Alterations in the intrinsic properties of the GPIbalpha-VWF tether bond define the kinetics of the platelet-type von Willebrand disease mutation, Gly233Val

Blood. 2003 Jul 1;102(1):152-60. doi: 10.1182/blood-2003-01-0072. Epub 2003 Mar 13.

Abstract

Platelet-type von Willebrand disease (PTVWD) is a bleeding disorder in which an increase of function mutation in glycoprotein Ibalpha (GPIbalpha), with respect to binding of von Willebrand factor (VWF), results in a loss of circulating high molecular weight VWF multimers together with a mild-moderate thrombocytopenia. To better ascertain the specific perturbations in adhesion associated with this disease state, we performed a detailed analysis of the kinetic and mechanical properties of tether bonds formed between PT-VWD platelets and the A1-domain of VWF. Results indicate that the GPIbalpha mutation, Gly233Val, promotes and stabilizes platelet adhesion to VWF at shear rates that do not support binding between the native receptor-ligand pair due to enhanced formation and increased longevity of the mutant tether bond (k0 off values for mutant versus native complex of 0.67 +/- 0.11 s-1 and 3.45 +/- 0.37 s-1, respectively). By contrast, the sensitivity of this interaction to an applied force, a measure of bond strength, was similar to the wild-type (WT) receptor. Although the observed alterations in the intrinsic properties of the GPIbalpha-VWF tether bond are comparable to those reported for the type 2B VWD, distinct molecular mechanisms may be responsible for these function-enhancing bleeding disorders, as interactions between the mutant receptor and mutant ligand resulted in a greater stability in platelet adhesion. We speculate that the enhanced cellular on-rate together with the prolongation in the lifetime of the mutant receptor-ligand bond contributes to platelet aggregation in circulating blood by permitting the formation of multiple GPIbalpha-VWF-A1 interactions.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Blood Platelets / chemistry
  • Blood Platelets / metabolism
  • Heterozygote
  • Humans
  • Kinetics
  • Models, Chemical
  • Mutation, Missense*
  • Perfusion
  • Platelet Adhesiveness / genetics
  • Platelet Glycoprotein GPIb-IX Complex / genetics*
  • Platelet Glycoprotein GPIb-IX Complex / metabolism*
  • Protein Binding / genetics
  • Stress, Mechanical
  • von Willebrand Diseases / genetics*
  • von Willebrand Factor / metabolism*

Substances

  • Platelet Glycoprotein GPIb-IX Complex
  • von Willebrand Factor