Pathogenetic analysis of a bleeding disorder characterized by platelet unresponsiveness to thromboxane A_2

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We already clarified that the Arg^<60> to Leu mutation in the first cytoplasmic loop of the thromboxane _2j (TXA_2) receptor causes a bleeding disorder characterized by platelet unresponsiveness to TXA_2. However, we found other causes of this type of bleeding disorder. The patients had mild to moderate bleeding tendencies, and their platelet aggregation and secretion induced by ADP, collagen, arachidonic acid, stable tyhromboxane A2 and Ca ionophore A23187 was defective or much reduced. The analysis of second messenger formation showed that the inositol 1, 4, 5-triphosphate formation or Ca mobilization induced by thrombin, STA2 or A23187 was normal. Furhtermore, the phosphorylation of 47 K Da protein (pleckstrin) and 20 K Da protein (myosin light chain, MLC) in response to those agonists was normal.These findings suggest that the defective site in the patients' platelets lies in the process distal to or independent of protein kinase C activation, Ca mobilization and MLC phosphorylation.