Exploiting the kinetic interplay between GPIb -VWF binding interfaces to regulate hemostasis and thrombosis

Chen, Jianchung and Zhou, Hairu and Diacovo, Alexander and Zheng, X. Long and Emsley, Jonas and Diacovo, Thomas G. (2014) Exploiting the kinetic interplay between GPIb -VWF binding interfaces to regulate hemostasis and thrombosis. Blood, 124 (25). pp. 3799-3807. ISSN 1528-0020

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Abstract

Platelet–von Willebrand factor (VWF) interactions must be tightly regulated in order to promote effective hemostasis and prevent occlusive thrombus formation. However, it is unclear what role the inherent properties of the bond formed between the platelet receptor glycoprotein Ibα and the A1 domain of VWF play in these processes. Using VWF-A1 knock-in mice with mutations that enhance (I1309V) or disrupt (R1326H) platelet receptor glycoprotein Ibα binding, we now demonstrate that the kinetic interplay between two distinct contact surfaces influences the site and extent to which platelets bind VWF. Incorporation of R1326H mutation into the major site shortened bond lifetime, yielding defects in hemostasis and thrombosis comparable to VWF-deficient animals. Similarly, disrupting this region of contact with an allosteric inhibitor impaired human platelet accrual in damaged arterioles. In contrast, the I1309V mutation near the minor site prolonged bond lifetime, which was essential for the development of a type 2B–like VWD phenotype. However, combining the R1326H and I1309V mutations normalized both bond kinetics and the hemostatic and thrombotic properties of VWF. These findings broaden our understanding of mechanisms governing platelet–VWF interactions in health and disease, and underscore the importance of combined biophysical and genetic approaches in identifying potential therapeutic avenues for treating bleeding and thrombotic disorders.

Item Type: Article
Additional Information: This research was originally published in Blood. Jianchung Chen, Hairu Zhou, Alexander Diacovo, X. Long Zheng, Jonas Emsley and Thomas G. Diacovo. Exploiting the kinetic interplay between GPIbα–VWF binding interfaces to regulate hemostasis and thrombosis. Blood. 2014; 124:3799-3807; © the American Society of Hematology.
Schools/Departments: University of Nottingham, UK > Faculty of Science > School of Pharmacy
Identification Number: https://doi.org/10.1182/blood-2014-04-569392
Depositing User: Eprints, Support
Date Deposited: 16 Mar 2018 14:09
Last Modified: 17 Mar 2018 15:57
URI: http://eprints.nottingham.ac.uk/id/eprint/50479

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