Pathogenesis of a bleeding disorder characterized by platelet unresponsiveness to thromboxane A2

A platelet disorder characterized by the absence of thromboxane A(2) (TXA(2))-induced platelet aggregation is a new clinical entity of platelet dysfunction. The platelets of three patients had the ability to bind exogenous TXA(2), but synthetic TXA(2) mimetic-induced postreceptor biochemical events, such as IP3 formation, Ca2+ mobilization, phosphatidic acid formation, and GTPase activities, were selectively defective, suggesting impaired coupling between the TXA(2) receptor and phospholipase C activation. Gene analysis of the TXA(2) receptor showed a substitution of Leu for Arg(60) in the first cytoplasmic loop in all patients, and this mutation seemed to be responsible for this platelet disorder.