title: Platelet interaction with von Willebrand factor is enhanced by shear-induced clustering of glycoprotein Ibα.
abstract: Initial platelet arrest at the exposed arterial vessel wall is mediated through glycoprotein Ibα binding to the A1 domain of von Willebrand factor. This interaction occurs at sites of elevated shear force, and strengthens upon increasing hydrodynamic drag. The increased interaction requires shear-dependent exposure of the von Willebrand factor A1 domain, but the contribution of glycoprotein Ibα remains ill defined. We have previously found that glycoprotein Ibα forms clusters upon platelet cooling and hypothesized that such a property enhances the interaction with von Willebrand factor under physiological conditions. We analyzed the distribution of glycoprotein Ibα with Förster resonance energy transfer using time-gated fluorescence lifetime imaging microscopy. Perfusion at a shear rate of 1,600 s(-1) induced glycoprotein Ibα clusters on platelets adhered to von Willebrand factor, while clustering did not require von Willebrand factor contact at 10,000 s(-1). Shear-induced clustering was reversible, not accompanied by granule release or αIIbβ3 activation and improved glycoprotein Ibα-dependent platelet interaction with von Willebrand factor. Clustering required glycoprotein Ibα translocation to lipid rafts and critically depended on arachidonic acid-mediated binding of 14-3-3ζ to its cytoplasmic tail. This newly identified mechanism emphasizes the ability of platelets to respond to mechanical force and provides new insights into how changes in hemodynamics influence arterial thrombus formation.
authors.affiliation: r.t.urbanus@umcutrecht.nl.
authors.forename: Eelo
authors.initials: E
authors.lastname: Gitz
authors.forename: Charlotte D
authors.initials: CD
authors.lastname: Koopman
authors.forename: Alèkos
authors.initials: A
authors.lastname: Giannas
authors.forename: Cornelis A
authors.initials: CA
authors.lastname: Koekman
authors.forename: Dave J
authors.initials: DJ
authors.lastname: van den Heuvel
authors.forename: Hans
authors.initials: H
authors.lastname: Deckmyn
authors.forename: Jan-Willem N
authors.initials: JW
authors.lastname: Akkerman
authors.forename: Hans C
authors.initials: HC
authors.lastname: Gerritsen
authors.forename: Rolf T
authors.initials: RT
authors.lastname: Urbanus
mesh_terms: D001792:Blood Platelets / Q000378:metabolism*; D002448:Cell Adhesion / Q000502:physiology; D016000:Cluster Analysis; D006801:Humans; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D011897:Random Allocation; D033081:Shear Strength / Q000502:physiology*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D019038:Platelet Glycoprotein GPIb-IX Complex; D014841:von Willebrand Factor