Defective Signal Transduction through the Thromboxane A₂ Receptor in a Patient with a Miid Bleeding Disorder: Deficiency of the Inositol 1,4,5-Triphosphate Formation despite Normal G-protein Activation

Summary

We describe an 11-year-old girl with a mild bleeding disorder since early childhood. The disorder was characterized by a prolonged bleeding time, and the patient’s platelets showed defective aggregation responses to thromboxane A₂ (TXA₂) mimetic U46619 and arachidonic acid. In contrast, the platelets showed normal responses to thrombin and Ca ionophore A23187. When the platelet TXA₂ receptor was examined with the [³H]-labeled TXA₂ agonist U46619, the equilibrium dissociation rate constants (kd) and the maximal concentration of binding sites (Bmax) of the patient's platelets were within normal ranges. Normal GTPase activity was also induced in the patient's platelets by stimulation 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 TXA₂ receptors.

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