Diminished platelet adenylate cyclase activation by prostaglandin D2 in acute thrombosis.
Prostaglandin D2 (PGD2) produced by platelets can inhibit aggregation via activation of platelet adenylate cyclase. PGD2 activation of platelet cyclase in platelet membrane fractions was studied in 20 consecutive patients hospitalized with acute deep-vein thrombosis and/or pulmonary embolism. In nine patients, PGD2-stimulated enzyme activity was decreased at all concentrations of PGD2 studied. This altered enzyme sensitivity was specific for PGD2 as basal enzyme activity, and prostaglandin E1, prostaglandin I2, and sodium fluoride stimulated adenylate cyclase was normal. The effect of PGD2 on platelet aggregation and 14C-serotonin release was also studied in one patient where a four-fold higher concentration of PGD2 was required to inhibit collagen-induced 14C-serotonin release. Binding studies using [3H]PGD2 as a radioligand indicated that this patient's platelets bound 10 fmole PGD2/10(8) platelets compared to 30 fmole/10(8) platelets in a normal control. Five patients had follow-up studies between 2 and 7 mo after their acute thrombotic event, and PGD2-stimulated adenylate cyclase activity returned towards normal in four. Since PGD2 is synthesized in platelets at concentrations sufficient to inhibit aggregation and activate adenylate cyclase, diminished platelet sensitivity to this prostaglandin could result in "hyperactivity" and contribute to the thrombosis observed in these patients.
D000262:Adenylyl Cyclases / Q000378:metabolism*; D001792:Blood Platelets / Q000201:enzymology*; D011464:Epoprostenol / Q000494:pharmacology; D005459:Fluorides / Q000494:pharmacology; D006801:Humans; D010974:Platelet Aggregation / Q000187:drug effects; D011453:Prostaglandins / Q000494:pharmacology*; D011457:Prostaglandins D / Q000494:pharmacology*; D011458:Prostaglandins E / Q000494:pharmacology; D011655:Pulmonary Embolism / Q000201:enzymology*; D013924:Thrombophlebitis / Q000201:enzymology*
D011453:Prostaglandins; D011457:Prostaglandins D; D011458:Prostaglandins E; D011464:Epoprostenol; D000262:Adenylyl Cyclases; D005459:Fluorides