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Complement-driven anemia: more than just paroxysmal nocturnal hemoglobinuria.
- Source :
-
Hematology. American Society of Hematology. Education Program [Hematology Am Soc Hematol Educ Program] 2018 Nov 30; Vol. 2018 (1), pp. 371-376. - Publication Year :
- 2018
-
Abstract
- 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.<br />Competing Interests: Conflict-of-interest disclosure: R.A.B. has consulted for Achillion Pharmaceuticals and Apellis Pharmaceuticals and is on the Board of Directors or an advisory committee for Alexion Pharmaceuticals. S.A.M. has served on the Board of Directors or an advisory committee for True North Therapeutics.<br /> (© 2018 by The American Society of Hematology. All rights reserved.)
- Subjects :
- 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
Hemolysis drug effects
Hemolysis genetics
Humans
Membrane Proteins blood
Membrane Proteins genetics
Penetrance
Antibodies, Monoclonal, Humanized therapeutic use
Atypical Hemolytic Uremic Syndrome blood
Atypical Hemolytic Uremic Syndrome drug therapy
Atypical Hemolytic Uremic Syndrome genetics
Hemoglobinuria, Paroxysmal blood
Hemoglobinuria, Paroxysmal drug therapy
Hemoglobinuria, Paroxysmal genetics
Mutation
Subjects
Details
- Language :
- English
- ISSN :
- 1520-4383
- Volume :
- 2018
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Hematology. American Society of Hematology. Education Program
- Publication Type :
- Academic Journal
- Accession number :
- 30504334
- Full Text :
- https://doi.org/10.1182/asheducation-2018.1.371