title: Selectin-like kinetics and biomechanics promote rapid platelet adhesion in flow: the GPIb(alpha)-vWF tether bond.
abstract: The ability of platelets to tether to and translocate on injured vascular endothelium relies on the interaction between the platelet glycoprotein receptor Ib alpha (GPIb(alpha)) and the A1 domain of von Willebrand factor (vWF-A1). To date, limited information exists on the kinetics that govern platelet interactions with vWF in hemodynamic flow. We now report that the GPIb(alpha)-vWF-A1 tether bond displays similar kinetic attributes as the selectins including: 1) the requirement for a critical level of hydrodynamic flow to initiate adhesion, 2) short-lived tethering events at sites of vascular injury in vivo, and 3) a fast intrinsic dissociation rate constant, k(0)(off) (3.45 +/- 0.37 s(-1)). Values for k(off), as determined by pause time analysis of transient capture/release events, were also found to vary exponentially (4.2 +/- 0.8 s(-1) to 7.3 +/- 0.4 s(-1)) as a function of the force applied to the bond (from 36 to 217 pN). The biological importance of rapid bond dissociation in platelet adhesion is demonstrated by kinetic characterization of the A1 domain mutation, I546V that is associated with type 2B von Willebrand disease (vWD), a bleeding disorder that is due to the spontaneous binding of plasma vWF to circulating platelets. This mutation resulted in a loss of the shear threshold phenomenon, a approximately sixfold reduction in k(off), but no significant alteration in the ability of the tether bond to resist shear-induced forces. Thus, flow dependent adhesion and rapid and force-dependent kinetic properties are the predominant features of the GPIb(alpha)-vWF-A1 tether bond that in part may explain the preferential binding of platelets to vWF at sites of vascular injury, the lack of spontaneous platelet aggregation in circulating blood, and a mechanism to limit thrombus formation.
authors.affiliation: Division of Newborn Medicine, Department of Pediatrics, Washington University and St. Louis Children's Hospital, St. Louis, Missouri 63110, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Doggett
authors.forename: Gaurav
authors.initials: G
authors.lastname: Girdhar
authors.forename: Avril
authors.initials: A
authors.lastname: Lawshé
authors.forename: David W
authors.initials: DW
authors.lastname: Schmidtke
authors.forename: Ian J
authors.initials: IJ
authors.lastname: Laurenzi
authors.forename: Scott L
authors.initials: SL
authors.lastname: Diamond
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Diacovo
mesh_terms: D000911:Antibodies, Monoclonal; D001792:Blood Platelets / Q000166:cytology; D002448:Cell Adhesion; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008863:Microspheres; D009010:Monte Carlo Method; D009154:Mutation; D010974:Platelet Aggregation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D019087:Selectins / Q000737:chemistry*; D013997:Time Factors; D014867:Water; D014841:von Willebrand Factor / Q000737:chemistry*
chemical_list: D000911:Antibodies, Monoclonal; D008024:Ligands; D019038:Platelet Glycoprotein GPIb-IX Complex; D010980:Platelet Membrane Glycoproteins; D011994:Recombinant Proteins; D019087:Selectins; C032193:glycoprotein receptor GPIb-IX; D014841:von Willebrand Factor; D014867:Water