UC Irvine

Shiga toxin-producing E. coli hemolytic-uremic syndrome (STEC-HUS) is characterized by acute renal failure associated with thrombocytopenia and mciroangiopathic hemolytic anemia following exposure to STEC. It may present with spectrum of multi-organ dysfunction syndrome (MODS). Pathogenesis of STEC-HUS is partially understood. Proposed is two sequential molecular pathogeneses. First path is from Shiga toxins to endotheliopathy as a result of organotropism and endothelial heterogeneity. Shiga toxins binding to Gb3-endowed ECs, leads to endotheliopathy in the kidneys and other organs. Also, Shiga toxins downregulating CD59 provoke unprotected activation of complement, in which C5b-9 causes channel formation and promotes additional endotheliopathy. Second path is from endotheliopathy to microthrombogenesis. Endotheliopathy triggers activation of two independent molecular pathways (i.e., inflammatory and microthrombotic), promoting inflammation and formation of “microthrombi” composed of platelet and unusually large von Willebrand factor multimers (ULVWF) complexes. Microthrombogenesis is initiated by the activated platelet and endothelial exocytosis of ULVWF. If ADAMTS13 is insufficient due to excessive production of ULVWF, uncleaved ULVWF are anchored to ECs. ULVWF anchored to Gb3-endowed and CD59-disendowed ECs in situ are long elongated strings and recruit the activated platelets to assemble microthrombi. Microthrombi cause disseminated intravascular microthrombosis (DIT), leading to vascular microthrombotic disease (VMTD). The result is organ phenotype syndromes of MODS such as HUS, encephalopathy, acute respiratory distress syndrome (ARDS), etc. DIT/VMTD triggers thrombotic thrombocytopenic purpura (TTP)-like syndrome. Current understanding of Gb3 and CD59 roles and experience with complement inhibition therapy support the complex molecular pathogenesis of STEC-HUS is due to heterogeneity-associated endotheliopathy, leading to impaired ADAMTS13 function.