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

Chen, Jianchung; Zhou, Hairu; Diacovo, Alexander; Zheng, X. Long; Emsley, Jonas; Diacovo, Thomas G.

Authors

Jianchung Chen

Hairu Zhou

Alexander Diacovo

X. Long Zheng

prof JONAS EMSLEY jonas.emsley@nottingham.ac.uk
Professor of Macromolecularcrystallography

Thomas G. Diacovo



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.

Journal Article Type Article
Publication Date Dec 12, 2014
Journal Blood
Print ISSN 0006-4971
Electronic ISSN 1528-0020
Publisher American Society of Hematology
Peer Reviewed Peer Reviewed
Volume 124
Issue 25
APA6 Citation Chen, J., Zhou, H., Diacovo, A., Zheng, X. L., Emsley, J., & Diacovo, T. G. (2014). Exploiting the kinetic interplay between GPIb -VWF binding interfaces to regulate hemostasis and thrombosis. Blood, 124(25), https://doi.org/10.1182/blood-2014-04-569392
DOI https://doi.org/10.1182/blood-2014-04-569392
Publisher URL http://www.bloodjournal.org/content/124/25/3799
Copyright Statement Copyright information regarding this work can be found at the following address: http://eprints.nottingh.../end_user_agreement.pdf
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 GPIba–VWF binding interfaces to regulate hemostasis and thrombosis. Blood. 2014; 124:3799-3807; © the American Society of Hematology.

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Copyright Statement
Copyright information regarding this work can be found at the following address: http://eprints.nottingham.ac.uk/end_user_agreement.pdf





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