Serum erythropoietin levels in paroxysmal nocturnal haemoglobinuria: implications for therapy

McMullin, Mary Frances; Hillmen, Peter; Elder, G. E.; Lappin, Terence; Luzzatto, Lucio

doi:10.1046/j.1365-2141.1996.421961.x

Cited by 18 publications

(10 citation statements)

References 10 publications

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“…Thus, strategies for iron chelation are not necessary; in fact these patients may sometimes even require iron supplementation to sustain the compensatory erythropoiesis (Rosse 1982). Similarly, vitamin B12 and folate supplementation are usually indicated to sustain the enhanced erythropoiesis (Rosse 1982); furthermore, endogenous erythropoiesis may also be increased by recombinant erythropoietin, mostly in cases with inadequate production (Stebler et al 1990; Bourantas 1994; McMullin et al 1996). Paradoxically, all these strategies, including iron replacement, may lead to increased hemolysis as a result of increased PNH hematopoiesis, contrary to what is seen following suppression of erythropoiesis by transfusions.…”

Section: Management: the Pre-eculizumab Eramentioning

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: Management: the Pre-eculizumab Eramentioning

confidence: 99%

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

Risitano¹

2008

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“…6 However, the level usually depends on the cause of anaemia, with higher levels in aplastic anaemia compared to the lower levels found in haemolytic anaemia. 7 This may suggest a case for a trial of erythropoietin in haemolytic anaemia when there may be a suboptimal endogenous drive. 7 The erythropoietin level at the start of treatment is not a reliable indicator of response to erythropoietin.…”

Section: Discussionmentioning

confidence: 99%

“…7 This may suggest a case for a trial of erythropoietin in haemolytic anaemia when there may be a suboptimal endogenous drive. 7 The erythropoietin level at the start of treatment is not a reliable indicator of response to erythropoietin. However, some studies on the use of cancer-related anaemia have suggested that those with levels 4500 U/l are less likely to respond, with the best results achieved if the erythropoietin level is below 100 U/l.…”

Section: Discussionmentioning

confidence: 99%

Novel uses for recombinant erythropoietin therapy in unlicensed indications

Macartney¹,

Adgey²,

Jones³

et al. 2004

Hematol J

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Clinical uses for recombinant human erythropoietin (rHuEPO) therapy continue to expand. Initial use was in anaemia associated with end-stage renal disease, but more recently there have been many reports of the benefits of erythropoietin in other clinical situations such as cancer-related anaemia. Recombinant erythropoietin reduces the need for blood transfusion and hence exposure to donor blood products as well as improving quality of life. We report four patients who were transfusion dependent, none of whom had licensed indications for the use of recombinant erythropoietin. Two patients had microangiopathic haemolytic anaemia secondary to mechanical valve haemolysis and were unsuitable for any further cardiac intervention. One patient had anaemia of chronic disease and anti-Vel red cell antibodies, making compatible blood transfusions difficult to obtain. The fourth patient had primary thrombocythaemia and developed transfusion-dependent anaemia secondary to myelosuppressive agents. All four patients had a relative deficiency in endogenous erythropoietin levels ranging between 7 and 41 IU/l. After commencing recombinant erythropoietin therapy, all had a response in haemoglobin of at least 1 g/dl with an overall improvement in their quality of life. We conclude that rHuEPO is a very convenient and useful form of treatment in transfusion-dependent anaemia and in some cases beyond the licensed indications.

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“…Growth factors have a blunted effect because of the underlying marrow defect. There is a suggestion that recombinant erythropoietin may have a use in patients with high transfusion requirements [40], although serum erythropoietin levels are very high in PNH patients, similar to levels found in AA [41]. …”

Section: Clinical Featuresmentioning

confidence: 99%

The Glycosylphosphatidylinositol Anchor and Paroxysmal Nocturnal Haemoglobinuria/Aplasia Model

Hall

Richards²,

Hillmen³

2002

Acta Haematol

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Paroxysmal nocturnal haemoglobinuria (PNH) is unique because it is an acquired haemolytic anaemia, resulting from an intrinsic red cell membrane disorder. The disease has been shown to be due to a somatic mutation of the phosphatidylinositol glycan complementation class A (pig-a) gene at the level of the haemopoietic stem cell. The defect in synthesis of the glycosylphosphatidylinositol (GPI) anchor results in a deficiency of all proteins that are GPI-bound to red cell, leucocyte and platelet membranes. The function of these proteins is extremely varied but a critical role is the protection of the cell from complement and it is the unopposed action of the complement cascade that results in the intravascular haemolysis and venous thrombosis which are hallmarks of the disease. The relationship between PNH and aplastic anaemia remains intriguing. It appears likely that an insult to a haemopoietic progenitor alters it in such a way that it becomes vulnerable to immune-mediated attack by cytotoxic T cells and/or cytokines. This attack requires one or more GPI-anchored molecules to be effective. Thus a GPI-negative clone would be at a relative advantage, and it is the balance between bone marrow impairment and proliferation of the GPI-negative clone(s) that determines the clinical picture. Prospects for molecular therapy continue to improve. Cell-to-cell transfer of GPI-linked proteins has been demonstrated in murine studies and recombinant CD59 has been expressed on GPI-deficient lymphocytes in vitro. Gene therapy remains a tantalising possibility, although a greater understanding of the pathophysiology of PNH is required, as well as advances in gene therapy techniques, before such an approach can be seriously considered.

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Serum erythropoietin levels in paroxysmal nocturnal haemoglobinuria: implications for therapy

Cited by 18 publications

References 10 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

Novel uses for recombinant erythropoietin therapy in unlicensed indications

The Glycosylphosphatidylinositol Anchor and Paroxysmal Nocturnal Haemoglobinuria/Aplasia Model

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