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Prepublished online as a Blood First Edition Paper on March 13, 2003; DOI 10.1182/blood-2003-01-0072.
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Blood, 1 July 2003, Vol. 102, No. 1, pp. 152-160
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Alterations in the intrinsic properties of the GPIb –VWF tether bond define the kinetics of the platelet-type von Willebrand disease mutation, Gly233Val
Teresa A. Doggett,
Gaurav Girdhar,
Avril Lawshe,
Jonathan L. Miller,
Ian J. Laurenzi,
Scott L. Diamond, and
Thomas G. Diacovo
From the Division of Newborn Medicine, Department of Pediatrics, Department of Pathology, and Department of Bioengineering, Washington University and St Louis Children's Hospital, MO; Department of Pathology, University of Chicago, IL; and Institute for Medicine and Engineering, Department of Chemical Engineering, University of Pennsylvania, Philadelphia.
Platelet-type von Willebrand disease (PTVWD) is a bleeding disorder in which an increase of function mutation in glycoprotein Ib (GPIb), 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 GPIb 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 (k0off 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 GPIb–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 GPIb–VWF-A1 interactions. (Blood. 2003;102:152-160)
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