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Semin Thromb Hemost 2014; 40(04): 444-464
DOI: 10.1055/s-0034-1376153
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Spectrum of Complement-Mediated Thrombotic Microangiopathies: Pathogenetic Insights Identifying Novel Treatment Approaches

Magdalena Riedl
1   Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria
2   Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
3   Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
,
Fadi Fakhouri
4   Department of Nephrology and Immunology, ITUN and INSERM UMR S-1064, CHU de Nantes, Nantes, France
,
Moglie Le Quintrec
5   Service de Nephrologie et de Transplantation Rénale, Hôpital Foch, Suresnes, France
6   INSERM U1138, Cordelier Research Center “Complement and Diseases” Paris, France
,
Damien G. Noone
2   Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
3   Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
,
Therese C. Jungraithmayr
1   Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria
,
Veronique Fremeaux-Bacchi
6   INSERM U1138, Cordelier Research Center “Complement and Diseases” Paris, France
7   Department of Immunology, Assistance Publique-Hôpitaux de Paris Hôpital Européen Georges Pompidou, Paris, France
,
Christoph Licht
2   Division of Nephrology, The Hospital for Sick Children, Toronto, Ontario, Canada
3   Research Institute, Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada
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Publikationsdatum:
09. Juni 2014 (online)

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Abstract

Thrombotic microangiopathy (TMA) is a rare but severe disorder characterized by endothelial cell activation and thrombus formation. It manifests with the triad of hemolytic anemia, thrombocytopenia, and organ failure. Prompt diagnosis and treatment initiation are crucial for long-term outcome. TMA often manifests subsequent to infectious events, of which (enterohemorrhagic) Escherichia coli is the most frequently reported. TMA also occurs on the background of genetic/autoimmune defects in the complement system (atypical hemolytic uremic syndrome [aHUS]) and underlying conditions, such as pregnancy, transplantation, drugs, other glomerulopathies, vasculitides, or metabolic defects. Complement activation or defects in its regulation have now been described in an increasing number of acquired diseases with TMA. Coinciding with this expanding spectrum of complement-mediated diseases, the question arises which patients might benefit from a complement-targeted therapy. Success of therapy depends on the individual contribution of complement activation in disease pathogenesis. The advent of eculizumab, a monoclonal antibody that blocks terminal complement activation, has markedly improved outcome and quality of life in patients with aHUS. This review discusses the contribution of complement and highlights its complex interaction with inflammation, coagulation, and the endothelium. Treatment experiences focusing on eculizumab therapy are discussed in detail across the emerging spectrum of complement-mediated thrombotic microangiopathies.

Keywords

thrombotic microangiopathy - hemolytic uremic syndrome - thrombotic thrombocytopenic purpura - complement - eculizumab - plasma therapy