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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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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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effect of eculizumab on hemolysis and transfusion requirements in patients with paroxysmal nocturnal Hemoglobinuria
The New England Journal of Medicine, 2004Co-Authors: Peter Hillmen, Stephen J. Richards, Matthew J. Cullen, Claire Hall, Judith C W Marsh, Modupe O Elebute, Michael P Bombara, Beth E Petro, Scott A Rollins, Christopher F MojcikAbstract:background Paroxysmal nocturnal Hemoglobinuria (PNH) arises from a somatic mutation of the PIG-A gene in a hematopoietic stem cell and the subsequent production of blood cells with a deficiency of surface proteins that protect the cells against attack by the complement system. We tested the clinical efficacy of eculizumab, a humanized antibody that inhibits the activation of terminal complement components, in patients with PNH. methods Eleven transfusion-dependent patients with PNH received infusions of eculizumab (600 mg) every week for four weeks, followed one week later by a 900-mg dose and then by 900 mg every other week through week 12. Clinical and biochemical indicators of hemolysis were measured throughout the trial. results Mean lactate dehydrogenase levels decreased from 3111 IU per liter before treatment to 594 IU per liter during treatment (P=0.002). The mean percentage of PNH type III erythrocytes increased from 36.7 percent of the total erythrocyte population to 59.2 percent (P = 0.005). The mean and median transfusion rates decreased from 2.1 and 1.8 units per patient per month to 0.6 and 0.0 units per patient per month, respectively (P=0.003 for the comparison of the median rates). Episodes of Hemoglobinuria were reduced by 96 percent (P<0.001), and measurements of the quality of life improved significantly. conclusions Eculizumab is safe and well tolerated in patients with PNH. This antibody against terminal complement protein C5 reduces intravascular hemolysis, Hemoglobinuria, and the need for transfusion, with an associated improvement in the quality of life in patients with PNH.
Robert A Brodsky - One of the best experts on this subject based on the ideXlab platform.
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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
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.
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narrative review paroxysmal nocturnal Hemoglobinuria the physiology of complement related hemolytic anemia
Annals of Internal Medicine, 2008Co-Authors: Robert A BrodskyAbstract:Paroxysmal nocturnal Hemoglobinuria (PNH) is a rare hematopoietic stem-cell disorder caused by a mutation that leads to increased susceptibility to complement-induced hemolysis. An expensive but hi...
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catheter directed thrombolysis and thrombectomy for the budd chiari syndrome in paroxysmal nocturnal Hemoglobinuria in three patients
Journal of Vascular and Interventional Radiology, 2006Co-Authors: Robert A BrodskyAbstract:Paroxysmal nocturnal Hemoglobinuria (PNH) is a rare hematopoietic stem cell disorder characterized by hemolytic anemia, Hemoglobinuria, bone marrow failure, and hypercoagulability. Thrombosis is the leading cause of mortality and occurs in one-half of PNH patients, with the hepatic veins being the most common site. Patients with hepatic vein thrombosis (Budd-Chiari syndrome) can present with abdominal pain, hepatomegaly, jaundice, and ascites. Prognosis is poor for these patients; death may occur from liver failure, vessel rupture, intestinal ischemia, infarction, necrosis, or sepsis. The authors report three consecutive cases of successful treatment with catheter-directed thrombolysis and thrombectomy directly in the hepatic veins in patients with PNH who developed acute hepatic vein thrombosis. This treatment represents a potential bridge toward more curative therapies such as allogeneic bone marrow transplant.
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natural history of paroxysmal nocturnal haemoglobinuria using modern diagnostic assays
British Journal of Haematology, 2004Co-Authors: Victor M Moyo, Galina L Mukhina, Elizabeth Garrett, Robert A BrodskyAbstract:Paroxysmal nocturnal haemoglobinuria (PNH) is an uncommon, acquired disorder of blood cells caused by mutation of the phosphatidylinositol glycan class A (PIG-A) gene. The disease often manifests with haemoglobinuria, peripheral blood cytopenias, and venous thrombosis. The natural history of PNH has been documented in retrospective series; but there has only been one study that correlated the more sensitive and specific flow cytometric assays that have become available in the last decade with severe symptoms associated with PNH. In a retrospective analysis of 49 consecutive patients with PNH evaluated at Johns Hopkins, large PNH clones were associated with an increased risk for thrombosis as well as haemoglobinuria, abdominal pain, oesophageal spasm, and impotence. Of the 14 (29%) patients that developed thrombosis, nine died; six of these from complications related to thromboses. According to logistic regression modelling, for a 10% change in PNH clone size, the odds ratio for risk of thrombosis was estimated to be 1.64. No patient with or =61% PNH granulocytes manifested with thrombosis. These data not only confirm that the size of the PNH clone correlates with the risk for thrombosis, but they also suggest a correlation of PNH clone size to more symptomatic PNH.
Neal S Young - One of the best experts on this subject based on the ideXlab platform.
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paroxysmal nocturnal Hemoglobinuria clones in severe aplastic anemia patients treated with horse anti thymocyte globulin plus cyclosporine
Haematologica, 2010Co-Authors: Phillip Scheinberg, Olga Nunez, Michael Marte, Neal S YoungAbstract:Background Clones of glycosylphosphatidylinositol-anchor protein-deficient cells are characteristic in paroxysmal nocturnal Hemoglobinuria and are present in about 40–50% of patients with severe aplastic anemia. Flow cytometry has allowed for sensitive and precise measurement of glycosylphosphatidylinositol-anchor protein-deficient red blood cells and neutrophils in severe aplastic anemia. Design and Methods We conducted a retrospective analysis of paroxysmal nocturnal Hemoglobinuria clones measured by flow cytometry in 207 consecutive severe aplastic anemia patients who received immunosuppressive therapy with a horse anti-thymocyte globulin plus cyclosporine regimen from 2000 to 2008. Results The presence of a glycosylphosphatidylinositol-anchor protein-deficient clone was detected in 83 (40%) patients pre-treatment, and the median clone size was 9.7% (interquartile range 3.5–29). In patients without a detectable clone pre-treatment, the appearance of a clone after immunosuppressive therapy was infrequent, and in most with a clone pre-treatment, clone size often decreased after immunosuppressive therapy. However, in 30 patients, an increase in clone size was observed after immunosuppressive therapy. The majority of patients with a paroxysmal nocturnal Hemoglobinuria clone detected after immunosuppressive therapy did not have an elevated lactate dehydrogenase, nor did they experience hemolysis or thrombosis, and they did not require specific interventions with anticoagulation and/or eculizumab. Of the 7 patients who did require therapy for clinical paroxysmal nocturnal Hemoglobinuria symptoms and signs, all had an elevated lactate dehydrogenase and a clone size greater than 50%. In all, 18 (8.6%) patients had a clone greater than 50% at any given time of sampling. Conclusions The presence of a paroxysmal nocturnal Hemoglobinuria clone in severe aplastic anemia is associated with low morbidity and mortality, and specific measures to address clinical paroxysmal nocturnal Hemoglobinuria are seldom required.
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large granular lymphocyte lgl like clonal expansions in paroxysmal nocturnal Hemoglobinuria pnh patients
Leukemia, 2005Co-Authors: Antonio M Risitano, Pawel Muranski, Marcin W Wlodarski, Christine L Okeefe, Elaine M. Sloand, Jaroslaw P Maciejewski, Neal S YoungAbstract:Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal Hemoglobinuria (PNH) patients
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paroxysmal nocturnal Hemoglobinuria cells in patients with bone marrow failure syndromes
Annals of Internal Medicine, 1999Co-Authors: Daniel E Dunn, Shoichi Nagakura, Patcharin Tanawattanacharoen, Piernicola Boccuni, Spencer W Green, Martha Kirby, Mysore Anil S Kumar, Stephen J Rosenfeld, Neal S YoungAbstract:Flow cytometric analysis is superior to the Ham test and permits concomitant diagnosis of paroxysmal nocturnal Hemoglobinuria in about 20% of patients with myelodysplasia (a rate similar to that se...
Ann Reed Gaines - One of the best experts on this subject based on the ideXlab platform.
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acute onset hemoglobinemia and or Hemoglobinuria and sequelae following rh o d immune globulin intravenous administration in immune thrombocytopenic purpura patients
Blood, 2000Co-Authors: Ann Reed GainesAbstract:Rh(o)(D) immune globulin intravenous (anti-D IGIV) was licensed by the United States Food and Drug Administration (FDA) in March 1995 to treat patients with immune thrombocytopenic purpura (ITP). Anti-D IGIV induces extravascular hemolysis, an expected adverse reaction that is consistent with the presumed mechanism of action. Between licensure and April 1999, the FDA received 15 reports of hemoglobinemia and/or Hemoglobinuria following anti-D IGIV administration that met the case definition for this review. The mechanism responsible for hemoglobinemia and/or Hemoglobinuria is unexplained. Review of these reports was prompted by the seriousness and the unexpectedness of treatment-associated sequelae experienced by 11 patients. Of these patients, 7 developed sufficient onset or exacerbation of anemia that orders were written for packed red blood cell transfusions, although only 6 patients were transfused. Eight patients experienced the onset or exacerbation of renal insufficiency, and 2 patients underwent dialysis. One patient died due to complications of exacerbated anemia. Six patients experienced 2 to 3 sequelae. Absent validated incidence data, a 1.5% estimated incidence rate from published clinical trial data and a 0.1% estimated reporting rate from FDA and drug utilization data were calculated for reported cases of hemoglobinemia and/or Hemoglobinuria. This review presents the first case series of anti-D-IGIV-associated hemoglobinemia and/or Hemoglobinuria and provides pretreatment and posttreatment clinical and laboratory findings of the case series patients. The primary purpose of this review is to increase awareness of this potentially serious occurrence among physicians and health care professionals who manage ITP patients treated with anti-D IGIV, thereby enabling prompt recognition and treatment of sequelae. (Blood. 2000;95:2523-2529)
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acute onset hemoglobinemia and or Hemoglobinuria and sequelae following rho d immune globulin intravenous administration in immune thrombocytopenic purpura patients
Blood, 2000Co-Authors: Ann Reed GainesAbstract:Rho(D) immune globulin intravenous (anti-D IGIV) was licensed by the United States Food and Drug Administration (FDA) in March 1995 to treat patients with immune thrombocytopenic purpura (ITP). Anti-D IGIV induces extravascular hemolysis, an expected adverse reaction that is consistent with the presumed mechanism of action. Between licensure and April 1999, the FDA received 15 reports of hemoglobinemia and/or Hemoglobinuria following anti-D IGIV administration that met the case definition for this review. The mechanism responsible for hemoglobinemia and/or Hemoglobinuria is unexplained. Review of these reports was prompted by the seriousness and the unexpectedness of treatment-associated sequelae experienced by 11 patients. Of these patients, 7 developed sufficient onset or exacerbation of anemia that orders were written for packed red blood cell transfusions, although only 6 patients were transfused. Eight patients experienced the onset or exacerbation of renal insufficiency, and 2 patients underwent dialysis. One patient died due to complications of exacerbated anemia. Six patients experienced 2 to 3 sequelae. Absent validated incidence data, a 1.5% estimated incidence rate from published clinical trial data and a 0.1% estimated reporting rate from FDA and drug utilization data were calculated for reported cases of hemoglobinemia and/or Hemoglobinuria. This review presents the first case series of anti-D-IGIV–associated hemoglobinemia and/or Hemoglobinuria and provides pretreatment and posttreatment clinical and laboratory findings of the case series patients. The primary purpose of this review is to increase awareness of this potentially serious occurrence among physicians and health care professionals who manage ITP patients treated with anti-D IGIV, thereby enabling prompt recognition and treatment of sequelae.
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CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS Disseminated
1995Co-Authors: Ann Reed GainesAbstract:intravascular coagulation associated with acute hemoglobinemia or Hemoglobinuria following Rho(D) immune globulin intravenous administration for immune thrombocytopenic purpur
Antonio M Risitano - One of the best experts on this subject based on the ideXlab platform.
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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, Regis Peffault De Latour, Michela Sica, Benedetta Peruzzi, Patrizia Ricci, 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.
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hematopoietic stem cell transplantation for paroxysmal nocturnal Hemoglobinuria long term results of a retrospective study on behalf of the gruppo italiano trapianto midollo osseo gitmo
Haematologica, 2010Co-Authors: Stella Santarone, Antonio M Risitano, Anna Paola Iori, Andrea Bacigalupo, Elena Tagliaferri, Erminia Di Bartolomeo, Alessandro Rambaldi, Emanuele Angelucci, Alessandra Spagnoli, Federico PapineschiAbstract:Background Paroxysmal nocturnal Hemoglobinuria is an acquired clonal disorder of the hemopoietic stem cells for which the only curative treatment is allogeneic hematopoietic stem cell transplantation.Design and Methods The aim of this retrospective study was to assess the long-term clinical and hematologic results in 26 paroxysmal nocturnal Hemoglobinuria patients who received hematopoietic stem cell transplantation in Italy between 1988 and 2006. The patients were aged 22 to 60 years (median 32 years). Twenty-three donors were HLA-identical (22 siblings and one unrelated) and 3 were HLA-mismatched (2 related and one unrelated).Results Fifteen patients received a myeloablative conditioning consisting of busulfan and cyclophosphamide (in all cases from identical donor) and 11 were given a reduced intensity conditioning (8 from identical donor and 3 from mismatched donor). The cumulative incidence of graft failure was 8% (4% primary and 4% secondary graft failure). Transplant-related mortality for all patients was 42% (26% and 63% for patients transplanted following myeloablative or reduced intensity conditioning, respectively). As of October 31, 2009, 15 patients (11 in the myeloablative conditioning group and 4 in the reduced intensity conditioning group) are alive with complete hematologic recovery and no evidence of paroxysmal nocturnal Hemoglobinuria following a median follow-up of 131 months (range 30–240). The 10-year Kaplan-Meier probability of disease-free survival was 57% for all patients: 65% for 23 patients transplanted from identical donor and 73% for 15 patients transplanted with myeloablative conditioning. No thromboembolic event nor recurrence of the disease were reported following transplant.Conclusions The findings of this study confirm that most patients with paroxysmal nocturnal Hemoglobinuria may be definitively cured with hematopoietic stem cell transplantation.
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paroxysmal nocturnal Hemoglobinuria and eculizumab
Haematologica, 2010Co-Authors: L Luzzatto, Antonio M Risitano, Rosario NotaroAbstract:Paroxysmal nocturnal Hemoglobinuria (PNH) is enough of a tongue-twister for patients and doctors alike and we all teach the students that PNH is a disorder characterized by the triad of intravascular hemolysis, venous thrombosis and cytopenias.[1][1]–[3][2] But in this journal, founded by Adolfo
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hemoglobin normalization after splenectomy in a paroxysmal nocturnal Hemoglobinuria patient treated by eculizumab
Blood, 2008Co-Authors: Antonio M Risitano, Ludovica Marando, Elisa Seneca, B RotoliAbstract:To the editor: In paroxysmal nocturnal Hemoglobinuria (PNH), hemolysis is due to the absence on red blood cell (RBC) surface of the 2 complement regulators CD55 and CD59,[1][1],[2][2] which causes uncontrolled complement activation and consequent chronic intravascular hemolysis via the membrane
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large granular lymphocyte lgl like clonal expansions in paroxysmal nocturnal Hemoglobinuria pnh patients
Leukemia, 2005Co-Authors: Antonio M Risitano, Pawel Muranski, Marcin W Wlodarski, Christine L Okeefe, Elaine M. Sloand, Jaroslaw P Maciejewski, Neal S YoungAbstract:Large granular lymphocyte (LGL)-like clonal expansions in paroxysmal nocturnal Hemoglobinuria (PNH) patients