Increased thromboxane biosynthesis in childhood hemolytic uremic syndrome

Abstract

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.

Shiga Toxin 2 and Lipopolysaccharide Induce Human Microvascular Endothelial Cells To Release Chemokines and Factors That Stimulate Platelet Function

“…7 outlines a general mechanism by which platelets may become activated as a consequence of Stx2 and LPS stimulation of endothelial cells, leading to platelet aggregation and platelet-monocyte interactions. These events are proposed to contribute to the known thrombotic complications and pathogenesis of HUS (8,39,41,60,66,81). We demonstrated (Fig.…”

Pathogenesis of Shiga Toxin-Associated Hemolytic Uremic Syndrome

“…Deficiency may be caused by low production secondary to damaged endothelium, or by high consumption, and may promote platelet aggregation. Thromboxane is a potent vasoconstrictor that is significantly elevated during acute HUS (176).…”

Increased Biosynthesis of Vasoactive Prostanoids in Schönlein-Henoch Purpura

“…In contrast, the present study demonstrates that the in vivo PGI z biosynthesis is increased in the acute phase of SHP. A similar discrepancy between in vivo and ex vivo PGI z production has also been observed in hemolyticuremic syndrome (14) and may be explained by the fact that 140 TONSHOFF ET AL. measurement of ex vivo POI2 stimulating activity, in contra st to POI 2-m etabolite excretion rates, does not reflect the actual biologically effective activity of POh in vivo.…”

“…As in healthy controls (6) and in conditions with increased platelet-vessel wall interaction (14,15), the end ogenous urinary l l-dehydro-TxB 2 excretion rates exceeded tho se of endogenous urina ry 2,3-dinor-TxB2 in the patients with SHP indicating that l l -deh ydro-Txli -is the more abundant urin ary TxA2 metabolite. The combined anal ysis of both the 2,3-dinor and the ll-dehydro metabolites permits us to rule out that incre ased excretion of one metabolite reflects ju st a shift in the metabolic disposit ion of TxA2 and not a true inc reased TxA2 biosynthe sis.…”

“…Increased TxA 2 and POI 2 formation have been reported in other diseases with increased platelet vessel wall interaction such as severe atherosclerosis (15), unstable coronary heart disease (29), a nd systemic sclerosis with Raynaud's phenomenon (30) as models of chronic degenerative vasculopath y and in hemolyticuremic syndrome (14) as a model of acute toxic vasculopathy. The similarity of these findings suggests that although dama ge to the vascular endothelium may result from a variety of insults the response of the vascular endothelium is rather uniform.…”