Hemorrhagic Thrombocytopathy with Platelet Thromboxane A₂ Receptor Abnormality: Defective Signal Transduction with Normal Binding Activity

Summary

Subnormal platelet responses to thromboxane A₂ (TXA₂) were found in a patient with polycythemia vera, and the mechanism of this dysfunction was analyzed. The patient’s platelets showed defective aggregation and release reaction to arachidonic acid, enzymatically generated TXA₂ and synthetic TXA₂ mimetics (STA₂, U-46619). In contrast, they showed normal responses to thrombin. When the platelet TXA₂ receptor was examined with both a ¹²⁵I-labelled derivative of a TXA₂ receptor antagonist ([¹²⁵I]-PTA-OH) and a ³H-labelled TXA₂ agonist ([³H]U-46619), the equilibrium dissociation rate constants (Kd) and the maximal concentrations of binding sites (B_max) of the patient’s platelets to both ligands were within normal ranges, suggesting that the binding capacity of their TXA₂ receptor was normal. STA₂ failed to induce normal elevation in the. cytoplasmic free calcium ion concentration, phosphatidic acid formation and 40 kD protein phosphorylation in the patient’s platelets, whereas these responses to thrombin were within normal ranges. 12-O-Tetradecanoyl-phorbol-13-acetate (TPA) also evoked normal response in the 40 kD protein phosphorylation in the patient’s platelets. These results suggested that the patient’s platelets had TXA₂ receptor abnormalities which were characterized by defective transduction of the binding signal to postreceptor reactions after normal TXA₂ binding.

Keywords

Platelet thromboxane A₂ receptor - Defective signal transduction - Platelet dysfunction - Polycythemia vera

• References

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