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Blood, 1 November 2006, Vol. 108, No. 9, pp. 3045-3052. Prepublished online as a Blood First Edition Paper on July 13, 2006; DOI 10.1182/blood-2006-03-006338. This Article Full Text (PDF) Supplemental Videos All Versions of this Article: blood-2006-03-006338v1 108/9/3045    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Cosemans, J. Articles by Heemskerk, J. Search for Related Content PubMed PubMed Citation Articles by Cosemans, J. Articles by Heemskerk, J. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted March 1, 2006 Accepted June 23, 2006 Continuous signaling via PI3K isoforms and is required for platelet ADP receptor function in dynamic thrombus stabilization Judith Cosemans, Imke Munnix, Reinhard Wetzker, Regine Heller, Shaun Jackson, and Johan Heemskerk* Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, The Netherlands Institute of Molecular Cell Biology, University Hospital Jena, Jena, Germany Australian Centre for Blood Diseases, Monash University, (AMREP), Melbourne, Victoria, Australia * Corresponding author; email: jwm.heemskerk{at}bioch.unimaas.nl. Signaling from collagen and G-protein-coupled receptors leads to platelet adhesion and subsequent thrombus formation. Paracrine agonists such as ADP, thromboxane and Gas6 are required for platelet aggregate formation. We hypothesized that thrombi are intrinsically unstable structures and that their stabilization requires persistent paracrine activity and continuous signaling, maintaining integrin IIb3 activation. Here, we studied the disassembly of human and murine thrombi formed on collagen under high shear conditions. Platelet aggregates rapidly disintegrated: (a) in the absence of fibrinogen-containing plasma; (b) by blocking or inhibiting IIb3; (c) by blocking P2Y12 receptors; (d) by suppression of phosphoinositide 3-kinase (PI3K). In murine blood, absence of PI3K led to formation of unstable thrombi, leading to dissociation of multi-platelet aggregates. In addition, blocking PI3K delayed initial thrombus formation, and reduced individual platelet-platelet contact. Similarly without flow, agonist-induced aggregation was reversed by late suppression of P2Y12 or PI3K isoforms, resulting in single platelets that had inactivated IIb3 and no longer bound fibrinogen. Together, the data indicates that continuous outside-in signaling via P2Y12 and both PI3K and PI3K isoforms is required for perpetuated IIb3 activation and maintenance of a platelet aggregate. This novel concept of intrinsic, dynamic thrombus instability gives possibilities for the use of anti-platelet therapy. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Thrombus formation: stability matters Lawrence F. Brass Blood 2006 108: 2883-2884. [Full Text] [PDF] This article has been cited by other articles: S. M. Schoenwaelder, A. Ono, S. Sturgeon, S. M. Chan, P. Mangin, M. J. Maxwell, S. Turnbull, M. Mulchandani, K. Anderson, G. Kauffenstein, et al. Identification of a Unique Co-operative Phosphoinositide 3-Kinase Signaling Mechanism Regulating Integrin {alpha}IIbbeta3 Adhesive Function in Platelets J. Biol. Chem., September 28, 2007; 282(39): 28648 - 28658. [Abstract] [Full Text] [PDF] A. O. Maree and D. J. Fitzgerald Variable Platelet Response to Aspirin and Clopidogrel in Atherothrombotic Disease Circulation, April 24, 2007; 115(16): 2196 - 2207. [Full Text] [PDF]

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