Impaired signal transduction in neonatal platelets

Previous in vitro studies of cord blood platelets from full-term and preter m neonates have demonstrated decreased responses to most physiologic agonis ts. This hyporesponsiveness is, in part, related to both deficient synthesi s of, and response to, an important mediator of platelet function, thrombox ane A(2)(TxA(2)). The poor response of neonatal platelets to TxA(2) is not due to differences in TxA(2) receptor binding characteristics, when compare d with platelets from adult controls. Therefore, the postreceptor signal tr ansduction pathway was investigated. The TxA(2) receptor is linked via the trimeric GTP-binding protein, Gq, to phospholipase C-beta (PLC beta), and s timulation of platelets with the stable TxA(2) mimetic, U46619, leads to ac tivation of PLC beta and subsequent intracellular signaling events. U46619- induced P-32-phosphatidic acid formation, an index of PLC beta activation, was decreased in platelets of neonates (166 +/- 10%) when compared with adu lt controls (206 +/- 22%) (p < 0.05). Mobilization of intracellular calcium was impaired in platelets of newborns (175 +/- 49 nM) in comparison to adu lt controls (506 +/- 130 nM) (p < 0.01), after stimulation with U46619. U46 619-stimulated GTPase activity was blunted in platelet membrane fractions f rom full-term neonates and almost absent in platelet membranes from preterm infants. Immunoblotting studies of the platelet membrane fractions, quanti fied by densitometric analysis, showed that levels of the G alpha q subunit were not significantly different between adult and neonate, and were not t he cause of the marked differences in GTPase activity. These data suggest t hat signal transduction through the TxA(2) receptor is affected by decrease d activity of Gq in platelets of neonates, and that this defect in signal t ransduction through PLC beta contributes to the observed poor response of n ewborns' platelets to TxA(2) and consequently to TxA(2)-dependent agonists such as collagen.