thromboxane-a2 and lotrafiban

Collagen and collagen-related peptide (CRP) activate platelets by interacting with glycoprotein (GP)VI. In addition, collagen binds to integrin alpha2beta1 and possibly to other receptors. In this study, we have compared the role of integrins alpha2beta1 and alphaIIbbeta3 in platelet activation induced by collagen and CRP. Inhibitors of ADP and thromboxane A2 (TxA2) substantially attenuated collagen-induced platelet aggregation and dense granule release, whereas CRP-induced responses were only partially inhibited. Under these conditions, a proportion of platelets adhered to the collagen fibres resulting in dense granule release and alphaIIbbeta3 activation. This adhesion was substantially mediated by alpha2beta1. The alphaIIbbeta3 antagonist lotrafiban potentiated CRP-induced dense granule release, suggesting that alphaIIbbeta3 outside-in signalling may attenuate GPVI signals. By contrast, lotrafiban inhibited collagen-induced dense granule release. These results emphasise the differential roles of alpha2beta1 and alphaIIbbeta3 in platelet activation induced by collagen and CRP. Further, they show that although ADP and TxA2 greatly facilitate collagen-induced platelet activation, collagen can induce full activation of those platelets to which it binds in the absence of these mediators, via a mechanism that is dependent on adhesion to alpha2beta1.

Topics: Adenosine Diphosphate; Benzodiazepines; Carrier Proteins; Collagen; Cytoplasmic Granules; Dual Specificity Phosphatase 2; Humans; Integrin alpha2beta1; P-Selectin; Peptides; Piperidines; Platelet Activation; Platelet Aggregation; Platelet Glycoprotein GPIIb-IIIa Complex; Platelet Membrane Glycoproteins; Protein Phosphatase 2; Protein Tyrosine Phosphatases; Thromboxane A2