Vascular endothelial cell damage plays a central role in the pathogenesis of the hemolytic uremic syndrome (HUS), resulting in intravascular platelet activation and thrombotic microangiopathy. A deficiency of the antiaggregatory prostacyclin (PGI2) has been postulated by experiments under ex vivo conditions. However, this observation has not been confirmed in vivo. The pathophysiological contribution of thromboxane (Tx)A2, a potent vasoconstrictor and platelet-aggregating prostanoid which is predominantly produced by platelets, has not been elucidated so far. In order to quantitate endogenous formation of TxA2 in children with HUS, plasma concentrations of the enzymatic metabolite 11-dehydro-TxB2 of TxA2 and urinary excretion rates of three major TxA2 metabolites, TxB2, 11-dehydro-TxB2 and 2,3-dinor-TxB2 were analyzed using gas chromatography/mass spectrometry. PGI2 biosynthesis was assessed by measuring urinary excretion of an index metabolite of its systemic production, 2,3-dinor-6-keto-prostaglandin (PG) F1 alpha, and an index of its renal production, 6-keto-PGF1 alpha. TxA2 biosynthesis was markedly elevated in the acute phase of HUS. This activation could be detected for a longer period of time than the presence of thrombocytopenia. Concomitantly in the acute phase, renal PGI2 formation was significantly elevated and systemic PGI2 formation was elevated in 50% of the patients. These data indicate that TxA2 formation is increased in the acute phase in patients with HUS. This enhanced biosynthesis is consistent with increased platelet activation, whereas the increased PGI2 biosynthesis reflects predominantly renal endothelial cell damage.

A8STRACT. Schonlein-Henoch purpura (SHP) is an acute immune-mediated vasculitis characterized by infiltration of polymorphonuclear leukocytes into the vessel wall causing damage to the vascular endothelium by the release of proteolytic enzymes. The local inflammatory and thrombotic process may be regulated by increased biosynthesis of vasoacti ve prostanoids. We investigated the biosynthesis of thromboxane A z (TxA z ), a potent vasoconstrictor and platelet agonist, prostacyclin (PGI z ), a vasodilator and platelet antagonist, and prostaglandin E z , a mediator of inflammation, in 14 children with SHP by physicochemical analysis of index metabolites in plasma and urine. TxA z and PGI2 biosynthesis in the systemic circulation was significantly elevated in the acute phase of the disease and correlated with the degree of clinical symptom s. Recurrent episodes of the disea se were associated with phasic increa ses of plasma and urinary TxA z and PGI z metabolites. Renal TxA 2 formation was highest in two patients presenting with the nephrotic syndrome and extracapillary glomerulonephritis. Pro staglandin E z biosynthesis in the systemic circulation was increased in the acute phase of the disea se. The enhanced TxAz formation is consistent with phasic platelet activation in SHP. The increased PGIz biosynthesis reflects endothelial cell damage and may be a response of vascular endothelium to modulate plateletvessel wall and leukocyte-vessel wall interactions. Increa sed prostaglandin E, formation, which probably derives from acti vated polymorphonuclear leukoc ytes and macrophages, is thought to be related to the inflammatory process in SHP. (Pediatr Res 32: 137-140, 1992 ) Abbreviations SHP, Schonlein-Henoch purpura SHP is the most com mon form of vasculitis in child ren (1). The vasculitis is initiated by the subendothelial deposition of IgA/IgG im m une complexes in small blood vessels (2). Complement activation induces infiltratio n of polym orph onuclear leukocytes, which by th e release of prot eolytic enzym es cause damage to th e vessel wall with secondary th rombosis and hem orrhage (3). Th e altered integrity of the vascular endothelium is likely to involve changes in prostanoid biosynthesis at the platelet vascular interface. Tx A 2 , the major cyclooxygenase product of ara chidonic acid in platelets, is a pot ent platelet aggregator and vasocon strictor (4). Th e potential pathophy siologic role of TxA 2 in acute immune-mediated vasculitic disorders has not yet been elucidated.In the present study, we investigated TxA z biosynthesis in childr en with SHP pros pectively during the disease process. To avoid sam pling and analytical probl em s, T xA z biosynthesis was examined by a highly specific and sensitive method, which measures two m ajor urinary enzymatic metabolites, I I-dehydroTx8 2 an d 2,3-dino r-TxB2, which are index metabolites of TxA 2 acti vatio n in th e systemic circulatio n (5, 6), and by measuri ng urin ary Tx B 2 , which predominantly reflects renal TxA 2 form ation (7). In addition , c...