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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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

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(IIb)beta(3) 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(IIb)beta(3); (3) by blocking P2Y(12) receptors; (4) by suppression of phosphoinositide 3-kinase ( PI3K) beta. In murine blood, absence of PI3Kgamma 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 P2Y(12) or PI3K isoforms, resulting in single platelets that had inactivated alpha(IIb)beta(3) and no longer bound fibrinogen. Together, the data indicate that continuous outside-in signaling via P2Y(12) and both PI3Kbeta and PI3Kgamma isoforms is required for perpetuated alpha(IIb)beta(3) activation and maintenance of a platelet aggregate. This novel concept of intrinsic, dynamic thrombus instability gives possibilities for the use of antiplatelet therapy.[1]


  1. Continuous signaling via PI3K isoforms beta and {gamma} is required for platelet ADP receptor function in dynamic thrombus stabilization. Cosemans, J.M., Munnix, I.C., Wetzker, R., Heller, R., Jackson, S.P., Heemskerk, J.W. Blood (2006) [Pubmed]
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