Document Detail

Achievements and limitations of complement inhibition by eculizumab in paroxysmal nocturnal hemoglobinuria: the role of complement component 3.
MedLine Citation:
PMID:  21561403     Owner:  NLM     Status:  MEDLINE    
Paroxysmal nocturnal hemoglobinuria (PNH) is a hematological disorder characterized by complementmediated hemolytic anemia, thrombophilia and bone marrow failure. The clinical hallmark of PNH is evident chronic hemolysis due to the absence of the complement regulators CD55 and CD59 on PNH erythrocytes. Intravascular hemolysis drives the major clinical features of PNH, including anemia, hemoglobinuria, fatigue and other hemolysisrelated disabling symptoms, such as painful abdominal crises, dysphagia and erectile dysfunction. A peculiar thromboembolic risk has been associated with the hemolysis in PNH, but its pathophysiologic cause remains unclear. The treatment of PNH has remained supportive until a few years ago, when the first complement inhibitor, designated eculizumab, became available. Chronic treatment with eculizumab results in sustained control of intravascular hemolysis, leading to hemoglobin stabilization and transfusion independence in half of the patients. However, residual anemia may persist in a substantial fraction of patients. Recent observations by different groups, including our own, have demonstrated that residual hemolysis may be due to persistent activation of the early phases of the complement cascade, leading to progressive C3-deposition on PNH erythrocytes and possible subsequent extravascular hemolysis through the reticuloendothelial system. Here we critically review the available clinical results of eculizumab treatment for PNH patients, pointing out the recent insights into the pathophysiology of the disease. We discuss the role of the different components of the complement cascade leading to hemolysis, in both the absence and presence of the terminal effector pathway inhibition by eculizumab. Finally, we provide a theoretical rationale for the development of novel strategies of complement inhibition which could in the future further improve on the already substantial efficacy of eculizumab.
A M Risitano; F Perna; C Selleri
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Publication Detail:
Type:  Journal Article; Review    
Journal Detail:
Title:  Mini reviews in medicinal chemistry     Volume:  11     ISSN:  1875-5607     ISO Abbreviation:  Mini Rev Med Chem     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-24     Completed Date:  2011-10-27     Revised Date:  2013-11-25    
Medline Journal Info:
Nlm Unique ID:  101094212     Medline TA:  Mini Rev Med Chem     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  528-35     Citation Subset:  IM    
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MeSH Terms
Antibodies, Monoclonal / therapeutic use*
Antibodies, Monoclonal, Humanized
Clinical Trials as Topic
Complement C3 / metabolism*,  physiology
Complement Inactivating Agents / therapeutic use*
Hemoglobinuria, Paroxysmal / drug therapy*,  etiology
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Complement C3; 0/Complement Inactivating Agents; A3ULP0F556/eculizumab

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

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