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Coordinated membrane ballooning and procoagulant spreading in human platelets

Agbani, Ejaife O., van den Bosch, Marion T.J., Brown, Ed, Williams, Christopher M., Mattheij, Nadine J.A., Cosemans, Judith M.E.M, Collins, Peter ORCID:, Heemskerk, Johan W.M., Hers, Ingeborg and Poole, Alastair W. 2015. Coordinated membrane ballooning and procoagulant spreading in human platelets. Circulation 132 (15) , pp. 1414-1424. 10.1161/CIRCULATIONAHA.114.015036

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Background—Platelets are central to the process of hemostasis, rapidly aggregating at sites of blood vessel injury and acting as coagulation nidus sites. On interaction with the subendothelial matrix, platelets are transformed into balloonlike structures as part of the hemostatic response. It remains unclear, however, how and why platelets generate these structures. We set out to determine the physiological relevance and cellular and molecular mechanisms underlying platelet membrane ballooning. Methods and Results—Using 4-dimensional live-cell imaging and electron microscopy, we show that human platelets adherent to collagen are transformed into phosphatidylserine-exposing balloonlike structures with expansive macro/microvesiculate contact surfaces, by a process that we termed procoagulant spreading. We reveal that ballooning is mechanistically and structurally distinct from membrane blebbing and involves disruption to the platelet microtubule cytoskeleton and inflation through fluid entry. Unlike blebbing, procoagulant ballooning is irreversible and a consequence of Na+, Cl–, and water entry. Furthermore, membrane ballooning correlated with microparticle generation. Inhibition of Na+, Cl–, or water entry impaired ballooning, procoagulant spreading, and microparticle generation, and it also diminished local thrombin generation. Human Scott syndrome platelets, which lack expression of Ano-6, also showed a marked reduction in membrane ballooning, consistent with a role for chloride entry in the process. Finally, the blockade of water entry by acetazolamide attenuated ballooning in vitro and markedly suppressed thrombus formation in vivo in a mouse model of thrombosis. Conclusions—Ballooning and procoagulant spreading of platelets are driven by fluid entry into the cells, and are important for the amplification of localized coagulation in thrombosis.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Uncontrolled Keywords: blood coagulation, blood platelets, cell-derived microparticles, collagen, fluorescent imaging, membrane ballooning, procoagulant-spreading
Publisher: American Heart Association
ISSN: 0009-7322
Date of Acceptance: 19 November 2014
Last Modified: 31 Oct 2022 10:40

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