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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.

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HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY

Continuous signaling via PI3K isoforms beta and {gamma} is required for platelet ADP receptor function in dynamic thrombus stabilization

Judith M. E. M. Cosemans, Imke C. A. Munnix, Reinhard Wetzker, Regine Heller, Shaun P. Jackson, and Johan W. M. Heemskerk

From the Departments of Biochemistry and Human Biology, Cardiovascular Research Institute Maastricht (CARIM), University of Maastricht, the Netherlands; Institute of Molecular Cell Biology, University Hospital Jena, Germany; and the Australian Centre for Blood Diseases, Monash University, Alfred Medical Research Centre and Education Precinct (AMREP), Melbourne, Victoria, Australia.

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 {alpha}IIbbeta3 activation. Here, we studied the disassembly of human and murine thrombi formed on collagen under high shear conditions. Platelet aggregates rapidly disintegrated (1) in the absence of fibrinogen-containing plasma; (2) by blocking or inhibiting {alpha}IIbbeta3; (3) by blocking P2Y12 receptors; (4) by suppression of phosphoinositide 3-kinase (PI3K) beta. In murine blood, absence of PI3K{gamma} led to formation of unstable thrombi, leading to dissociation of multiplatelet aggregates. In addition, blocking PI3Kbeta 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 {alpha}IIbbeta3 and no longer bound fibrinogen. Together, the data indicate that continuous outside-in signaling via P2Y12 and both PI3Kbeta and PI3K{gamma} isoforms is required for perpetuated {alpha}IIbbeta3 activation and maintenance of a platelet aggregate. This novel concept of intrinsic, dynamic thrombus instability gives possibilities for the use of antiplatelet therapy.


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