Spectrum of complement-mediated thrombotic microangiopathies: pathogenetic insights identifying novel treatment approaches

Semin Thromb Hemost. 2014 Jun;40(4):444-64. doi: 10.1055/s-0034-1376153. Epub 2014 Jun 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Antiphospholipid Syndrome
  • Atypical Hemolytic Uremic Syndrome / immunology
  • Autoimmune Diseases
  • Bone Marrow Transplantation
  • Complement Activation
  • Complement System Proteins / immunology*
  • Diacylglycerol Kinase / immunology
  • Enterohemorrhagic Escherichia coli
  • Escherichia coli Infections / complications
  • Female
  • Homeostasis
  • Humans
  • Inflammation
  • Kidney Transplantation
  • Male
  • Pregnancy
  • Pregnancy Complications
  • Quality of Life
  • Recurrence
  • Stem Cell Transplantation
  • Thrombotic Microangiopathies / immunology*
  • Thrombotic Microangiopathies / microbiology
  • Thrombotic Microangiopathies / therapy*
  • Treatment Outcome


  • Antibodies, Monoclonal, Humanized
  • Complement System Proteins
  • eculizumab
  • Diacylglycerol Kinase