Impaired platelet response to thromboxane-A2 and defective calcium mobilization in a patient with a bleeding disorder.
Platelet aggregation, secretion, and thromboxane formation induced by various agonists, including arachidonate, prostaglandin-G2 (PGG2), and thromboxane-A2 (TxA2), were examined in a patient with a bleeding disorder who was previously reported to have a TxA2-related defect. Aggregation and 14C-5HT secretion were decreased, and no TxB2 formation occurred in response to adenosine diphosphate (ADP), epinephrine, or collagen. Arachidonate-induced aggregation and TxB2 formation, and PGG2-induced aggregation (but not TxB2 formation) were impaired at low agonist concentrations. The patient's platelets did not aggregate in response to TxA2 generated from arachidonate in normal platelets, but were capable of synthesizing TxA2 from both arachidonate and PGG2. In addition, aggregation and secretion induced by low concentrations of the ionophore A23187 were impaired in platelet-rich plasma (PRP) and in gel-filtered platelets in the absence of extracellular calcium; these responses became normal at higher A23187 concentrations or, in GFP, at low A23187 concentrations in the presence of exogenous calcium. These findings indicate that the TxA2 defect in this patient does not result from a thromboxane synthetase deficiency, but may be due to impaired mobilization of platelet calcium, and thus are consistent with the possibility that TxA2 may act as a calcium ionophore.
D001095:Arachidonic Acids / Q000494:pharmacology; D001778:Blood Coagulation Disorders / Q000097:blood*; D001792:Blood Platelets / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D006801:Humans; D007476:Ionophores; D010974:Platelet Aggregation / Q000187:drug effects; D011462:Prostaglandins G; D012701:Serotonin / Q000378:metabolism; D013928:Thromboxane A2 / Q000494:pharmacology*; D013931:Thromboxanes / Q000494:pharmacology*
D001095:Arachidonic Acids; D007476:Ionophores; D011462:Prostaglandins G; D013931:Thromboxanes; D012701:Serotonin; D013928:Thromboxane A2; D002118:Calcium