Thromboxane A2 biosynthesis in human disease

Thromboxane A2 (TxA2), the predominant cyclooxygenase product of human platelets, is a potent vasoconstrictor and platelet agonist. Although its biological properties are readily appreciable in vitro, it has been difficult to define its biological importance in vivo. To a large extent this reflected the problems associated with efforts to monitor biosynthesis of this eicosanoid and the lack of selective pharmacological probes that prevented the synthesis of TxA2 or antagonized its biological action in vivo. Recently the analysis of urinary metabolites of TxB2 has become simplified so that the methodology is readily applicable to clinical studies. This provides a noninvasive, time-integrated index of Tx biosynthesis. Although one cannot definitively establish a tissue of origin for metabolites measured in urine, indirect evidence suggests that urinary TxB2 derives primarily from the kidney whereas its dinor metabolite predominantly reflects platelet biosynthesis under physiological conditions. Although plasma concentrations of TxB2 are readily confounded by platelet activation ex vivo, the enzymatic metabolites formed from TxB2 have recently been identified and appear to bypass this problem. Combined analysis of long-lived (e.g., 11-dehydro-TxB2) and short-lived (e.g., 2,3-dinor-TxB2) metabolites in plasma promise to more accurately localize phasic increases in the biosynthesis of TxA2 and have been paralleled by the development of antagonists of the TxA2/prostaglandin endoperoxide receptor and their study of humans. The use of such specific probes in conditions characterized by abnormal biosynthesis of TxA2 promises to define the biological role of this mediator for humans.