improved outcome in a mouse model of ischemic stroke, although the thrombi were resistant to fibrinolysis or traditional antithrombotic agents. Overall, our study demonstrates that disruption of GpIbα-VWF interactions restores vessel patency after occlusive thrombosis by specifically disaggregating the external layer of occlusive thrombi, which is constituted of platelet aggregates formed under very high shear rates.

Original languageEnglish
Pages (from-to)3354-63
Number of pages10
JournalBlood
Volume123
Issue number21
DOIs
Publication statusPublished - 22 May 2014

Keywords

  • Animals
  • Benzofurans
  • Blood Platelets/metabolism
  • Blood Vessels/metabolism
  • Hemorheology
  • Male
  • Mice
  • Platelet Aggregation
  • Platelet Glycoprotein GPIb-IX Complex/metabolism
  • Protein Interaction Maps
  • Quinolines
  • Thrombosis/metabolism
  • von Willebrand Factor/metabolism

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