The roles of ADP and TXA2 in botrocetin/VWF-induced aggregation of washed platelets

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Abstract

Background: Binding of von Willebrand factor (VWF) to the platelet membrane glycoprotein (GP) Ib-IX-V complex initiates a cascade of events leading to αIIbβ3 activation and platelet aggregation. The roles of ADP and thromboxane A2 (TYA2) in agglutination-induced GPIbα-mediated platelet activation have not been fully described. Methods: Botrocetin and human VWF were used to stimulate washed mouse platelets. Platelets deficient in TXA2 receptors, Gαq, or αIIbβ3, and inhibitors and chelating agents were used to investigate the roles of TXA2, ADP, αIIbβ3, and Ca2+ in botrocetin/VWF-induced signaling. Results: Our data demonstrate that botrocetin/VWF/GPIbα-mediated agglutination results in calcium-independent protein kinase C (PKC) and phospholipase A2 (PLA2) activities required for GPIbα-elicited TXA2 production that in turn causes dense granule secretion. Aggregation of washed platelets requires TXA2-induced αIIbβ3 activation and ADP signaling. TXA2 or ADP can activate αIIbβ3, but both are required for α-granule secretion and aggregation. Botrocetin/VWF-induced dense granule secretion is Gαq-dependent. α-Granule secretion requires initial ADP signaling through P2Y1 and subsequent signaling through P2Y12. Signaling initiated by agglutination is propagated and amplified in an αIIbβ3-dependent manner. Conclusions: In contrast to adhesion or shear stress-induced GPIb-elicited signaling, agglutination-elicited GPIb signaling that activates αIIbβ3 requires TXA2. Agglutination-elicited TXA2 production is independent of Ca2+ influx and mobilization of internal Ca2+ stores. Therefore, our results demonstrate that agglutination-elicited GPIb signaling causes αIIbβ3 activation by a mechanism that is distinct from those used by adhesion, or shear stress-induced GPIb signaling. © 2004 International Society on Thrombosis and Haemostasis.

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Liu, J., Pestina, T. I., Berndt, M. C., Steward, S. A., Jackson, C. W., & Gartner, T. K. (2004). The roles of ADP and TXA2 in botrocetin/VWF-induced aggregation of washed platelets. Journal of Thrombosis and Haemostasis, 2(12), 2213–2222. https://doi.org/10.1111/j.1538-7836.2004.01023.x

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