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Aggregation is an essential prerequisite for activation of human platelets by von Willebrand factor
Author(s) -
Kermode John C,
Zheng Qi
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a666-c
Subject(s) - platelet , chemistry , thromboxane a2 , von willebrand factor , ristocetin , platelet activation , glycoprotein ib , platelet membrane glycoprotein , calcium , hemostasis , biophysics , gpvi , endocrinology , receptor , microbiology and biotechnology , medicine , biochemistry , biology , organic chemistry
Interaction of von Willebrand factor (VWF) with the platelet is essential to hemostasis upon vascular injury. Binding to its receptor, glycoprotein Ib‐IX‐V (GpIb‐IX‐V), triggers a rise in intracellular calcium ([Ca 2+ ] i ) and platelet activation. With most agonists, platelets aggregate only after their activation. However, multimeric VWF can cause platelet aggregation (strictly, agglutination) prior to activation. This study examined the role of such aggregation in VWF signaling. Platelet [Ca 2+ ] i was monitored with Fura‐PE3, aggregation simultaneously through changes in light transmittance, and activation through secretion of [ 14 C]serotonin. Ristocetin‐mediated binding of VWF induced a calcium transient and serotonin secretion only when stirring of the platelet suspension permitted aggregation. Moreover, the primary phase of aggregation preceded the calcium signal. Inhibition of cyclo‐oxygenase abolished the VWF‐induced calcium signal and platelet activation. However, the signal in aspirin‐treated platelets was partially restored when they were mixed with untreated platelets. These data suggest that binding of VWF to GpIb‐IX‐V leads to generation of a limited amount of thromboxane A 2 , which attains a concentration sufficient to trigger a calcium rise only within the confines of a platelet aggregate. Interchange of thromboxane A 2 between neighboring platelets in an aggregate plays a major role in signaling. This mechanism may be a means to prevent inadvertent activation of the platelet when only limited binding of VWF occurs, for example under conditions of moderate shear stress or in the event of a small vascular lesion. [Supported by AHA (Southeast Affiliate) and NSF.]