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Glycoprotein IIb/IIIa inhibition attenuates platelet-activating factor-induced platelet activation by reducing protein kinase C activity.

W Zhang, N Li, H Hu

Journal: Journal of thrombosis and haemostasis : JTH 2004;1(8):1805-12

PMID: 12911597

Free Full Text on Elsevier Science View on PubMed

Abstract

Glycoprotein (GP)IIb/IIIa inhibition may abolish activated leukocyte-induced platelet activation, in which leukocyte-released platelet-activating factor (PAF) is a major mediator. The present study thus investigated if and how GPIIb/IIIa inhibitors interfere with PAF-induced platelet activation. Platelet and leukocyte activation were monitored by flow cytometry and immunoblotting. GPIIb/IIIa inhibitors (c7E3, non-peptide SR121566, and MAb RFGP56) attenuated PAF-induced, but not adenosine diphosphate (ADP)- or thrombin receptor activating peptide (TRAP)-induced platelet P-selectin expression in whole blood. GPIIb/IIIa blockade enhanced ADP- or TRAP-induced leukocyte CD11b expression, but not the response to PAF. GPIIb/IIIa blockade attenuated PAF-induced, but enhanced ADP- or TRAP-induced platelet-leukocyte aggregation. Under the present experimental conditions, thromboxane A2 receptor antagonism did not significantly influence PAF-induced platelet activation, and GPIIb/IIIa inhibition did not interfere with calcium mobilization/influx in platelets. Protein kinase C (PKC) blockade inhibited PAF-induced platelet P-selectin expression, and PAF-induced PKC activity was reduced by GPIIb/IIIa inhibition. PAF (=1 micro m) did not induce MEK 1/2 or ERK 1/2 phosphorylation, whilst thrombin induced marked responses, which were enhanced by GPIIb/IIIa blockade. Thus, GPIIb/IIIa inhibition attenuates PAF-induced platelet activation via inhibiting PKC activity. GPIIb/IIIa blockade enhances thrombin-induced platelet MEK 1/2 and ERK 1/2 activation, and augments ADP- and TRAP-induced leukocyte activation by enhancing platelet-leukocyte aggregation.

Address: Department of Medicine, Karolinska Hospital, Karolinska Institute, Stockholm, Sweden.
DOI: 10.1046/j.1538-7836.2003.00324.x

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MeSH Terms: Adenosine Diphosphate, Adolescent, Adult, Antibodies, Monoclonal, Blood Platelets, CD11b Antigen, Dose-Response Relationship, Drug, Female, Flow Cytometry, Humans, Immunoblotting, Leukocytes, MAP Kinase Kinase 1, MAP Kinase Kinase 2, Male, Middle Aged, Mitogen-Activated Protein Kinase 1, Mitogen-Activated Protein Kinase 3, Mitogen-Activated Protein Kinase Kinases, Mitogen-Activated Protein Kinases, P-Selectin, Peptide Fragments, Peptides, Phosphorylation, Platelet Activating Factor, Platelet Activation, Platelet Glycoprotein GPIIb-IIIa Complex, Protein Kinase C, Protein-Tyrosine Kinases, Receptors, Thromboxane A2, Prostaglandin H2, Time Factors
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