Impaired thromboxane synthesis in preactivated human blood platelets: agonist-specific, irreversible desensitization to thrombin.
The causes for reduced platelet thromboxane synthesis in patients with acquired platelet storage pool disease are incompletely understood. The present study was designed to define the nature of the defect(s) underlying diminished thromboxane synthesis in human platelets previously exposed to thrombin in vitro. Platelets pretreated with high concentrations of thrombin were unable to form measurable amounts of thromboxane in response to a second stimulation with thrombin. In contrast, thrombin-pretreated platelets formed additional thromboxane in response to arachidonate, collagen, or A23,187. Thrombin-pretreated platelets did not recover with respect to thrombin-inducible thromboxane synthesis when incubated for two hours in plasma either in the presence or absence of added arachidonic acid. These observations suggest that neither inactivation of cyclooxygenase nor depletion of endogenous arachidonic acid is responsible for the impaired thrombin-induced thromboxane synthesis in thrombin-prestimulated platelets. Impaired thrombin-induced thromboxane synthesis in these platelets may be due to agonist-specific, irreversible receptor uncoupling.
D001095:Arachidonic Acids / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D000001:Calcimycin / Q000494:pharmacology; D006801:Humans; D013917:Thrombin / Q000494:pharmacology*; D013929:Thromboxane B2 / Q000096:biosynthesis*
D001095:Arachidonic Acids; D000001:Calcimycin; D013929:Thromboxane B2; D013917:Thrombin