Increased formation of thromboxane in vivo in humans with mastocytosis

Clinical manifestations of mastocytosis are mediated, at least in part, by release of the mast cell mediators histamine and prostaglandin D-2, It has been previously reported that in addition to prostaglandin D-2, mast cells produce other eicosanoids, including thromboxane, Nonetheless, little infor mation exists regarding the formation of other prostanoids in vivo. The mos t accurate method to examine the systemic production of eicosanoids in vivo is the quantitation of urinary metabelites. We previously developed a high ly accurate assay employing mass spectrometry to measure a major urinary me tabolite of thromboxane, Il-dehydro-thromboxane B-2, in humans. We utilized this assay to quantitate thromboxane production in 17 patients with histol ogically proven mastocytosis. We report that thromboxane formation was sign ificantly increased (>2 SD above the mean) in at least one urine sample fro m 65% of patients studied. Of these, 91% of patients with documented system ic involvement had elevated thromboxane generation, In addition, endogenous formation of thromboxane was highly correlated with the urinary excretion of the major urinary metabolite of prostaglandin D-2 (r = 0.98) and N-tau-m ethylhistamine (r = 0.91), suggesting that the cellular source of increased thromboxane in vivo could be the mastocyte, Enhanced thromboxane formation in patients with this disorder is unlikely to be of platelet origin as oth er markers of platelet activation, platelet factor 4 and beta-thromboglobul in, were not increased in three patients with marked overproduction of thro mboxane. Furthermore, the recovery of 11-dehydro-thromboxane B-2 excretion in two patients after the administration of aspirin occurred significantly more rapidly than the recovery of platelet thromboxane generation. These st udies, therefore, report that thromboxane production is significantly incre ased in the majority of patients with mastocytosis that we examined and pro vide the basis to elucidate the role of this eicosanoid in disorders of mas t cell activation.