Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

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.

Key Points

  • 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

  • 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

  • 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

  • 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

  • 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

  • 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

Your institute does not have access to this article

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Representation of the classical, lectin and alternative pathways of complement activation, including regulatory molecules.
Figure 2: Complement activation as a common pathogenetic link in STEC-HUS, aHUS and TTP.

References

  1. Ruggenenti, P., Noris, M. & Remuzzi, G. Thrombotic microangiopathy, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura. Kidney Int. 60, 831–846 (2001).

    Article  CAS  PubMed  Google Scholar 

  2. Remuzzi, G. et al. von Willebrand factor cleaving protease (ADAMTS13) is deficient in recurrent and familial thrombotic thrombocytopenic purpura and hemolytic uremic syndrome. Blood 100, 778–785 (2002).

    Article  CAS  PubMed  Google Scholar 

  3. Remuzzi, G. HUS and TTP: variable expression of a single entity. Kidney Int. 32, 292–308 (1987).

    Article  CAS  PubMed  Google Scholar 

  4. Tarr, P. I., Gordon, C. A. & Chandler, W. L. Shiga-toxin-producing Escherichia coli and haemolytic uraemic syndrome. Lancet 365, 1073–1086 (2005).

    CAS  PubMed  Google Scholar 

  5. Noris, M. & Remuzzi, G. Atypical hemolytic-uremic syndrome. N. Engl. J. Med. 361, 1676–1687 (2009).

    Article  CAS  PubMed  Google Scholar 

  6. Kavanagh, D. & Goodship, T. Genetics and complement in atypical HUS. Pediatr. Nephrol. 25, 2431–2442 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  7. Furlan, M. et al. von Willebrand factor-cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic-uremic syndrome. N. Engl. J. Med. 339, 1578–1584 (1998).

    Article  CAS  PubMed  Google Scholar 

  8. Tsai, H. M. & Lian, E. C. Antibodies to von Willebrand factor-cleaving protease in acute thrombotic thrombocytopenic purpura. N. Engl. J. Med. 339, 1585–1594 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Tsai, H. M. Pathophysiology of thrombotic thrombocytopenic purpura. Int. J. Hematol. 91, 1–19 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  10. Tsai, H. M. Is severe deficiency of ADAMTS-13 specific for thrombotic thrombocytopenic purpura? Yes. J. Thromb. Haemost. 1, 625–631 (2003).

    Article  PubMed  Google Scholar 

  11. Sarma, J. V. & Ward, P. A. The complement system. Cell Tissue Res. 343, 227–235 (2011).

    Article  CAS  PubMed  Google Scholar 

  12. Ricklin, D., Hajishengallis, G., Yang, K. & Lambris, J. D. Complement: a key system for immune surveillance and homeostasis. Nat. Immunol. 11, 785–797 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Morigi, M. et al. Alternative pathway activation of complement by Shiga toxin promotes exuberant C3a formation that triggers microvascular thrombosis. J. Immunol. 187, 172–180 (2011).

    Article  CAS  PubMed  Google Scholar 

  14. Ikeda, K. et al. C5a induces tissue factor activity on endothelial cells. Thromb. Haemost. 77, 394–398 (1997).

    Article  CAS  PubMed  Google Scholar 

  15. Tedesco, F. et al. The cytolytically inactive terminal complement complex activates endothelial cells to express adhesion molecules and tissue factor procoagulant activity. J. Exp. Med. 185, 1619–1627 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Platt, J. L. et al. Release of heparan sulfate from endothelial cells. Implications for pathogenesis of hyperacute rejection. J. Exp. Med. 171, 1363–1368 (1990).

    Article  CAS  PubMed  Google Scholar 

  17. Saadi, S. & Platt, J. L. Transient perturbation of endothelial integrity induced by natural antibodies and complement. J. Exp. Med. 181, 21–31 (1995).

    Article  CAS  PubMed  Google Scholar 

  18. Kilgore, K. S., Ward, P. A. & Warren, J. S. Neutrophil adhesion to human endothelial cells is induced by the membrane attack complex: the roles of P-selectin and platelet activating factor. Inflammation 22, 583–598 (1998).

    Article  CAS  PubMed  Google Scholar 

  19. Albrecht, E. A. et al. C5a-induced gene expression in human umbilical vein endothelial cells. Am. J. Pathol. 164, 849–859 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Dobrina, A. et al. Cytolytically inactive terminal complement complex causes transendothelial migration of polymorphonuclear leukocytes in vitro and in vivo. Blood 99, 185–192 (2002).

    Article  CAS  PubMed  Google Scholar 

  21. Niculescu, F. & Rus, H. Mechanisms of signal transduction activated by sublytic assembly of terminal complement complexes on nucleated cells. Immunol. Res. 24, 191–199 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Klos, A. et al. The role of the anaphylatoxins in health and disease. Mol. Immunol. 46, 2753–2766 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Polley, M. J. & Nachman, R. The human complement system in thrombin-mediated platelet function. J. Exp. Med. 147, 1713–1726 (1978).

    Article  CAS  PubMed  Google Scholar 

  24. Polley, M. J. & Nachman, R. L. Human platelet activation by C3a and C3a des-arg. J. Exp. Med. 158, 603–615 (1983).

    Article  CAS  PubMed  Google Scholar 

  25. Wiedmer, T. & Sims, P. J. Effect of complement proteins C5b-9 on blood platelets. Evidence for reversible depolarization of membrane potential. J. Biol. Chem. 260, 8014–8019 (1985).

    CAS  PubMed  Google Scholar 

  26. Ando, B., Wiedmer, T., Hamilton, K. K. & Sims, P. J. Complement proteins C5b-9 initiate secretion of platelet storage granules without increased binding of fibrinogen or von Willebrand factor to newly expressed cell surface GPIIb-IIIa. J. Biol. Chem. 263, 11907–11914 (1988).

    CAS  PubMed  Google Scholar 

  27. Wiedmer, T., Esmon, C. T. & Sims, P. J. On the mechanism by which complement proteins C5b-9 increase platelet prothrombinase activity. J. Biol. Chem. 261, 14587–14592 (1986).

    CAS  PubMed  Google Scholar 

  28. Sims, P. J., Faioni, E. M., Wiedmer, T. & Shattil, S. J. Complement proteins C5b-9 cause release of membrane vesicles from the platelet surface that are enriched in the membrane receptor for coagulation factor Va and express prothrombinase activity. J. Biol. Chem. 263, 18205–18212 (1988).

    CAS  PubMed  Google Scholar 

  29. Ståhl, A. L. et al. Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation. Blood 111, 5307–5315 (2008).

    Article  CAS  PubMed  Google Scholar 

  30. Gushiken, F. C., Han, H., Li, J., Rumbaut, R. E. & Afshar-Kharghan, V. Abnormal platelet function in C3-deficient mice. J. Thromb. Haemost. 7, 865–870 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Høgåsen, A. K., Würzner, R., Abrahamsen, T. G. & Dierich, M. P. Human polymorphonuclear leukocytes store large amounts of terminal complement components C7 and C6, which may be released on stimulation. J. Immunol. 154, 4734–4740 (1995).

    PubMed  Google Scholar 

  32. Botto, M., Lissandrini, D., Sorio, C. & Walport, M. J. Biosynthesis and secretion of complement component (C3) by activated human polymorphonuclear leukocytes. J. Immunol. 149, 1348–1355 (1992).

    CAS  PubMed  Google Scholar 

  33. Vogt, W. Complement activation by myeloperoxidase products released from stimulated human polymorphonuclear leukocytes. Immunobiology 195, 334–346 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Camous, L. et al. Complement alternative pathway acts as a positive feedback amplification of neutrophil activation. Blood 117, 1340–1349 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Peerschke, E. I., Yin, W. & Ghebrehiwet, B. Complement activation on platelets: implications for vascular inflammation and thrombosis. Mol. Immunol. 47, 2170–2175 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Amara, U. et al. Molecular intercommunication between the complement and coagulation systems. J. Immunol. 185, 5628–5636 (2010).

    Article  CAS  PubMed  Google Scholar 

  37. Frank, C. et al. for the HUS Investigation Team. Epidemic profile of Shiga-toxin-producing Escherichia coli O104:H4 outbreak in Germany. N. Engl. J. Med. 365, 1771–1780 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Rasko, D. A. et al. Origins of the E. coli strain causing an outbreak of hemolytic-uremic syndrome in Germany. N. Engl. J. Med. 365, 709–717 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Obrig, T. G. et al. Endothelial heterogeneity in Shiga toxin receptors and responses. J. Biol. Chem. 268, 15484–15488 (1993).

    CAS  PubMed  Google Scholar 

  40. Johannes, L. & Römer, W. Shiga toxins—from cell biology to biomedical applications. Nat. Rev. Microbiol. 8, 105–116 (2010).

    Article  CAS  PubMed  Google Scholar 

  41. Zoja, C. et al. Shiga toxin-2 triggers endothelial leukocyte adhesion and transmigration via NF-κB dependent up-regulation of IL-8 and MCP-1. Kidney Int. 62, 846–856 (2002).

    Article  CAS  PubMed  Google Scholar 

  42. Petruzziello-Pellegrini, T. N. et al. The CXCR4/CXCR7/SDF-1 pathway contributes to the pathogenesis of Shiga toxin-associated hemolytic uremic syndrome in humans and mice. J. Clin. Invest. 122, 759–776 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Morigi, M. et al. Verotoxin-1 promotes leukocyte adhesion to cultured endothelial cells under physiologic flow conditions. Blood 86, 4553–4558 (1995).

    CAS  PubMed  Google Scholar 

  44. Morigi, M. et al. Verotoxin-1-induced up-regulation of adhesive molecules renders microvascular endothelial cells thrombogenic at high shear stress. Blood 98, 1828–1835 (2001).

    Article  CAS  PubMed  Google Scholar 

  45. Nestoridi, E., Tsukurov, O., Kushak, R. I., Ingelfinger, J. R. & Grabowski, E. F. Shiga toxin enhances functional tissue factor on human glomerular endothelial cells: implications for the pathophysiology of hemolytic uremic syndrome. J. Thromb. Haemost. 3, 752–762 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Karpman, D. et al. Platelet activation by Shiga toxin and circulatory factors as a pathogenetic mechanism in the hemolytic uremic syndrome. Blood 97, 3100–3108 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. van Setten, P. A., Monnens, L. A., Verstraten, R. G., van den Heuvel, L. P. & van Hinsbergh, V. W. Effects of verocytotoxin-1 on nonadherent human monocytes: binding characteristics, protein synthesis, and induction of cytokine release. Blood 88, 174–183 (1996).

    CAS  PubMed  Google Scholar 

  48. Cameron, J. S. & Vick, R. Letter: Plasma-C3 in haemolytic-uraemic syndrome and thrombotic thrombocytopenic purpura. Lancet 2, 975 (1973).

    Article  CAS  PubMed  Google Scholar 

  49. Kaplan, B. S., Thomson, P. D. & MacNab, G. M. Letter: Serum-complement levels in haemolytic-uraemic syndrome. Lancet 2, 1505–1506 (1973).

    Article  CAS  PubMed  Google Scholar 

  50. Monnens, L., Hendrickx, G., van Wieringen, P. & van Munster, P. Letter: Serum-complement levels in haemolytic-uraemic syndrome. Lancet 2, 294 (1974).

    Article  CAS  PubMed  Google Scholar 

  51. Robson, W. L., Leung, A. K., Fick, G. H. & McKenna, A. I. Hypocomplementemia and leukocytosis in diarrhea-associated hemolytic uremic syndrome. Nephron 62, 296–299 (1992).

    Article  CAS  PubMed  Google Scholar 

  52. Lapeyraque, A. L. et al. Eculizumab in severe Shiga-toxin-associated HUS. N. Engl. J. Med. 364, 2561–2563 (2011).

    Article  CAS  PubMed  Google Scholar 

  53. Monnens, L., Molenaar, J., Lambert, P. H., Proesmans, W. & van Munster, P. The complement system in hemolytic-uremic syndrome in childhood. Clin. Nephrol. 13, 168–171 (1980).

    CAS  PubMed  Google Scholar 

  54. Thurman, J. M. et al. Alternative pathway of complement in children with diarrhea-associated hemolytic uremic syndrome. Clin. J. Am. Soc. Nephrol. 4, 1920–1924 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Ståhl, A. L., Sartz, L. & Karpman, D. Complement activation on platelet-leukocyte complexes and microparticles in enterohemorrhagic Escherichia coli-induced hemolytic uremic syndrome. Blood 117, 5503–5513 (2011).

    Article  CAS  PubMed  Google Scholar 

  56. Del Conde, I., Crúz, M. A., Zhang, H., López, J. A. & Afshar-Kharghan, V. Platelet activation leads to activation and propagation of the complement system. J. Exp. Med. 201, 871–879 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Orth, D. et al. Shiga toxin activates complement and binds factor H: evidence for an active role of complement in hemolytic uremic syndrome. J. Immunol. 182, 6394–6400 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Karmali, M. A. et al. The association between idiopathic hemolytic uremic syndrome and infection by verotoxin-producing Escherichia coli. J. Infect. Dis. 151, 775–782 (1985).

    Article  CAS  PubMed  Google Scholar 

  59. Caprioli, A. et al. Hemolytic-uremic syndrome and Vero cytotoxin-producing Escherichia coli infection in Italy. The HUS Italian Study Group. J. Infect. Dis. 166, 154–158 (1992).

    Article  CAS  PubMed  Google Scholar 

  60. Stühlinger, W., Kourilsky, O., Kanfer, A. & Sraer, J. D. Letter: Haemolytic-uraemic syndrome: evidence for intravascular C3 activation. Lancet 2, 788–789 (1974).

    Article  PubMed  Google Scholar 

  61. Carreras, L. et al. Familial hypocomplementemic hemolytic uremic syndrome with HLA-A3,B7 haplotype. JAMA 245, 602–604 (1981).

    Article  CAS  PubMed  Google Scholar 

  62. Warwicker, P. et al. Genetic studies into inherited and sporadic hemolytic uremic syndrome. Kidney Int. 53, 836–844 (1998).

    Article  CAS  PubMed  Google Scholar 

  63. Noris, M., Bresin, E., Mele, C., Remuzzi, G. & Caprioli, J. Atypical hemolytic-uremic syndrome. NCBI Bookshelf [online], (2011).

    Google Scholar 

  64. Neumann, H. P. et al. Haemolytic uraemic syndrome and mutations of the factor H gene: a registry-based study of German speaking countries. J. Med. Genet. 40, 676–681 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Caprioli, J. et al. Genetics of HUS: the impact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 108, 1267–1279 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Richards, A. et al. Factor H mutations in hemolytic uremic syndrome cluster in exons 18–20, a domain important for host cell recognition. Am. J. Hum. Genet. 68, 485–490 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Noris, M. et al. Familial haemolytic uraemic syndrome and an MCP mutation. Lancet 362, 1542–1547 (2003).

    Article  CAS  PubMed  Google Scholar 

  68. Richards, A. et al. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc. Natl Acad. Sci. USA 100, 12966–12971 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Fremeaux-Bacchi, V. et al. Complement factor I: a susceptibility gene for atypical haemolytic uraemic syndrome. J. Med. Genet. 41, e84 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Kavanagh, D. et al. Mutations in complement factor I predispose to development of atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 16, 2150–2155 (2005).

    Article  CAS  PubMed  Google Scholar 

  71. Bienaime, F. et al. Mutations in components of complement influence the outcome of factor I-associated atypical hemolytic uremic syndrome. Kidney Int. 77, 339–349 (2010).

    Article  CAS  PubMed  Google Scholar 

  72. Delvaeye, M. et al. Thrombomodulin mutations in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 361, 345–357 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Frémeaux-Bacchi, V. et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 112, 4948–4952 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Goicoechea de Jorge, E. et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc. Natl Acad. Sci. USA 104, 240–245 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Dragon-Durey, M. A. et al. Anti-factor H autoantibodies associated with atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 16, 555–563 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Dragon-Durey, M. A. et al. Clinical features of anti-factor H autoantibody-associated hemolytic uremic syndrome. J. Am. Soc. Nephrol. 21, 2180–2187 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  77. Ferreira, V. P. et al. The binding of factor H to a complex of physiological polyanions and C3b on cells is impaired in atypical hemolytic uremic syndrome. J. Immunol. 182, 7009–7018 (2009).

    Article  CAS  PubMed  Google Scholar 

  78. Manuelian, T. et al. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J. Clin. Invest. 111, 1181–1190 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Heinen, S. et al. Hemolytic uremic syndrome: a factor H mutation (E1172Stop) causes defective complement control at the surface of endothelial cells. J. Am. Soc. Nephrol. 18, 506–514 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Strobel, S. et al. Functional analyses indicate a pathogenic role of factor H autoantibodies in atypical haemolytic uraemic syndrome. Nephrol. Dial. Transplant. 25, 136–144 (2010).

    Article  CAS  PubMed  Google Scholar 

  81. Józsi, M. et al. Anti factor H autoantibodies block C-terminal recognition function of factor H in hemolytic uremic syndrome. Blood 110, 1516–1518 (2007).

    Article  CAS  PubMed  Google Scholar 

  82. Fremeaux-Bacchi, V. et al. Genetic and functional analyses of membrane cofactor protein (CD46) mutations in atypical hemolytic uremic syndrome. J. Am. Soc. Nephrol. 17, 2017–2025 (2006).

    Article  CAS  PubMed  Google Scholar 

  83. Kavanagh, D. et al. Characterization of mutations in complement factor I (CFI) associated with hemolytic uremic syndrome. Mol. Immunol. 45, 95–105 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Roumenina, L. T. et al. Hyperfunctional C3 convertase leads to complement deposition on endothelial cells and contributes to atypical hemolytic uremic syndrome. Blood 114, 2837–2845 (2009).

    Article  CAS  PubMed  Google Scholar 

  85. Noris, M. et al. Hypocomplementemia discloses genetic predisposition to hemolytic uremic syndrome and thrombotic thrombocytopenic purpura: role of factor H abnormalities. Italian Registry of Familial and Recurrent Hemolytic Uremic Syndrome/Thrombotic Thrombocytopenic Purpura. J. Am. Soc. Nephrol. 10, 281–293 (1999).

    CAS  PubMed  Google Scholar 

  86. Landau, D. et al. Familial hemolytic uremic syndrome associated with complement factor H deficiency. J. Pediatr. 138, 412–417 (2001).

    Article  CAS  PubMed  Google Scholar 

  87. Ohali, M. et al. Hypocomplementemic autosomal recessive hemolytic uremic syndrome with decreased factor H. Pediatr. Nephrol. 12, 619–624 (1998).

    Article  CAS  PubMed  Google Scholar 

  88. Zachwieja, J., Strzykala, K., Golda, W. & Maciejewski, J. Familial, recurrent haemolytic-uraemic syndrome with hypocomplementaemia. Pediatr. Nephrol. 6, 221–222 (1992).

    Article  CAS  PubMed  Google Scholar 

  89. Vaziri-Sani, F. et al. Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome. Kidney Int. 69, 981–988 (2006).

    Article  CAS  PubMed  Google Scholar 

  90. Richards, A. Glomerular endothelial microvascular heterogeneity and response to cytokines predispose to development of atypical HUS [abstract]. Mol. Immunol. 48, 1732 (2011).

    Article  Google Scholar 

  91. Noris, M. et al. Relative role of genetic complement abnormalities in sporadic and familial aHUS and their impact on clinical phenotype. Clin. J. Am. Soc. Nephrol. 5, 1844–1859 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Moore, I. et al. Association of factor H autoantibodies with deletions of CFHR1, CFHR3, CFHR4, and with mutations in CFH, CFI, CD46, and C3 in patients with atypical hemolytic uremic syndrome. Blood 115, 379–387 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Esparza-Gordillo, J. et al. Insights into hemolytic uremic syndrome: segregation of three independent predisposition factors in a large, multiple affected pedigree. Mol. Immunol. 43, 1769–1775 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Esparza-Gordillo, J. et al. Predisposition to atypical hemolytic uremic syndrome involves the concurrence of different susceptibility alleles in the regulators of complement activation gene cluster in 1q32. Hum. Mol. Genet. 14, 703–712 (2005).

    Article  CAS  PubMed  Google Scholar 

  95. Pickering, M. C. et al. Spontaneous hemolytic uremic syndrome triggered by complement factor H lacking surface recognition domains. J. Exp. Med. 204, 1249–1256 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Fakhouri, F. et al. Pregnancy-associated hemolytic uremic syndrome revisited in the era of complement gene mutations. J. Am. Soc. Nephrol. 21, 859–867 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Galbusera, M. et al. In patients with atypical hemolytic uremic syndrome C5 activation causes loss of endothelial thromboresistance [abstract]. Mol. Immunol. 48, 1680 (2011).

    Article  Google Scholar 

  98. Fang, C. J. et al. Membrane cofactor protein mutations in atypical hemolytic uremic syndrome (aHUS), fatal Stx-HUS, C3 glomerulonephritis, and the HELLP syndrome. Blood 111, 624–632 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sadler, J. E. Von Willebrand factor, ADAMTS13, and thrombotic thrombocytopenic purpura. Blood 112, 11–18 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Plaimauer, B. et al. Cloning, expression, and functional characterization of the von Willebrand factor-cleaving protease (ADAMTS13). Blood 100, 3626–3632 (2002).

    Article  CAS  PubMed  Google Scholar 

  101. Levy, G. G. et al. Mutations in a member of the ADAMTS gene family cause thrombotic thrombocytopenic purpura. Nature 413, 488–494 (2001).

    Article  CAS  PubMed  Google Scholar 

  102. Donadelli, R. et al. In-vitro and in-vivo consequences of mutations in the von Willebrand factor cleaving protease ADAMTS13 in thrombotic thrombocytopenic purpura. Thromb. Haemost. 96, 454–464 (2006).

    Article  CAS  PubMed  Google Scholar 

  103. Vesely, S. K. et al. ADAMTS13 activity in thrombotic thrombocytopenic purpura-hemolytic uremic syndrome: relation to presenting features and clinical outcomes in a prospective cohort of 142 patients. Blood 102, 60–68 (2003).

    Article  CAS  PubMed  Google Scholar 

  104. Veyradier, A., Obert, B., Houllier, A., Meyer, D. & Girma, J. P. Specific von Willebrand factor-cleaving protease in thrombotic microangiopathies: a study of 111 cases. Blood 98, 1765–1772 (2001).

    Article  CAS  PubMed  Google Scholar 

  105. Weisenburger, D. D., O'Conner, M. L. & Hart, M. N. Thrombotic thrombocytopenic purpura with C3 vascular deposits: report of a case. Am. J. Clin. Pathol. 67, 61–63 (1977).

    Article  CAS  PubMed  Google Scholar 

  106. Wright, J. F. et al. Characterization of platelet glycoproteins and platelet/endothelial cell antibodies in patients with thrombotic thrombocytopenic purpura. Br. J. Haematol. 107, 546–555 (1999).

    Article  CAS  PubMed  Google Scholar 

  107. Ruiz-Torres, M. P. et al. Complement activation: the missing link between ADAMTS-13 deficiency and microvascular thrombosis of thrombotic microangiopathies. Thromb. Haemost. 93, 443–452 (2005).

    Article  CAS  PubMed  Google Scholar 

  108. Réti, M. et al. Complement activation in thrombotic thrombocytopenic purpura. J. Thromb. Haemost. 10, 791–798 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Chapin, J., Weksler, B., Magro, C. & Laurence, J. Eculizumab in the treatment of refractory idiopathic thrombotic thrombocytopenic purpura. Br. J. Haematol. 157, 772–774 (2012).

    Article  CAS  PubMed  Google Scholar 

  110. Huber-Lang, M. et al. Generation of C5a in the absence of C3: a new complement activation pathway. Nat. Med. 12, 682–687 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Dubois, E. A. & Cohen, A. F. Eculizumab. Br. J. Clin. Pharmacol. 68, 318–319 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  112. Stahl, R. Eculizumab experience in HUS. Presented at the 2011 American Society of Nephrology Kidney Week.

  113. US National Library of Medicine. ClinicalTrials.gov [online], (2012).

  114. Kielstein, J. et al. Best supportive care and therapeutic plasma exchange [abstract SAP179]. Nephrol. Dial. Transplant. 27 (Suppl. 2), ii373–ii374 (2012).

    Google Scholar 

  115. Gruppo, R. A. & Rother, R. P. Eculizumab for congenital atypical hemolytic-uremic syndrome. N. Engl. J. Med. 360, 544–546 (2009).

    Article  CAS  PubMed  Google Scholar 

  116. Ariceta, G., Arrizabalaga, B., Aguirre, M., Morteruel, E. & Lopez-Trascasa, M. Eculizumab in the treatment of atypical hemolytic uremic syndrome in infants. Am. J. Kidney Dis. 59, 707–710 (2012).

    Article  CAS  PubMed  Google Scholar 

  117. Nürnberger, J. et al. Eculizumab for atypical hemolytic-uremic syndrome. N. Engl. J. Med. 360, 542–544 (2009).

    Article  PubMed  Google Scholar 

  118. Châtelet, V. et al. Eculizumab: safety and efficacy after 17 months of treatment in a renal transplant patient with recurrent atypical hemolytic-uremic syndrome: case report. Transplant. Proc. 42, 4353–4355 (2010).

    Article  CAS  PubMed  Google Scholar 

  119. Zimmerhackl, L. B. et al. Prophylactic eculizumab after renal transplantation in atypical hemolytic-uremic syndrome. N. Engl. J. Med. 362, 1746–1748 (2010).

    Article  PubMed  Google Scholar 

  120. Weitz, M., Amon, O., Bassler, D., Koenigsrainer, A. & Nadalin, S. Prophylactic eculizumab prior to kidney transplantation for atypical hemolytic uremic syndrome. Pediatr. Nephrol. 26, 1325–1329 (2011).

    Article  PubMed  Google Scholar 

  121. Licht, C. et al. Ph II study of eculizumab (ECU) in patients (PTS) with atypical hemolytic uremic syndrome (aHUS) receiving chronic plasma exchange/infusion (PE/PI) [abstract TH-PO366]. J. Am. Soc. Nephrol. 22, 197A (2011).

    Article  Google Scholar 

  122. Greenbaum, L. A. et al. Continued improvements in renal function with sustained eculizumab (ECU) in patients (PTS) with atypical hemolytic uremic syndrome (aHUS) resistant to plasma exchange/infusion (PE/PI) [abstract TH-PO367]. J. Am. Soc. Nephrol. 22, 197A (2011).

    Article  Google Scholar 

  123. Woodruff, T. M., Nandakumar, K. S. & Tedesco, F. Inhibiting the C5-C5a receptor axis. Mol. Immunol. 48, 1631–1642 (2011).

    Article  CAS  PubMed  Google Scholar 

  124. Troutbeck, R., Al-Qureshi, S. & Guymer, R. H. Therapeutic targeting of the complement system in age-related macular degeneration: a review. Clin. Experiment. Ophthalmol. 40, 18–26 (2012).

    Article  PubMed  Google Scholar 

  125. Risitano, A. M. et al. Complement fraction 3 binding on erythrocytes as additional mechanism of disease in paroxysmal nocturnal hemoglobinuria patients treated by eculizumab. Blood 113, 4094–4100 (2009).

    Article  CAS  PubMed  Google Scholar 

  126. Noris, M. & Remuzzi, G. Genetics and genetic testing in hemolytic uremic syndrome/thrombotic thrombocytopenic purpura. Semin. Nephrol. 30, 395–408 (2010).

    Article  PubMed  Google Scholar 

  127. Salmon, J. E. et al. Mutations in complement regulatory proteins predispose to preeclampsia: a genetic analysis of the PROMISSE cohort. PLoS Med. 8, e1001013 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Le Quintrec, M. et al. Complement mutation-associated de novo thrombotic microangiopathy following kidney transplantation. Am. J. Transplant. 8, 1694–1701 (2008).

    Article  CAS  PubMed  Google Scholar 

  129. Lonze, B. E., Singer, A. L. & Montgomery, R. A. Eculizumab and renal transplantation in a patient with CAPS. N. Engl. J. Med. 362, 1744–1745 (2010).

    Article  CAS  PubMed  Google Scholar 

  130. Lazar, H. L. et al. Soluble human complement receptor 1 limits ischemic damage in cardiac surgery patients at high risk requiring cardiopulmonary bypass. Circulation 110, II274–II279 (2004).

    PubMed  Google Scholar 

  131. Testa, L. et al. Pexelizumab in ischemic heart disease: a systematic review and meta-analysis on 15,196 patients. J. Thorac. Cardiovasc. Surg. 136, 884–893 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Vergunst, C. E. et al. Blocking the receptor for C5a in patients with rheumatoid arthritis does not reduce synovial inflammation. Rheumatology (Oxford) 46, 1773–1778 (2007).

    Article  CAS  Google Scholar 

Download references

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).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding author

Correspondence to Giuseppe Remuzzi.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneph.2012.195

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing