title: STEC-HUS, atypical HUS and TTP are all diseases of complement activation.
abstract: Haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP) are diseases characterized by microvascular thrombosis, with consequent thrombocytopaenia, haemolytic anaemia and dysfunction of affected organs. Advances in our understanding of the molecular pathology led to the recognition of three different diseases: typical HUS caused by Shiga toxin-producing Escherichia coli (STEC-HUS); atypical HUS (aHUS), associated with genetic or acquired disorders of regulatory components of the complement system; and TTP that results from a deficiency of ADAMTS13, a plasma metalloprotease that cleaves von Willebrand factor. In this Review, we discuss data indicating that complement hyperactivation is a common pathogenetic effector that leads to endothelial damage and microvascular thrombosis in all three diseases. In STEC-HUS, the toxin triggers endothelial complement deposition through the upregulation of P-selectin and possibly interferes with the activity of complement regulatory molecules. In aHUS, mutations in the genes coding for complement components predispose to hyperactivation of the alternative pathway of complement. In TTP, severe ADAMTS13 deficiency leads to generation of massive platelet thrombi, which might contribute to complement activation. More importantly, evidence is emerging that pharmacological targeting of complement with the anti-C5 monoclonal antibody eculizumab can effectively treat not only aHUS for which it is indicated, but also STEC-HUS and TTP in some circumstances.
authors.affiliation: Clinical Research Center for Rare Diseases, Aldo e Cele Daccò, Mario Negri Institute for Pharmacological Research, Via G. B. Camozzi 3, Ranica, 24020 Bergamo, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Noris
authors.forename: Federica
authors.initials: F
authors.lastname: Mescia
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Remuzzi
mesh_terms: D051722:ADAM Proteins / Q000172:deficiency; D000071120:ADAMTS13 Protein; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000627:therapeutic use; D065766:Atypical Hemolytic Uremic Syndrome; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology*; D003179:Complement C3b / Q000276:immunology; D004730:Endothelium, Vascular / Q000276:immunology; D006463:Hemolytic-Uremic Syndrome / Q000188:drug therapy / Q000276:immunology* / Q000382:microbiology*; D006801:Humans; D007155:Immunologic Factors / Q000276:immunology; D015539:Platelet Activation / Q000502:physiology; D011697:Purpura, Thrombotic Thrombocytopenic / Q000188:drug therapy / Q000276:immunology*
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D007155:Immunologic Factors; D003179:Complement C3b; C481642:eculizumab; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human