Establishment of the platelet disorders characterized by impaired signal transduction

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Ca^<2+> ionophores such as A23187 and ionomycin, which transport divalent cations across membranes, were reported to induce platelet activation. Several evidences suggested that secretion and phospholipase C activation induced by Ca^<2+> ionophore are totally dependent upon intact thromboxane. This suggests that platelets with impaired thromboxane formation or impaired response to thromboxane show defective Ca^<2+> ionophore-induced platelet aggregation. In fact, we previously reported that Ca^<2+> ionophore A23187-induced platelet aggregation was markedly reduced in patients with congenital platelet cyclo-oxygenase or with defective TXA_2-induced platelet aggregation. As to the latter disorder, we clarified that Arg^<60> to Leu mutation in the first cytoplasmic loop of the TXA_2 receptor(TXR) causes impaired coupUng between TXR and phoshoplipase C activation.On the other hand, several cases with bleeding tendencies whose platelets respond defectively to Ca^<2+> ionophore without those causes have been reported However, since these cases are rare, the defective site has not been fully elucidated.We analyzed the effect of PGE_1-induced increase in platelet cAMP levels and its inhibition by ADP and epinephrine hi three patients characterized by impaired ADP-induced platelet aggregation. We found that ADP as well as epinephrine lowered the PGE_1-induced cAMP increase in the patient's platelets. This suggests that the patient does not have a defect of the platelet P2Y_<12> receptor for ADP, since, in the patients with this defect, it was reported that epinephrine normally lowered the PGE_1-stimulated platelet cAMP increase, but ADP was without effect. 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^<2+> mobilization and MLC phosphorylation.