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

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.

• Authors: Teresa A Doggett, Gaurav Girdhar, Avril Lawshe, Jonathan L Miller, Ian J Laurenzi, Scott L Diamond, Thomas G Diacovo
• Journal: Blood (Blood) Vol. 102 Issue 1 Pg. 152-60 (Jul 01 2003) ISSN: 0006-4971 [Print] United States
• PMID: 12637314 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Platelet Glycoprotein GPIb-IX Complex
• von Willebrand Factor

Topics

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