Paroxysmal Nocturnal Hemoglobinuria

Rotoli, Bruno; Luzzatto, Lucio

doi:10.1007/978-1-59259-963-9_86

Cited by 63 publications

(40 citation statements)

References 67 publications

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“…Paroxysmal nocturnal hemoglobinuria (PNH), first described in the 18th century, is characterized by the typical clinical triad of hemolytic anemia, bone marrow failure, and propensity to thromboembolism (Rotoli and Luzzatto 1989; Dunn et al 2000; Rotoli et al 2006; Hill et al 2007a). It is a rare disease, with a worldwide prevalence estimated in the range of 1–5 cases per million (Rosse 1996) regardless of ethnicity; an increased prevalence is reported in some regions which also harbor higher incidence of aplastic anemia (eg, Thailand and some other Asian countries) (Pramoonjago et al 1999).…”

Section: Introductionmentioning

confidence: 99%

Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents

Risitano¹

2008

BTT

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Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal non-malignant hematological disease characterized by the expansion of hematopoietic stem cells (HSCs) and progeny mature cells, whose surfaces lack all the proteins linked through the glycosyl-phosphatidyl inositol anchor. This defect arises from an acquired somatic mutation in the X-linked phosphatidylinositol glycan class A gene, with subsequent clonal expansion of the mutated HSCs as a result of a concomitant, likely immune-mediated, selective pressure. The disease is characterized by complement-mediated chronic intravascular hemolysis, resulting in hemolytic anemia and hemosiderinuria; capricious exacerbations lead to recurrent gross hemoglobinuria. Additional cardinal manifestations of PNH are a variable degree of bone marrow failure and an intrinsic propensity to thromboembolic events. The disease is markedly invalidating, with chronic symptoms requiring supportive therapy – usually including periodical transfusions; possible life-threatening complications may also ensue. The biology of PNH has been progressively elucidated in the past few years, but therapeutic strategies remained unsatisfactory for decades, the only exception being stem cell transplantation, which is restricted to selected patients and retains significant morbidity and mortality. Recently, a biological agent to treat PNH has been developed – the terminal complement inhibitor eculizumab – which has been tested in a number of clinical trials, with exciting results. All the data from worldwide clinical trials confirm that eculizumab radically modifies the symptoms, the biology, and the natural history of PNH, strongly improving the quality of life of PNH patients.

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Section: Introductionmentioning

confidence: 99%

Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents

Risitano¹

2008

BTT

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“…Thus, some degree of marrow failure is common in PNH patients, ranging from mild cytopenias to severe aplastic anemia [1,2]; of note, the specific picture of each individual patient may change during the disease course, with patients initially presenting with normal marrow function and subsequently developing more severe marrow failure, as well as patients initially diagnosed as aplastic anemia subsequently developing PNH [51]. According to a recent proposal of classification, distinct subtypes of PNH may be identified: classic PNH (which has hemolysis but not cytopenia), PNH with an underlying bone marrow disorder (with cytopenia and hemolysis) and subclinical PNH (presence of PNH cells without relevant hemolysis, usually in the context of other hematological disorders) [5].…”

Section: Bone Marrow Failurementioning

confidence: 99%

“…PNH is characterized by a triad of clinical features which is unique in medicine: intravascular hemolysis, thromboembolic events and cytopenia [1][2][3]5].…”

Section: The Clinical Features Of Pnhmentioning

confidence: 99%

“…The hallmark of PNH is the chronic, complement-mediated, intravascular hemolysis, with subsequent hemoglobinuria and anemia; however, the typical clinical triad includes two other features: thromboembolic events (usually at venous sites) and bone marrow failure [1][2][3]. While the treatment options for PNH remained unsatisfactory for decades [5], with allogeneic stem cell transplantation being the only potentially curative option [6], the new century brought the availability of the complement inhibitor eculizumab [7], which has drastically changed the management of PNH patients.…”

Section: Introductionmentioning

confidence: 99%

“…Paroxysmal nocturnal hemoglobinuria (PNH) [1][2][3] is a complex hematological disorder characterized by the clonal expansion of abnormal hematopoietic stem cell(s), which are unable to express glycosylphosphatidylinositol (GPI)-linked proteins on their surface due to a mutation in the X-linked phosphatidylinositol glycan class A (PIG-A) gene [4]. The hallmark of PNH is the chronic, complement-mediated, intravascular hemolysis, with subsequent hemoglobinuria and anemia; however, the typical clinical triad includes two other features: thromboembolic events (usually at venous sites) and bone marrow failure [1][2][3].…”

Section: Introductionmentioning

confidence: 99%

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Achievements and Limitations of Complement Inhibition by Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: The Role of Complement Component 3

Risitano¹,

Perna²,

Selleri

2011

MRMC

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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.

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Thymoma followed by paroxysmal nocturnal hemoglobinuria: A unique clinical association in the context of multiorgan autoimmunity with a potential role for CD8+ T lymphocytes

et al. 2006

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Seven years after a surgically resected thymoma, a female patient affected by myasthenia gravis and Good's syndrome presented with paroxysmal nocturnal hemoglobinuria (PNH). Co-culture experiments and spectratyping analyses indicated that CD8+ lymphocytes were involved in damaging hematopoietic precursors. While PNH clones have been identified in various hematological disorders, the sequential association of thymoma and PNH has been unreported so far. Am. J. Hematol. 81:774-778, 2006. V V C 2006 Wiley-Liss, Inc.

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Paroxysmal Nocturnal Hemoglobinuria

Cited by 63 publications

References 67 publications

Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents

Paroxysmal nocturnal hemoglobinuria: pathophysiology, natural history and treatment options in the era of biological agents

Achievements and Limitations of Complement Inhibition by Eculizumab in Paroxysmal Nocturnal Hemoglobinuria: The Role of Complement Component 3

Thymoma followed by paroxysmal nocturnal hemoglobinuria: A unique clinical association in the context of multiorgan autoimmunity with a potential role for CD8+ T lymphocytes

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