Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation

Mhairi Jane Maxwell, Erik Westein, Warwick Scott Nesbitt, Simon Giuliano, Sacha M Dopheide, Shaun Jackson

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Abstract

Disturbances of blood flow at sites of atherosclerotic plaque rupture are one of the key pathogenic events promoting platelet activation and arterial thrombus formation. Shear effects of platelets have been extensively investigated in vitro; however, the mechanisms by which shear promotes platelet aggregation in vivo remain incompletely understood. By employing high-resolution imaging techniques to in vitro and in vivo thrombosis models, we demonstrate a unique mechanism initiating shear-dependent platelet aggregation involving aggregate formation between discoid platelets. These discoid platelet aggregates are initially unstable and result from the development of membrane tethers between coadhering platelets. Tether formation involves the adhesive function of GPIb/V/IX and integrin alphaIIbbeta3, and conversion of discoid platelet aggregates into stable aggregates requires released ADP. The efficiency of this process is regulated by 3 independent variables, including the reactivity of the adhesive substrate, the level of shear flow, and the platelet density at the adhesive surface. These studies identify a new mechanism initiating platelet aggregation that is critically influenced by shear, physical proximity between translocating platelets, and membrane tether formation. Moreover, they provide a model to explain how the discoid morphology of platelets facilitates the maintenance of adhesive interactions with thrombogenic surfaces under high shear stress conditions.
Original languageEnglish
Pages (from-to)566 - 576
Number of pages11
JournalBlood
Volume109
Issue number2
Publication statusPublished - 2007

Cite this

Maxwell, M. J., Westein, E., Nesbitt, W. S., Giuliano, S., Dopheide, S. M., & Jackson, S. (2007). Identification of a 2-stage platelet aggregation process mediating shear-dependent thrombus formation. Blood, 109(2), 566 - 576.