Escherichia coli O157:H7-associated hemolytic uremic syndrome (HUS) remains a challenging medical problem. Extensive thrombogenesis, with accompanying fibrinolysis inhibition, precede the earliest indications of renal injury. Trends in thrombogenesis moreover predict the severity of ensuing HUS. Presumably, a massive endothelial injury before renal injury leads to HUS. This injury is amenable to study, and, possibly, to the attenuation of its effects. In this grant, the thrombogenic process in infected children will be studied intensively. Specifically, we will test the hypotheses that thrombogenesis clearly precedes renal injury, and that the rate of fibrin formation on initial assessment of E. coli O157:H7 infections is associated with outcome (Aim 1). To further assess the coagulation lesion, we will also test the hypotheses that net interval accumulation of fibrin between the first and second day of observation predicts outcome of this infection, and that time-dependent changes in prothrombotic kinetics underlie the pathophysiologic cascade leading to the development of HUS (Aim 2). We will also use our unique population to test the hypotheses that (a) the degree of activation of the complement system predicts outcome in children with E. coli O157:H7 infection, and (b) one or more factor H gene polymorphisms is associated with this outcome (Aim 3). Finally, because the endothelial cell is likely to be critical in the evolution of HUS, we will test the hypothesis that differences between the concentration of circulating endothelial cells in infected children predict outcome. We shall also test the subsidiary hypothesis that these cells express proteins plausibly related to their in situ injury or activation (Aim 4). A unique network has been assembled to identify children at risk of developing HUS an average of three days before HUS develops. This is an inadequately studied, but absolutely appropriate, model for toxin-related HUS. This network will be amalgamated with investigative expertise in the fields of coagulation assessment, complement pathophysiology and genetics, and endothelial cell biology. The project seeks a more complete understanding of the cascade leading to HUS, and, with this knowledge, the successful interdiction of this process.
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