Abstract

Thromboxane (TXA2), a potent proaggregatory and vasoconstricting eicosanoid, is produced at a very low rate and is cleared rapidly from the human circulation. Its chemically stable hydration product, TXB2, is extensively metabolized through dehydrogenation of the hemiacetal alcohol group at C-11 and beta-oxidation, resulting in the formation of two main enzymatic derivatives (i.e., 11-dehydro-TXB2 and 2,3-dinor-TXB2). A large discrepancy exists between the platelet biosynthetic capacity and actual TXA2 production in vivo. This has both methodological and pathophysiological relevance. Platelet synthesis of TXA2 can be reduced by cyclooxygenase and thromboxane-synthase inhibitors. Furthermore, the platelet and vascular actions of TXA2 can be antagonized by prostaglandin H2/TXA2-receptor antagonists. The combined administration of a thromboxane-synthase inhibitor and a TXA2-receptor antagonist gives stronger inhibition of platelet aggregation and prolongs bleeding time more than either drug alone or acetylsalicylic acid. Finally, TXA2-dependent glomerular damage, as seen in lupus nephritis, might represent a unique therapeutic target for receptor antagonists and/or tissue-selective synthase inhibitors.