title: GpIbα-VWF blockade restores vessel patency by dissolving platelet aggregates formed under very high shear rate in mice.
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.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Audrey
authors.initials: A
authors.lastname: Le Behot
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Maxime
authors.initials: M
authors.lastname: Gauberti
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Sara
authors.initials: S
authors.lastname: Martinez De Lizarrondo
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Axel
authors.initials: A
authors.lastname: Montagne
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Eloïse
authors.initials: E
authors.lastname: Lemarchand
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Yohann
authors.initials: Y
authors.lastname: Repesse
authors.affiliation: Normandie Université, Université de Caen, Laboratoire Universitaire des Sciences Appliquées de Cherbourg, EA 4253, BP 78, Cherbourg-Octeville, France; and.
authors.forename: Sylvain
authors.initials: S
authors.lastname: Guillou
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U770, Université Paris-Sud, Le Kremlin-Bicêtre, France.
authors.forename: Cécile V
authors.initials: CV
authors.lastname: Denis
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Eric
authors.initials: E
authors.lastname: Maubert
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Cyrille
authors.initials: C
authors.lastname: Orset
authors.affiliation: Institut National de la Santé et de la Recherche Médicale, Unité Mixte de Recherche Scientifique U919, "Serine Proteases and Pathophysiology of the Neurovascular Unit", Groupement d'Intérêt Public Cyceron, Caen, France;
authors.forename: Denis
authors.initials: D
authors.lastname: Vivien
mesh_terms: D000818:Animals; D001572:Benzofurans; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology*; D001808:Blood Vessels / Q000378:metabolism / Q000473:pathology; D018056:Hemorheology; D008297:Male; D051379:Mice; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D060066:Protein Interaction Maps; D011804:Quinolines; D013927:Thrombosis / Q000378:metabolism* / Q000473:pathology*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: C576715:(3aS,4S,9bS)-N-(2-(8-cyano-1-formyl-2,3,3a,4,5,9b-hexahydro-1H-pyrrolo(3,2-c)quinolin-4-yl)-2-methylpropyl)-4,6-difluorobenzofuran-2-carboxyamide; D001572:Benzofurans; D019038:Platelet Glycoprotein GPIb-IX Complex; D011804:Quinolines; C094990:adhesion receptor; D014841:von Willebrand Factor