Analysis of the Defective Signal Transduction Mechanism through the Platelet Thromboxane A₂ Receptor in a Patient with Polycythemia Vera^[1]

 

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Summary

We previously reported a patient with polycythemia vera whose platelets showed subnormal responses to thromboxane A₂ (TXA₂) (Thromb Haemostas 1987; 57: 158-64). The patient’s platelets showed normal binding activity to TXA₂ analogues but the generation of second messengers was defective. We further studied the mechanism of this dysfunction in this work. The coupling of TXA₂ receptor with its relevant GTP binding protein was examined using STA₂(a synthetic TXA₂ mimetic)-induced augmentation of GTPase activity as its measure. Only subnormal increase in the GTPase activity of the patient’s platelet membrane was found after STA₂ stimulation. Down regulation of TXA₂ receptor of the patient’s platelet also showed abnormal behavior. These results suggested that the defective coupling of TXA₂ receptor with GTP binding protein could be included as a cause of defective signal transduction in this patient’s platelets. This defect might be due to the abnormality of TXA₂ receptor itself if the receptor was down regulated by its phosphorylation through agonist-induced conformational change.

Portions of this work were presented at the 23rd Congress of the International Society of Hematology and 32nd Annual Meeting of the American Society of Hematology, Boston, 1990 and have appeared in abstract form (Blood 76, Suppl 1, 1990; 470a)

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