Alterations in Platelet Secretion Differentially Affect Thrombosis and Hemostasis

Authors

Smita Joshi, University of KentuckyFollow
Meenakshi Banerjee, University of KentuckyFollow
Jinchao Zhang, University of KentuckyFollow
Akhil Kesaraju, University of Kentucky
Irina D. Pokrovskaya, University of Arkansas for Medical Sciences
Brian Storrie, University of Arkansas for Medical Sciences
Sidney W. Whiteheart, University of KentuckyFollow

Abstract

We genetically manipulated the major platelet vesicle-associated membrane proteins (VAMP2, VAMP3, and VAMP8) to create mice with varying degrees of disrupted platelet secretion. As previously shown, loss of VAMP8 reduced granule secretion, and this defect was exacerbated by further deletion of VAMP2 and VAMP3. VAMP2^Δ3^Δ8^−/− platelets also had reduced VAMP7. Loss of VAMP2 and VAMP3 (VAMP2^Δ3^Δ) had a minimal impact on secretion when VAMP7 and VAMP8 were present. Integrin αIIbβ3 activation and aggregation were not affected, although spreading was reduced in VAMP2^Δ3^Δ8^−/− platelets. Using these mice as tools, we asked how much secretion is needed for proper thrombosis and hemostasis in vivo. VAMP2^Δ3^Δ mice showed no deficiency, whereas VAMP8^−/− mice had attenuated formation of occlusive thrombi upon FeCl₃-induced arterial injury but no excessive bleeding upon tail transection. VAMP2^Δ3^Δ8^−/− mice bled profusely and failed to form occlusive thrombi. Plasma-coagulation factors were normal in all of the strains, but phosphatidylserine exposure was reduced in VAMP2^Δ3^Δ and VAMP2^Δ3^Δ8^−/− platelets. From our data, an ∼40% to 50% reduction in platelet secretion in vitro (dense and α granule) correlated with reduced occlusive thrombosis but no compromise in hemostasis. At a > 50% reduction, thrombosis and hemostasis were defective in vivo. Our studies are the first systematic manipulation of platelet exocytic machinery to demonstrate a quantitative linkage between in vitro platelet secretion and hemostasis and thrombosis in vivo. The animals described will be invaluable tools for future investigations into how platelet secretion affects other vascular processes.

Document Type

Article

Publication Date

9-11-2018

Notes/Citation Information

Published in Blood Advances, v. 2, no. 17, p. 2187-2198.

This research was originally published in Blood Advances. Smita Joshi, Meenakshi Banerjee, Jinchao Zhang, Akhil Kesaraju, Irina D. Pokrovskaya, Brian Storrie and Sidney W. Whiteheart. Alterations in platelet secretion differentially affect thrombosis and hemostasis. Blood Adv. 2018;2:2187-2198. © 2018 by The American Society of Hematology

The copyright holder has granted the permission for posting the article here.

Digital Object Identifier (DOI)

https://doi.org/10.1182/bloodadvances.2018019166

Funding Information

This work was supported by grants from the National Institutes of Health, National Heart, Lung, and Blood Institute (HL119393 [B.S.]; HL56652 and HL138179 [S.W.W.]), American Heart Association Grant-in-Aid AHA16GRNT27620001, a Veterans Affairs Merit Award (S.W.W.), and American Heart Association predoctoral fellowship 15PRE25550020 (S.J.).

Related Content

The full-text version of this article contains a data supplement.

Repository Citation

Joshi, Smita; Banerjee, Meenakshi; Zhang, Jinchao; Kesaraju, Akhil; Pokrovskaya, Irina D.; Storrie, Brian; and Whiteheart, Sidney W., "Alterations in Platelet Secretion Differentially Affect Thrombosis and Hemostasis" (2018). Molecular and Cellular Biochemistry Faculty Publications. 144.
https://uknowledge.uky.edu/biochem_facpub/144