BLOCKING PLATELET-AGGREGATION INHIBITS THROMBOXANE A(2) FORMATION BY LOW-DOSE AGONISTS BUT DOES NOT INHIBIT PHOSPHORYLATION AND ACTIVATION OF CYTOSOLIC PHOSPHOLIPASE A(2)

Inhibition of aggregation by Ro 44-9883, a potent and selective non-pe ptide GPIIb/IIIa antagonist, resulted in inhibition of serotonin secre tion induced by weak agonists such as ADP or low doses of either throm bin receptor agonist peptide (TRAP) or collagen. In contrast, alpha gr anule secretion was inhibited to different extents dependent on donor, averaging 60% inhibition. Inhibition of serotonin secretion correlate d with an inhibition of thromboxane A(2) (TxA(2)) formation, both of w hich were overcome by higher doses of TRAP or collagen. Ro 44-9883 had no effect on the already reduced serotonin secretion and TxA(2) forma tion in Glanzmann's thrombasthenic platelets. Restoration of serotonin secretion in the absence of aggregation requires both TxA(2) and lyso phosphatidic acid. In addition, Ro 44-9883 inhibition of TxA(2) format ion was not due to a lack of phospholipase A(2) (PLA(2)) phosphorylati on and activation as assayed in vitro. These results suggest that aggr egation is required for weak or low dose agonist induced in vivo activ ity of PLA(2), possibly by either regulating phospholipid substrate av ailability or interaction of PLA(2) with platelet membranes. (C) 1997 Elsevier Science Ltd.