Von Willebrand factor binding to platelet GPIb initiates signals for platelet activation

The hypothesis that von Willebrand factor (vWF) binding to platelet membrane glycoprotein lb (GpIb) initiates intracellu-lar pathways of platelet activation was studied. We measured the biochemical responses of intact human platelets treated with ristocetin plus vWF multimers purified from human cryo-precipitate. vWF plus ristocetin causes the breakdown of phos-phatidylinositol 4,5-bisphosphate, the production of phospha-tidic acid (PA), the activation of protein kinase C (PKC), in-crease of ionized cytoplasmic calcium (ICa2`J), and the synthesis of thromboxane A2. PA production, PKC activation, and the rise of [Ca211 stimulated by the ristocetin-induced bind-ing ofvWF multimers to platelets are inhibited by an anti-GpIb monoclonal antibody, but are unaffected by anti-GpIIb-IIIa monoclonal antibodies. Indomethacin also inhibits these re-sponses without impairing platelet aggregation induced by vWF plus ristocetin. These results indicate that vWF binding to platelets initiates specific intraplatelet signaling pathways. The mechanism by which this occurs involves an arachidonic acid metabolite-dependent activation of phospholipase C after vWF binding to platelet membrane GpIb. This signal then causes PKC activation and increases of [Ca2+'], which promote platelet secretion and potentiate aggregation. (J. Clin. Invest