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Blood, 15 September 2004, Vol. 104, No. 6, pp. 1703-1710.
Prepublished online as a Blood First Edition Paper on April 22, 2004; DOI 10.1182/blood-2003-10-3428.
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Submitted October 8, 2003
Accepted April 10, 2004
Impaired platelet response to thrombin and collagen in AKT-1 deficient mice
Juhua Chen, Sarmishtha De, Derek Damron, William S Chen, Nissim Hay, and Tatiana V Byzova*
Department of Molecular Cardiology and Cardiology, Cleveland Clinic Foundation, Cleveland, OH, USA
Department of Anesthesiology, Cleveland Clinic Foundation, Cleveland, OH, USA
Department of Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA
* Corresponding author; email: byzovat{at}ccf.org.
We investigated the role of Akt-1, one of the major downstream effectors of PI3K, in platelet functions using mice in which the gene for Akt-1 had been inactivated. Using ex vivo techniques, we showed that Akt-1 deficient mice exhibited impaired platelet aggregation and spreading in response to various agonists. These differences were most apparent in platelets activated with low concentrations of thrombin. Although Akt-1 is not the predominant Akt isoform in mouse platelets, its absence diminished amount of total phosphoAkt and inhibited increases in intracellular Ca2+ concentration in response to thrombin. Moreover, thrombin-induced platelet  -granule release as well as release of ATP from dense granules was also defective in Akt-1 null platelets. While the absence of Akt-1 did not influence expression of the major platelet receptors for thrombin and collagen, fibrinogen binding in response to these agonists was significantly reduced. As a consequence of impaired aIIbb3 activation and platelet aggregation, Akt-1 null mice showed significantly longer bleeding times than wild type mice.
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