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Vol. 63, Issue 3, 639-645, March 2003
VA Medical Center, Baylor College of Medicine and Rice University,
Houston, Texas (J.C.R., S.F., G.J., K.A.F., M.C.B., M.H.K.); Wihuri
Research Institute, Helsinki, Finland (J.C.R.); and Monash University,
Clayton, Victoria, Australia (M.C.B.)
Pathologically elevated shear stress triggers aspirin-insensitive
platelet thrombosis. Signaling mechanisms involved in shear-induced platelet thrombosis are not well understood. To investigate these, we
examined the hypothesis that functionally important platelet phosphatidylinositol 3-kinase (PI3-K) activity is stimulated by an in
vitro shear stress of 120 dynes/cm2 (shear rate of 6000 sec
1). Phosphatidylinositol 3,4,5-trisphosphate
(PIP3) production was examined in washed human platelets
subjected to pathological shear stress in a cone-plate viscometer.
PIP3 production peaks 30 s after shear begins and is
initiated by von Willebrand factor (VWF) binding to the glycoprotein
(Gp) Ib-IX-V complex. Inhibiting PI3-K with wortmannin or
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002) results in the inhibition of shear-induced platelet aggregation. In resting platelets, class IA PI3-K associates with the
tyrosine kinase Syk. Within 30 s of beginning shear,
PI3-K-associated Syk becomes tyrosine phosphorylated. Inhibiting Syk
activation with piceatannol results in the inhibition of
PIP3 production and aggregation. Selective blockade of the
P2Y12 receptor results in the inhibition of Syk
phosphorylation, PIP3 production, and aggregation. These
results indicate that shear-induced VWF binding to platelet GpIb-IX-V
stimulates functionally important PI3-K activity. PI3-K activation is
signaled by rapid feedback amplification that involves
P2Y12 receptor-mediated activation of Syk.
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