What is the role of genetics in the pathophysiology of pediatric hemolytic uremic syndrome (HUS)?

Updated: Nov 12, 2018
  • Author: Robert S Gillespie, MD, MPH; Chief Editor: Craig B Langman, MD  more...
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TXA2 levels are increased during the acute stage of hemolytic-uremic syndrome, leading to increased platelet aggregation. Another possible cause for increased platelet aggregation is large vWF multimers. In vitro, these large multimers have a greater ability to aggregate platelets than the normal, smaller multimers. Normal plasma contains a vWF-cleaving metalloproteinase (ADAMTS13) that rapidly degrades large vWF multimers. Many cases of TTP are associated with deficient function of ADAMTS13.

Abnormalities of ADAMTS13 may take the form of decreased quantity or absence of the enzyme, a mutation resulting in normal quantity of a defective enzyme, or an antibody inhibitor of the enzyme. Genetic or acquired defects in this protease have also been reported in patients with aHUS, but less frequently than in patients with TTP. Alterations in ADAMTS13 are not involved in the pathogenesis of STEC-HUS. The role of ADAMTS13 in both TTP and, less commonly, aHUS, remains incompletely understood.

WBCs are usually elevated in the blood of patients with hemolytic-uremic syndrome. Activated neutrophils are believed to damage endothelial cells by releasing elastase (a catabolic enzyme that promotes endothelial cell detachment) and by producing free radicals. Monocytes may be stimulated to release cytokines (ie, interleukin 1 and tumor necrosis factor [TNF]) that also damage endothelial cells.

aHUS has several genetic forms. Genetically induced cases are usually not preceded by diarrheal illness, often manifest a recurrent course, and are associated with a more guarded long-term prognosis regarding maintenance of normal kidney function. The best-studied genetic variant of hemolytic-uremic syndrome involves mutations in one of the short consensus repeat segments of the gene for factor H, a protein that regulates complement. Hemolytic-uremic syndrome with factor H mutations usually progresses to end-stage renal disease (ESRD) and has a nearly 100% recurrence rate in renal allografts. [2]

Mutations in factor I and membrane cofactor protein (MCP), also complement regulatory proteins, are also associated with aHUS. Factor I mutations are associated with a very high rate of recurrence, but patients with MCP mutations may have a more favorable long-term prognosis. Mutations of thrombomodulin, another complement regulatory protein, were identified in 5% of a group of patients with aHUS. [3] Autosomal dominant and autosomal recessive forms of aHUS due to a yet unidentified mutation have also been described.

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