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Peter Hillmen - One of the best experts on this subject based on the ideXlab platform.
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thrombosis in Paroxysmal Nocturnal Hemoglobinuria
Blood, 2013Co-Authors: Anita Hill, Richard Kelly, Peter HillmenAbstract:The most frequent and feared complication of Paroxysmal Nocturnal Hemoglobinuria (PNH) is thrombosis. Recent research has demonstrated that the complement and coagulation systems are closely integrated with each influencing the activity of the other to the extent that thrombin itself has recently been shown to activate the alternative pathway of complement. This may explain some of the complexity of the thrombosis in PNH. In this review, the recent changes in our understanding of the pathophysiology of thrombosis in PNH, as well as the treatment of thrombosis, will be discussed. Mechanisms explored include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other glycosylphosphatidylinositol-linked proteins such as urokinase-type plasminogen activator receptor and endothelial dysfunction. Complement inhibition with eculizumab has a dramatic effect in PNH and has a major impact in the prevention of thrombosis as well as its management in this disease.
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Long-term treatment with eculizumab in Paroxysmal Nocturnal Hemoglobinuria: sustained efficacy and improved survival
Blood, 2011Co-Authors: Richard Kelly, Anita Hill, Louise Arnold, Gemma L Brooksbank, Stephen J. Richards, Matthew J. Cullen, Lindsay D Mitchell, Dena Cohen, Walter M Gregory, Peter HillmenAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with eculizumab was not different from age- and sex-matched normal controls ( P = .46) but was significantly better than 30 similar patients managed before eculizumab ( P = .030). Three patients on eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on eculizumab (0.8 events per 100 patient-years; P P
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eculizumab prevents intravascular hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Russell P. Rother, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Peter HillmenAbstract: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.
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eculizumab prevents intravascular hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Russell P. Rother, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Peter HillmenAbstract: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
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diagnosis and management of Paroxysmal Nocturnal Hemoglobinuria
Blood, 2005Co-Authors: Charles J Parker, Neal S Young, Stephen J. Richards, Peter Hillmen, Russell E Ware, Junichi Nishimura, Monica Bessler, L Luzzatto, Mitsuhiro Omine, Taroh KinoshitaAbstract:The primary clinical manifestations of Paroxysmal Nocturnal Hemoglobinuria (PNH) are hemolytic anemia, marrow failure, and thrombophilia. However, PNH is not a simple binary diagnosis and both flow cytometric characterization of glycosyl phosphatidylinositol–anchored protein expression on peripheral blood cells and marrow analysis are required for comprehensive disease classification. For optimum management, the contribution of both hemolysis and marrow failure to the complex anemia of PNH should be determined. Complement inhibition by eculizumab is a promising new approach to treating the hemolytic anemia. Stem cell transplantation is potentially curative, but the decision on use is best made on a case-by-case basis because of the heterogeneous natural history of the disease. PNH clone size and ethnic/geographic factors appear to influence thrombophilic propensity, but a consensus on prophylactic anticoagulation has not been reached. Involvement of unusual sites (hepatic, mesenteric, cerebral, dermal veins) is characteristic of the thrombophilia of PNH. Indefinite anticoagulation is recommended following a thromboembolic event and thrombolytic therapy should be considered for acute hepatic vein thrombosis (Budd-Chiari syndrome). Pregnancy in a patient with PNH is complicated and requires careful management including prophylactic anticoagulation. To obtain a broad overview of the natural history, approaches to management, and outcome, the International PNH Registry was recently established.
Anita Hill - One of the best experts on this subject based on the ideXlab platform.
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thrombosis in Paroxysmal Nocturnal Hemoglobinuria
Blood, 2013Co-Authors: Anita Hill, Richard Kelly, Peter HillmenAbstract:The most frequent and feared complication of Paroxysmal Nocturnal Hemoglobinuria (PNH) is thrombosis. Recent research has demonstrated that the complement and coagulation systems are closely integrated with each influencing the activity of the other to the extent that thrombin itself has recently been shown to activate the alternative pathway of complement. This may explain some of the complexity of the thrombosis in PNH. In this review, the recent changes in our understanding of the pathophysiology of thrombosis in PNH, as well as the treatment of thrombosis, will be discussed. Mechanisms explored include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other glycosylphosphatidylinositol-linked proteins such as urokinase-type plasminogen activator receptor and endothelial dysfunction. Complement inhibition with eculizumab has a dramatic effect in PNH and has a major impact in the prevention of thrombosis as well as its management in this disease.
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Long-term treatment with eculizumab in Paroxysmal Nocturnal Hemoglobinuria: sustained efficacy and improved survival
Blood, 2011Co-Authors: Richard Kelly, Anita Hill, Louise Arnold, Gemma L Brooksbank, Stephen J. Richards, Matthew J. Cullen, Lindsay D Mitchell, Dena Cohen, Walter M Gregory, Peter HillmenAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with eculizumab was not different from age- and sex-matched normal controls ( P = .46) but was significantly better than 30 similar patients managed before eculizumab ( P = .030). Three patients on eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on eculizumab (0.8 events per 100 patient-years; P P
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eculizumab prevents intravascular hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Russell P. Rother, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Peter HillmenAbstract: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.
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eculizumab prevents intravascular hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Russell P. Rother, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Peter HillmenAbstract: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
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Eculizumab in the Treatment of Paroxysmal Nocturnal Hemoglobinuria
SAGE Publishing, 2009Co-Authors: Anita HillAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is a potentially life-threatening acquired clonal stem cell disorder resulting in hemolysis and thrombosis. A somatic mutation in the phosphatidylinositol glycan A gene in hematopoietic stem cells results in a deficiency of the complement regulatory proteins, CD55 and CD59. There is a consequent increased sensitivity to complement mediated lysis. Eculizumab is a recombinant, humanized monoclonal antibody directed against C5 of the complement system. It blocks terminal complement activation and the formation of the membrane attack complex. It has been demonstrated in 3 clinical studies that this blockade of the terminal complement system effectively and significantly prevents intravascular hemolysis thereby abolishing or reducing the need for transfusions, reduces thromboses, improves quality of life and appears to prevent renal damage and improve pulmonary pressures. The drug is very well tolerated with few safety concerns. Case reports of the use of eculizumab in pregnancy, cold agglutinin disease and atypical hemolytic syndrome are also described
Robert A Brodsky - One of the best experts on this subject based on the ideXlab platform.
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danicopan an oral complement factor d inhibitor for Paroxysmal Nocturnal Hemoglobinuria
Haematologica, 2020Co-Authors: Antonio M Risitano, Jaroslaw P Maciejewski, Mingjun Huang, Robert A Brodsky, Austin G. Kulasekararaj, Rosario Notaro, Jong Wook Lee, Michael Geffner, Peter BrowettAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.
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Stem cell transplantation for Paroxysmal Nocturnal Hemoglobinuria
2015Co-Authors: Robert A BrodskyAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rareblood disease that results from clonal expansion of amultipotent hematolopoietic stem cell harboring a PIG-A mutation.1 The PIG-A gene product is required for the biosynthesis of glycophosphatidylinositol anchors, a glycol-ipid moiety that tethers dozens of proteins to lipid bilayer of cell membranes. Consequently, the PNH stem cell and its progeny have a reduction or absence of all GPI-anchored pro-teins. Two of these proteins, CD55 and CD59, are comple-ment regulatory proteins and are fundamental to the patho-physiology of Paroxysmal Nocturnal Hemoglobinuria.2,3 CD55 inhibits C3 convertases and CD59 blocks formation of the membrane attack complex (MAC). The loss of complement regulatory proteins renders PNH erythrocytes susceptible to both intravascular (due to CD59 deficiency) and extravascu-lar (due to CD55 deficiency) hemolysis, but it is the intravas-cular hemolysis that contributes to much of the morbidit
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Paroxysmal Nocturnal Hemoglobinuria a complement mediated hemolytic anemia
Hematology-oncology Clinics of North America, 2015Co-Authors: Amy E Dezern, Robert A BrodskyAbstract:Paroxysmal Nocturnal Hemoglobinuria is manifests with a chronic hemolytic anemia from uncontrolled complement activation, a propensity for thrombosis and marrow failure. The hemolysis is largely mediated by the alternative pathway of complement. Clinical manifestations result from the lack of specific cell surface proteins, CD55 and CD59, on PNH cells. Complement inhibition by eculizumab leads to dramatic clinical improvement. While this therapeutic approach is effective, there is residual complement activity resulting from specific clinical scenarios as well as from upstream complement components that can account for suboptimal responses in some patients. Complement inhibition strategies are an area of active research.
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Paroxysmal Nocturnal Hemoglobinuria: Stem Cells and Clonality
2015Co-Authors: Robert A BrodskyAbstract:Paroxysmal Nocturnal Hemoglobinuria is a clonal hematopoietic stem cell disease that manifests with intravascular hemolysis, bone marrow failure, throm-bosis, and smooth muscle dystonias. The disease can arise de novo or in the setting of acquired aplastic anemia. All PNH patients to date have been shown to harbor PIG-A mutations; the product of this gene is required for the synthesis of glycosylphosphatidyl-inositol (GPI) anchored proteins. In PNH patients, PIG-A mutations arise from a multipotent hematopoietic stem cell. Interestingly, PIG-A mutations can also be found in the peripheral blood of most healthy controls; however, these mutations arise from progenitor cells rather than multipotent hematopoietic stem cells and do not propagate the disease. The mechanism of whereby PNH stem cells achieve clonal dominance remains unclear. The leading hypotheses to explain clonal outgrowth in PNH are: 1) PNH cells evade immune attack possibly, because of an absent cell surface GPI-AP that is the target of the immune attack; 2) The PIG-A mutation confers an intrinsic resistance to apoptosis that becomes more conspicu-ous when the marrow is under immune attack; and 3) A second mutation occurs in the PNH clone to give it an intrinsic survival advantage. These hypotheses may not be mutually exclusive, since data in support of all three models have been generated
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Paroxysmal Nocturnal Hemoglobinuria
Blood, 2014Co-Authors: Robert A BrodskyAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is a rare bone marrow failure disorder that manifests with hemolytic anemia, thrombosis, and peripheral blood cytopenias. The absence of two glycosylphosphatidylinositol (GPI)-anchored proteins, CD55 and CD59, leads to uncontrolled complement activation that accounts for hemolysis and other PNH manifestations. GPI anchor protein deficiency is almost always due to somatic mutations in phosphatidylinositol glycan class A (PIGA), a gene involved in the first step of GPI anchor biosynthesis; however, alternative mutations that cause PNH have recently been discovered. In addition, hypomorphic germ-line PIGA mutations that do not cause PNH have been shown to be responsible for a condition known as multiple congenital anomalies-hypotonia-seizures syndrome 2. Eculizumab, a first-in-class monoclonal antibody that inhibits terminal complement, is the treatment of choice for patients with severe manifestations of PNH. Bone marrow transplantation remains the only cure for PNH but should be reserved for patients with suboptimal response to eculizumab.
Richard Kelly - One of the best experts on this subject based on the ideXlab platform.
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eculizumab in pregnant patients with Paroxysmal Nocturnal Hemoglobinuria
The New England Journal of Medicine, 2015Co-Authors: Richard Kelly, Antonio M Risitano, Austin G. Kulasekararaj, J Szer, Sophie De Guibert, Britta Hochsmann, Alexander Roth, Ilene C Weitz, Elina Armstrong, Christopher J PatriquinAbstract:BackgroundEculizumab, a humanized monoclonal antibody against complement protein C5 that inhibits terminal complement activation, has been shown to prevent complications of Paroxysmal Nocturnal Hemoglobinuria (PNH) and improve quality of life and overall survival, but data on the use of eculizumab in women during pregnancy are scarce. MethodsWe designed a questionnaire to solicit data on pregnancies in women with PNH and sent it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. We assessed the safety and efficacy of eculizumab in pregnant patients with PNH by examining the birth and developmental records of the children born and adverse events in the mothers. ResultsOf the 94 questionnaires that were sent out, 75 were returned, representing a response rate of 80%. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and three fetal deaths (4%). Six miscarriages (8%) occurred during the first tr...
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thrombosis in Paroxysmal Nocturnal Hemoglobinuria
Blood, 2013Co-Authors: Anita Hill, Richard Kelly, Peter HillmenAbstract:The most frequent and feared complication of Paroxysmal Nocturnal Hemoglobinuria (PNH) is thrombosis. Recent research has demonstrated that the complement and coagulation systems are closely integrated with each influencing the activity of the other to the extent that thrombin itself has recently been shown to activate the alternative pathway of complement. This may explain some of the complexity of the thrombosis in PNH. In this review, the recent changes in our understanding of the pathophysiology of thrombosis in PNH, as well as the treatment of thrombosis, will be discussed. Mechanisms explored include platelet activation, toxicity of free hemoglobin, nitric oxide depletion, absence of other glycosylphosphatidylinositol-linked proteins such as urokinase-type plasminogen activator receptor and endothelial dysfunction. Complement inhibition with eculizumab has a dramatic effect in PNH and has a major impact in the prevention of thrombosis as well as its management in this disease.
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Long-term treatment with eculizumab in Paroxysmal Nocturnal Hemoglobinuria: sustained efficacy and improved survival
Blood, 2011Co-Authors: Richard Kelly, Anita Hill, Louise Arnold, Gemma L Brooksbank, Stephen J. Richards, Matthew J. Cullen, Lindsay D Mitchell, Dena Cohen, Walter M Gregory, Peter HillmenAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is an acquired clonal hematopoietic disorder with increased mortality and morbidity resulting from intravascular hemolysis. Eculizumab, a monoclonal antibody against the complement protein 5, stops the intravascular hemolysis in PNH. We evaluated 79 consecutive patients treated with eculizumab in Leeds between May 2002 and July 2010. The survival of patients treated with eculizumab was not different from age- and sex-matched normal controls ( P = .46) but was significantly better than 30 similar patients managed before eculizumab ( P = .030). Three patients on eculizumab, all over 50 years old, died of causes unrelated to PNH. Twenty-one patients (27%) had a thrombosis before starting eculizumab (5.6 events per 100 patient-years) compared with 2 thromboses on eculizumab (0.8 events per 100 patient-years; P P
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eculizumab prevents intravascular hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Russell P. Rother, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Peter HillmenAbstract: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.
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eculizumab prevents intravascular hemolysis in patients with Paroxysmal Nocturnal Hemoglobinuria and unmasks low level extravascular hemolysis occurring through c3 opsonization
Haematologica, 2010Co-Authors: Anita Hill, Russell P. Rother, Richard Kelly, Louise Arnold, Stephen J. Richards, Matthew J. Cullen, Peter HillmenAbstract: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
Antonio M Risitano - One of the best experts on this subject based on the ideXlab platform.
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danicopan an oral complement factor d inhibitor for Paroxysmal Nocturnal Hemoglobinuria
Haematologica, 2020Co-Authors: Antonio M Risitano, Jaroslaw P Maciejewski, Mingjun Huang, Robert A Brodsky, Austin G. Kulasekararaj, Rosario Notaro, Jong Wook Lee, Michael Geffner, Peter BrowettAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is characterised by complement-mediated intravascular hemolysis (IVH) due to absence of complement regulators CD55 and CD59 on affected erythrocytes. Danicopan is a first-in-class oral proximal, complement alternative pathway factor D (FD) inhibitor. Therapeutic FD inhibition was designed to control IVH and prevent C3-mediated extravascular hemolysis (EVH). In this open-label, phase 2, dose-finding trial, 10 untreated hemolytic PNH patients received danicopan monotherapy (100-200 mg thrice daily). Endpoints included change in lactate dehydrogenase (LDH) at day 28 (primary) and day 84 and hemoglobin. Safety, pharmacokinetics/pharmacodynamics, and patient-reported outcomes were measured. Ten patients reached the primary endpoint; two later discontinued: one for a serious adverse event (elevated aspartate aminotransferase/alanine aminotransferase coincident with breakthrough hemolysis, resolving without sequelae) and one for personal reasons unrelated to safety. Eight patients completed treatment. IVH was inhibited, demonstrated by mean decreased LDH (5.7 times upper limit of normal [ULN] at baseline vs 1.8 times ULN [day 28] and 2.2 times ULN [day 84]; both p.
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expanding complement therapeutics for the treatment of Paroxysmal Nocturnal Hemoglobinuria
Seminars in Hematology, 2018Co-Authors: Dimitrios C Mastellos, Antonio M Risitano, Edimara S Reis, Despina Yancopoulou, John D LambrisAbstract:Paroxysmal Nocturnal Hemoglobinuria (PNH) is widely regarded as an archetypal complement-mediated disorder that has propelled complement drug discovery in recent decades. Its pathology is driven by chronic complement dysregulation resulting from the lack of the glycosyl phosphatidyl inositol-linked regulators DAF and CD59 on susceptible erythrocytes. This complement imbalance fuels persistent C3 activation on affected erythrocytes, which culminates in chronic complement-mediated intravascular hemolysis. The clinical application of eculizumab, a humanized anti-C5 antibody that blocks terminal pathway activation, has led to drastic improvement of therapeutic outcomes but has also unveiled hitherto elusive pathogenic mechanisms that are now known to contribute to the clinical burden of a significant proportion of patients with PNH. These emerging clinical needs have sparked a true resurgence of complement therapeutics that offer the promise of even more effective, disease-tailored therapies for PNH. Here, we review the current state of complement therapeutics with a focus on the clinical development of C3-targeted and alternative pathway-directed drug candidates for the treatment of PNH. We also discuss the relative advantages and benefits offered by each complement-targeting approach, including translational considerations that might leverage a more comprehensive clinical intervention for PNH.
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eculizumab in pregnant patients with Paroxysmal Nocturnal Hemoglobinuria
The New England Journal of Medicine, 2015Co-Authors: Richard Kelly, Antonio M Risitano, Austin G. Kulasekararaj, J Szer, Sophie De Guibert, Britta Hochsmann, Alexander Roth, Ilene C Weitz, Elina Armstrong, Christopher J PatriquinAbstract:BackgroundEculizumab, a humanized monoclonal antibody against complement protein C5 that inhibits terminal complement activation, has been shown to prevent complications of Paroxysmal Nocturnal Hemoglobinuria (PNH) and improve quality of life and overall survival, but data on the use of eculizumab in women during pregnancy are scarce. MethodsWe designed a questionnaire to solicit data on pregnancies in women with PNH and sent it to the members of the International PNH Interest Group and to the physicians participating in the International PNH Registry. We assessed the safety and efficacy of eculizumab in pregnant patients with PNH by examining the birth and developmental records of the children born and adverse events in the mothers. ResultsOf the 94 questionnaires that were sent out, 75 were returned, representing a response rate of 80%. Data on 75 pregnancies in 61 women with PNH were evaluated. There were no maternal deaths and three fetal deaths (4%). Six miscarriages (8%) occurred during the first tr...
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complement c3dg mediated erythrophagocytosis implications for Paroxysmal Nocturnal Hemoglobinuria
Blood, 2015Co-Authors: Zhuoer Lin, Antonio M Risitano, Christoph Q Schmidt, Sophia Koutsogiannaki, Patrizia Ricci, John D Lambris, Daniel RicklinAbstract:The clinical management of Paroxysmal Nocturnal Hemoglobinuria (PNH), a rare but life-threatening hematologic disease, has fundamentally improved with the introduction of a therapeutic that prevents complement-mediated intravascular hemolysis. However, a considerable fraction of PNH patients show insufficient treatment response and remain transfusion dependent. Because the current treatment only prevents C5-induced lysis but not upstream C3 activation, it has been speculated that ongoing opsonization with C3 fragments leads to recognition and phagocytosis of PNH erythrocytes by immune cells. Here, for the first time, we provide experimental evidence for such extravascular hemolysis and demonstrate that PNH erythrocytes from anti–C5-treated patients are phagocytosed by activated monocytes in vitro. Importantly, we show that this uptake can be mediated by the end-stage opsonin C3dg, which is not traditionally considered a phagocytic marker, via interaction with complement receptor 3 (CR3). Interaction studies confirmed that C3dg itself can act as a ligand for the binding domain of CR3. The degree of C3dg-mediated erythrophagocytosis in samples from different PNH patients correlated well with the individual level of C3dg opsonization. This finding may guide future treatment options for PNH but also has potential implications for the description and management of other complement-mediated diseases.
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polymorphism of the complement receptor 1 gene correlates with the hematologic response to eculizumab in patients with Paroxysmal Nocturnal Hemoglobinuria
Haematologica, 2014Co-Authors: Tommaso Rondelli, Antonio M Risitano, Régis Peffault De Latour, Patrizia Ricci, Michela Sica, Benedetta Peruzzi, Wilma Barcellini, Anna Paola Iori, Carla Boschetti, Veronica ValleAbstract:Complement blockade by eculizumab is clinically effective in hemolytic Paroxysmal Nocturnal Hemoglobinuria. However, the response is variable and some patients remain dependent on red blood cell transfusions. In 72 patients with hemolytic Paroxysmal Nocturnal Hemoglobinuria on eculizumab we tested the hypothesis that response may depend on genetic polymorphisms of complement-related genes. We found no correlation between the complement component C3 genotypes and the need for blood transfusions. On the other hand, we found a significant correlation with the HindIII polymorphism of a complement regulatory gene, the complement receptor 1 (CR1) gene. At this locus two co-dominant alleles are known, of which H (common) is associated with high expression, whereas L (rare) is associated with low expression of CR1 on red blood cells. Patients who still needed blood transfusion on eculizumab accounted for 18% of the H/H homozygotes, 33% of the H/L heterozygotes and 68% of the L/L homozygotes (P=0.016). Thus, patients with Paroxysmal Nocturnal Hemoglobinuria who have the L/L genotype are seven times more likely to be sub-optimal responders to eculizumab. Both in vitro and in vivo we found that the CR1 HindIII genotype correlates with the abundance of Paroxysmal Nocturnal Hemoglobinuria red cells that have bound C3, and with the kinetics of C3 binding. These results are consistent with the notion that by affecting C3 binding the CR1 genotype influences the response to eculizumab treatment, and this emerges as a novel example of pharmacogenetics.