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INTRODUCTION

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SUMMARY

In contrast to all other intrinsic abnormalities of the erythrocyte, paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, not an inherited, disorder. PNH arises as a consequence of somatic mutation, involving one or more hematopoietic stem cells, of PIGA, a gene located on the X chromosome that is required for synthesis of the glycosylphosphatidylinositol (GPI) moiety that anchors some proteins to the cell surface. Consequently, all GPI-anchored proteins (GPI-APs) that are normally expressed are deficient on the mutant hematopoietic stem cells and their progeny. The complement-mediated intravascular hemolytic anemia and the resulting hemoglobinuria that are the clinical hallmarks of PNH are a consequence of deficiency of the GPI-anchored complement regulatory proteins, CD55 and CD59. Although PNH is a neoplastic (clonal) disease, it is not a malignant disease in that there is no exaggerated proliferation of neoplastic cells and replacement of marrow or spread to other tissues, and the extent to which the mutant clones expand varies greatly among patients. Thus, the blood cells of patients with PNH are a mosaic of phenotypically normal and abnormal cells. The size of the mutant clone is an important determinant of the clinical manifestations of the disease, which include hemolysis, thrombophilia, and, in many patients, pancytopenia as a result of marrow failure. The diagnosis of PNH is confirmed using flow cytometry to detect and quantify the percentage of blood erythrocytes and leukocytes (i. e., neutrophils and monocytes) that lack GPI-APs measured as intensity of CD55 and CD59 on the cell surface. The intravascular hemolysis of PNH can be controlled with eculizumab, a humanized monoclonal antibody that blocks formation of the cytolytic membrane attack complex of complement. Although treatment with eculizumab favorably modifies the natural history of PNH, it has no effect on the underlying disease process (i.e., the PIGA-mutant hematopoietic stem cell clone). The PIGA-mutant mutant clone can be eradicated and normal hematopoiesis restored by allogeneic hematopoietic stem cell transplantation, but the relatively benign natural history of PNH in patients treated with eculizumab has tempered enthusiasm for transplantation because of concerns about subjecting patients to the risk of treatment-related morbidity.

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Acronyms and Abbreviations:

APC, alternative pathway of complement; CD55, an antigen encoding DAF; CD59, an antigen encoding MAC-inhibitory protein; DAF, decay-accelerating factor; GPI, glycosylphosphatidylinositol; GPI-APs, glycosylphosphatidylinositol-anchored proteins; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; INR, international normalized ratio of prothrombin assay data; LDH, lactate dehydrogenase; MAC, membrane attack complex of complement; MDS, myelodysplastic syndrome; MIRL, membrane inhibitor of reactive lysis; PIGA, phosphatidylinositol glycan class A; PMN, polymorphonuclear cell; PNH, paroxysmal nocturnal hemoglobinuria; PNH-sc, subclinical PNH; RA, refractory anemia; RAEB, refractory anemia with excess of blasts; RAEB-t, refractory anemia with excess of blasts in transformation; RA-PNH+, RA with a population of PNH cells; RA-PNH−, RA without a population of PNH cells; RARS, refractory anemia with ringed sideroblasts; RBCs, red blood cells; RCMD, refractory cytopenias with multilineage dysplasia; WHO, World Health Organization.

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DEFINITION AND HISTORY

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