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Extravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and re... Full description

Journal Title: Immunobiology (1979) 2016, Vol.222 (2), p.363-371
Main Author: Subías Hidalgo, Marta
Other Authors: Martin Merinero, Hector , López, Alicia , Anter, Jaouad , García, Sheila Pinto , Ataúlfo Gonzalez-Fernández, Fernando , Forés, Rafael , Lopez-Trascasa, Margarita , Villegas, Ana , Ojeda, Emilio , Rodríguez de Córdoba, Santiago
Format: Electronic Article Electronic Article
Language: English
Subjects:
PNH
Quelle: Alma/SFX Local Collection
Publisher: Netherlands: Elsevier GmbH
ID: ISSN: 0171-2985
Link: https://www.ncbi.nlm.nih.gov/pubmed/27644115
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title: Extravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment
format: Article
creator:
  • Subías Hidalgo, Marta
  • Martin Merinero, Hector
  • López, Alicia
  • Anter, Jaouad
  • García, Sheila Pinto
  • Ataúlfo Gonzalez-Fernández, Fernando
  • Forés, Rafael
  • Lopez-Trascasa, Margarita
  • Villegas, Ana
  • Ojeda, Emilio
  • Rodríguez de Córdoba, Santiago
subjects:
  • Advanced Basic Science
  • Allergy and Immunology
  • Anemia
  • Antibodies, Monoclonal, Humanized - therapeutic use
  • Care and treatment
  • Child
  • Child, Preschool
  • Complement
  • Complement Activation - drug effects
  • Complement Activation - immunology
  • Complement C3 - immunology
  • Complement C5 - immunology
  • Complement Inactivating Agents - therapeutic use
  • Complement receptor 1
  • Complement System Proteins - immunology
  • Cytotoxicity, Immunologic
  • Disease susceptibility
  • Eculizumab
  • Extravascular hemolysis
  • Female
  • Genetic Predisposition to Disease
  • Genetic Variation
  • Genotype
  • Hemoglobinuria, Paroxysmal - blood
  • Hemoglobinuria, Paroxysmal - diagnosis
  • Hemoglobinuria, Paroxysmal - drug therapy
  • Hemoglobinuria, Paroxysmal - immunology
  • Hemolysis - immunology
  • Hemolysis and hemolysins
  • Humans
  • Infant
  • Male
  • Medicina
  • PNH
  • Receptors, Complement 3b - genetics
  • Receptors, Complement 3b - metabolism
  • Treatment Outcome
ispartof: Immunobiology (1979), 2016, Vol.222 (2), p.363-371
description: Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n = 12) for signs of hemolysis and assessed complement biomarkers. Patients were also genotyped for complement receptor 1 (CR1, CD35) and C5 polymorphisms and evaluated for free eculizumab in plasma. We report that 10 patients (83%) present parameters suggesting persistent hemolysis, although they did not require additional transfusions. Seven of them (58%) become direct Coombs-test positive as a consequence of treatment, including all patients carrying the low-expression CR1-L allele. CH50 and sC5b-9 assays demonstrate that the persistent low-level hemolysis identified in our treated patients is not a consequence of incomplete C5 blockade, supporting that this hemolysis, as has been suggested previously, results from the extravascular removal of C3 opsonized PNH erythrocytes. We also show that continuous alternative pathway activation in eculizumab-treated individuals carrying the CR1-L allele results in abnormally decreased levels of C3 in plasma that could, potentially, increase their susceptibility to bacterial infections. Finally, we encourage a routine evaluation of free eculizumab levels and terminal pathway activity to personalize eculizumab administration.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0171-2985
fulltext: fulltext
issn:
  • 0171-2985
  • 1878-3279
url: Link


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titleExtravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment
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creatorSubías Hidalgo, Marta ; Martin Merinero, Hector ; López, Alicia ; Anter, Jaouad ; García, Sheila Pinto ; Ataúlfo Gonzalez-Fernández, Fernando ; Forés, Rafael ; Lopez-Trascasa, Margarita ; Villegas, Ana ; Ojeda, Emilio ; Rodríguez de Córdoba, Santiago
creatorcontribSubías Hidalgo, Marta ; Martin Merinero, Hector ; López, Alicia ; Anter, Jaouad ; García, Sheila Pinto ; Ataúlfo Gonzalez-Fernández, Fernando ; Forés, Rafael ; Lopez-Trascasa, Margarita ; Villegas, Ana ; Ojeda, Emilio ; Rodríguez de Córdoba, Santiago
descriptionAbstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n = 12) for signs of hemolysis and assessed complement biomarkers. Patients were also genotyped for complement receptor 1 (CR1, CD35) and C5 polymorphisms and evaluated for free eculizumab in plasma. We report that 10 patients (83%) present parameters suggesting persistent hemolysis, although they did not require additional transfusions. Seven of them (58%) become direct Coombs-test positive as a consequence of treatment, including all patients carrying the low-expression CR1-L allele. CH50 and sC5b-9 assays demonstrate that the persistent low-level hemolysis identified in our treated patients is not a consequence of incomplete C5 blockade, supporting that this hemolysis, as has been suggested previously, results from the extravascular removal of C3 opsonized PNH erythrocytes. We also show that continuous alternative pathway activation in eculizumab-treated individuals carrying the CR1-L allele results in abnormally decreased levels of C3 in plasma that could, potentially, increase their susceptibility to bacterial infections. Finally, we encourage a routine evaluation of free eculizumab levels and terminal pathway activity to personalize eculizumab administration.
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subjectAdvanced Basic Science ; Allergy and Immunology ; Anemia ; Antibodies, Monoclonal, Humanized - therapeutic use ; Care and treatment ; Child ; Child, Preschool ; Complement ; Complement Activation - drug effects ; Complement Activation - immunology ; Complement C3 - immunology ; Complement C5 - immunology ; Complement Inactivating Agents - therapeutic use ; Complement receptor 1 ; Complement System Proteins - immunology ; Cytotoxicity, Immunologic ; Disease susceptibility ; Eculizumab ; Extravascular hemolysis ; Female ; Genetic Predisposition to Disease ; Genetic Variation ; Genotype ; Hemoglobinuria, Paroxysmal - blood ; Hemoglobinuria, Paroxysmal - diagnosis ; Hemoglobinuria, Paroxysmal - drug therapy ; Hemoglobinuria, Paroxysmal - immunology ; Hemolysis - immunology ; Hemolysis and hemolysins ; Humans ; Infant ; Male ; Medicina ; PNH ; Receptors, Complement 3b - genetics ; Receptors, Complement 3b - metabolism ; Treatment Outcome
ispartofImmunobiology (1979), 2016, Vol.222 (2), p.363-371
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1Martin Merinero, Hector
2López, Alicia
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6Forés, Rafael
7Lopez-Trascasa, Margarita
8Villegas, Ana
9Ojeda, Emilio
10Rodríguez de Córdoba, Santiago
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descriptionAbstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n = 12) for signs of hemolysis and assessed complement biomarkers. Patients were also genotyped for complement receptor 1 (CR1, CD35) and C5 polymorphisms and evaluated for free eculizumab in plasma. We report that 10 patients (83%) present parameters suggesting persistent hemolysis, although they did not require additional transfusions. Seven of them (58%) become direct Coombs-test positive as a consequence of treatment, including all patients carrying the low-expression CR1-L allele. CH50 and sC5b-9 assays demonstrate that the persistent low-level hemolysis identified in our treated patients is not a consequence of incomplete C5 blockade, supporting that this hemolysis, as has been suggested previously, results from the extravascular removal of C3 opsonized PNH erythrocytes. We also show that continuous alternative pathway activation in eculizumab-treated individuals carrying the CR1-L allele results in abnormally decreased levels of C3 in plasma that could, potentially, increase their susceptibility to bacterial infections. Finally, we encourage a routine evaluation of free eculizumab levels and terminal pathway activity to personalize eculizumab administration.
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1Allergy and Immunology
2Anemia
3Antibodies, Monoclonal, Humanized - therapeutic use
4Care and treatment
5Child
6Child, Preschool
7Complement
8Complement Activation - drug effects
9Complement Activation - immunology
10Complement C3 - immunology
11Complement C5 - immunology
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13Complement receptor 1
14Complement System Proteins - immunology
15Cytotoxicity, Immunologic
16Disease susceptibility
17Eculizumab
18Extravascular hemolysis
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20Genetic Predisposition to Disease
21Genetic Variation
22Genotype
23Hemoglobinuria, Paroxysmal - blood
24Hemoglobinuria, Paroxysmal - diagnosis
25Hemoglobinuria, Paroxysmal - drug therapy
26Hemoglobinuria, Paroxysmal - immunology
27Hemolysis - immunology
28Hemolysis and hemolysins
29Humans
30Infant
31Male
32Medicina
33PNH
34Receptors, Complement 3b - genetics
35Receptors, Complement 3b - metabolism
36Treatment Outcome
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titleExtravascular hemolysis and complement consumption in Paroxysmal Nocturnal Hemoglobinuria patients undergoing eculizumab treatment
authorSubías Hidalgo, Marta ; Martin Merinero, Hector ; López, Alicia ; Anter, Jaouad ; García, Sheila Pinto ; Ataúlfo Gonzalez-Fernández, Fernando ; Forés, Rafael ; Lopez-Trascasa, Margarita ; Villegas, Ana ; Ojeda, Emilio ; Rodríguez de Córdoba, Santiago
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8Complement Activation - drug effects
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abstractAbstract Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia characterized by complement-mediated intravascular hemolysis that is effectively treated with eculizumab. However, treatment responses are reported heterogeneous with some patients presenting residual hemolysis and requiring RBC transfusions. Recent reports have shown that both extravascular hemolysis and incomplete C5 blockade can explain these suboptimal hematological responses. Here we have tested our eculizumab-treated PNH patients (n = 12) for signs of hemolysis and assessed complement biomarkers. Patients were also genotyped for complement receptor 1 (CR1, CD35) and C5 polymorphisms and evaluated for free eculizumab in plasma. We report that 10 patients (83%) present parameters suggesting persistent hemolysis, although they did not require additional transfusions. Seven of them (58%) become direct Coombs-test positive as a consequence of treatment, including all patients carrying the low-expression CR1-L allele. CH50 and sC5b-9 assays demonstrate that the persistent low-level hemolysis identified in our treated patients is not a consequence of incomplete C5 blockade, supporting that this hemolysis, as has been suggested previously, results from the extravascular removal of C3 opsonized PNH erythrocytes. We also show that continuous alternative pathway activation in eculizumab-treated individuals carrying the CR1-L allele results in abnormally decreased levels of C3 in plasma that could, potentially, increase their susceptibility to bacterial infections. Finally, we encourage a routine evaluation of free eculizumab levels and terminal pathway activity to personalize eculizumab administration.
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