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.
Key Points
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The main characteristics of haemolytic uraemic syndrome (HUS) and thrombotic thrombocytopaenic purpura (TTP) are microvascular thrombosis and endothelial damage, with consequent thrombocytopaenia, haemolytic anaemia and multiorgan dysfunction
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Clinical presentation of these conditions frequently overlaps, but molecular studies have identified three distinct causes: Shiga toxins (Stxs) trigger STEC-HUS; defects in complement regulation cause atypical HUS (aHUS); and ADAMTS13 deficiency underlies TTP
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The complement system is comprised of a complex array of plasma proteins central in innate immunity, with key functions in the clearance of pathogens and cell debris and amplification of inflammation and haemostasis
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Healthy cells are equipped with a series of complement regulators, preventing its inappropriate activation; if such mechanisms are dysfunctional or overridden, complement hyperactivation can culminate in endothelial perturbation and microvascular thrombosis
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Complement hyperactivation stems from the effects of Stxs on the endothelium and complement regulators in STEC-HUS, genetic defects in the complement system in aHUS, and platelet thrombi arising as a result of ADAMTS13 deficiency in TTP
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Clinical use of eculizumab has produced promising preliminary results not only in aHUS, but also in STEC-HUS and TTP, providing additional evidence that complement may be a common pathogenetic link in these three disorders
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Acknowledgements
The authors' work has been partially supported by grants from Fondazione ART per la Ricerca sui Trapianti ONLUS (Milan, Italy), and Fondazione ARMR ONLUS Aiuti per la Ricerca sulle Malattie Rare (Bergamo, Italy).
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F. Mescia researched data to include in the manuscript. M. Noris and F. Mescia wrote the manuscript. M. Noris and G. Remuzzi contributed to discussion of content for the article, and reviewed and edited the manuscript before submission.
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Noris, M., Mescia, F. & Remuzzi, G. STEC-HUS, atypical HUS and TTP are all diseases of complement activation. Nat Rev Nephrol 8, 622–633 (2012). https://doi.org/10.1038/nrneph.2012.195
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DOI: https://doi.org/10.1038/nrneph.2012.195
