Document Detail

Eculizumab prevents intravascular hemolysis in patients with paroxysmal nocturnal hemoglobinuria and unmasks low-level extravascular hemolysis occurring through C3 opsonization.
MedLine Citation:
PMID:  20145265     Owner:  NLM     Status:  MEDLINE    
BACKGROUND: Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia characterized by intravascular hemolysis which has been demonstrated to be effectively controlled with eculizumab. However, lactate dehydrogenase levels remain slightly elevated and haptoglobin levels remain low in some patients suggesting residual low-level hemolysis. This may be due to C3-mediated clearance of paroxysmal nocturnal hemoglobinuria red blood cells through the reticuloendothelial system.
DESIGN AND METHODS: Thirty-nine samples from patients not treated with eculizumab and 31 samples from patients treated with eculizumab were obtained (for 17 of these 31 samples there were also samples taken prior to eculizumab treatment). Membrane bound complement was assessed by flow cytometry. Direct antiglobulin testing was carried out using two methods. Lactate dehydrogenase was assayed to assess the degree of hemolysis.
RESULTS: Three of 39 patients (8%) with paroxysmal nocturnal hemoglobinuria not on eculizumab had a positive direct antiglobulin test, while the test was positive in 21 of 31 (68%) during eculizumab treatment. Of these 21 patients who had a positive direct antiglobulin test during eculizumab treatment, 17 had been tested prior to treatment; only one was positive. Flow cytometry using anti-C3 monoclonal antibodies was performed on the 21 direct antiglobulin test-positive, eculizumab-treated patients; the median proportion of C3-positive total red blood cells was 26%. Among the eculizumab-treated patients, 16 of the 21 (76.2%) with a positive direct antiglobulin test received at least one transfusion compared with one of ten (10.0%) of those with a negative test (P<0.01). Among the eculizumab-treated patients, the mean hemoglobin value for the 21 with a positive direct antiglobulin test was 9.6+/-0.3 g/dL, whereas that in the ten patients with a negative test was 11.0+/-0.4 g/dL (P=0.02).
CONCLUSIONS: These data demonstrate a previously masked mechanism of red cell clearance in paroxysmal nocturnal hemoglobinuria and suggests that blockade of complement at C5 allows C3 fragment accumulation on some paroxysmal nocturnal hemoglobinuria red cells, explaining the residual low-level hemolysis occurring in some eculizumab-treated patients.
Anita Hill; Russell P Rother; Louise Arnold; Richard Kelly; Matthew J Cullen; Stephen J Richards; Peter Hillmen
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Publication Detail:
Type:  Comparative Study; Journal Article     Date:  2010-02-09
Journal Detail:
Title:  Haematologica     Volume:  95     ISSN:  1592-8721     ISO Abbreviation:  Haematologica     Publication Date:  2010 Apr 
Date Detail:
Created Date:  2010-04-09     Completed Date:  2010-08-24     Revised Date:  2013-11-25    
Medline Journal Info:
Nlm Unique ID:  0417435     Medline TA:  Haematologica     Country:  Italy    
Other Details:
Languages:  eng     Pagination:  567-73     Citation Subset:  IM    
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MeSH Terms
Antibodies, Monoclonal / therapeutic use*
Antibodies, Monoclonal, Humanized
Blood Transfusion
Complement C3 / immunology*
Complement C5 / antagonists & inhibitors,  immunology
Erythrocytes / metabolism
Flow Cytometry
Hemoglobins / metabolism
Hemoglobinuria, Paroxysmal / blood,  immunology,  prevention & control*
Hemolysis / drug effects*
L-Lactate Dehydrogenase / metabolism
Reg. No./Substance:
0/Antibodies, Monoclonal; 0/Antibodies, Monoclonal, Humanized; 0/Complement C3; 0/Complement C5; 0/Hemoglobins; A3ULP0F556/eculizumab; EC Dehydrogenase
Comment In:
Haematologica. 2010 Apr;95(4):523-6   [PMID:  20378572 ]

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

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