von Willebrand factor binding to platelet GpIb initiates signals for platelet activation.
The hypothesis that von Willebrand factor (vWF) binding to platelet membrane glycoprotein Ib (GpIb) initiates intracellular pathways of platelet activation was studied. We measured the biochemical responses of intact human platelets treated with ristocetin plus vWF multimers purified from human cryoprecipitate. vWF plus ristocetin causes the breakdown of phosphatidylinositol 4,5-bisphosphate, the production of phosphatidic acid (PA), the activation of protein kinase C (PKC), increase of ionized cytoplasmic calcium ([Ca2+]i), and the synthesis of thromboxane A2. PA production, PKC activation, and the rise of [Ca2+]i stimulated by the ristocetin-induced binding of vWF multimers to platelets are inhibited by an anti-GpIb monoclonal antibody, but are unaffected by anti-GpIIb-IIIa monoclonal antibodies. Indomethacin also inhibits these responses 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+]i, which promote platelet secretion and potentiate aggregation.
Kroll
M H
MH
Houston Veterans Affairs Medical Center, Baylor College of Medicine, Texas 77030.
Harris
T S
TS
Moake
J L
JL
Handin
R I
RI
Schafer
A I
AI
D002118:Calcium / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D010766:Phosphorylation; D015539:Platelet Activation; D010974:Platelet Aggregation; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism*; D011493:Protein Kinase C / Q000502:physiology; D012310:Ristocetin / Q000494:pharmacology; D015398:Signal Transduction / Q000502:physiology*; D013928:Thromboxane A2 / Q000096:biosynthesis; D014841:von Willebrand Factor / Q000378:metabolism*
D010980:Platelet Membrane Glycoproteins; D014841:von Willebrand Factor; D012310:Ristocetin; D013928:Thromboxane A2; D011493:Protein Kinase C; D002118:Calcium