Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria

Hematology Am Soc Hematol Educ Program. 2018 Nov 30;2018(1):371-376. doi: 10.1182/asheducation-2018.1.371.


Atypical hemolytic uremic syndrome (aHUS); hemolysis, elevated liver function tests, and low platelets syndrome; and transplant-associated thrombotic microangiopathy are related conditions, in that many patients harbor germline heterozygous mutations in genes that regulate the alternative pathway of complement (APC). Penetrance is variable because development of clinically significant disease appears to require supervention of a process such as inflammation. Complement activation on the endothelial surfaces leads to endothelial damage, platelet consumption, microthrombi, and a mechanical hemolytic anemia with schistocytes. Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic disease caused by expansion of a stem cell that harbors a somatic mutation in PIGA PIGA mutant blood cells are deficient in the complement regulator proteins CD55 and CD59, making them susceptible to intravascular hemolysis due to a failure to regulate the APC on erythrocytes. Eculizumab is a monoclonal antibody that binds to C5 and inhibits terminal complement by interfering with the cleavage of C5 by the C5 convertases. The drug is approved by the US Food and Drug Administration for the treatment of aHUS and PNH; however, a new generation of complement inhibitors that block C5 and other components of the complement cascade is showing promise in preclinical and clinical trials.

Publication types

  • Review

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use*
  • Atypical Hemolytic Uremic Syndrome* / blood
  • Atypical Hemolytic Uremic Syndrome* / drug therapy
  • Atypical Hemolytic Uremic Syndrome* / genetics
  • CD55 Antigens / blood
  • CD55 Antigens / genetics
  • CD59 Antigens / blood
  • CD59 Antigens / genetics
  • Complement C5 / antagonists & inhibitors
  • Complement C5 / genetics
  • Complement C5 / metabolism
  • Complement C5 Convertase, Alternative Pathway / antagonists & inhibitors
  • Complement C5 Convertase, Alternative Pathway / genetics
  • Complement C5 Convertase, Alternative Pathway / metabolism
  • Complement Pathway, Alternative / drug effects
  • Complement Pathway, Alternative / genetics
  • Hemoglobinuria, Paroxysmal* / blood
  • Hemoglobinuria, Paroxysmal* / drug therapy
  • Hemoglobinuria, Paroxysmal* / genetics
  • Hemolysis / drug effects
  • Hemolysis / genetics
  • Humans
  • Membrane Proteins / blood
  • Membrane Proteins / genetics
  • Mutation*
  • Penetrance


  • Antibodies, Monoclonal, Humanized
  • CD55 Antigens
  • CD59 Antigens
  • Complement C5
  • Membrane Proteins
  • phosphatidylinositol glycan-class A protein
  • CD59 protein, human
  • eculizumab
  • Complement C5 Convertase, Alternative Pathway