DEFECTIVE SIGNAL-TRANSDUCTION THROUGH THE THROMBOXANE A(2) RECEPTOR IN A PATIENT WITH A MILD BLEEDING DISORDER - DEFICIENCY OF THE INOSITOL1,4,5-TRIPHOSPHATE FORMATION DESPITE NORMAL G-PROTEIN ACTIVATION

We describe an 11-year-old girl with a mild bleeding disorder since ea rly childhood. The disorder was characterized by a prolonged bleeding time, and the patient's platelets showed defective aggregation respons es to thromboxane A(2) (TXA(2)) mimetic U46619 and arachidonic acid. I n contrast, the platelets showed normal responses to thrombin and Ca i onophore A23187. When the platelet TXA(2) receptor was exam examined w ith the [H-3]-labeled TXA(2) agonist U46619, the equilibrium dissociat ion rate constants (kd) and the maximal concentration of binding sites (Bmax) of the patient's platelets were within normal ranges. Normal G TPase activity was also induced in the patient's platelets by stimulat ion with U46619, however, inositol 1,4,5-triphosphate (IP3) formation was not induced by U46619. These results suggested that the patient's platelets had a defect in phospholipase C activation beyond TXA(2) rec eptors.