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In contrast to all other intrinsic abnormalities of the erythrocyte, paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, rather than an inherited, disorder. PNH arises as a consequence of somatic mutation, affecting one or more hematopoietic stem/progenitor cells (HS/PCs), of PIGA, a gene located on the X chromosome that is required for synthesis of the glycosyl phosphatidylinositol (GPI) moiety that anchors a functionally diverse group of proteins to the cell surface. Consequently, all GPI-anchored proteins (GPI-APs) that are normally expressed are deficient on the mutant HS/PC stem cell and its 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 clonal disease, it is not a malignant disease in that there is no inexorable proliferation of neoplastic cells (as is the case with acute myeloid leukemia) or invasion of nonmarrow tissue, and the extent to which the mutant clone(s) expand varies greatly among patients. Therefore, the blood cells of patients with PNH is 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 and thrombophilia. An element of immune-mediated marrow failure (of varying degrees and types) is present in all patients, but PNH is a consequence rather than a cause of immune-mediated bone marrow failure. The diagnosis of PNH is determined by using flow cytometry to detect and quantify the percentage of blood erythrocytes and leukocytes (ie, neutrophils and monocytes) that lack GPI-APs as measured by binding of immunoflorescently labeled probes that bind to GPI-anchored cell surface proteins, including CD55 and CD59. The intravascular hemolysis of PNH can be controlled with a humanized monoclonal anticomplement C5 antibody that blocks formation of the cytolytic membrane attack complex of complement (commercially available as eculizumab and ravulizumab). Although treatment with eculizumab/ravulizumab favorably modifies the natural history of PNH, it has no effect on the underlying disease process (ie, on the PIGA-mutant HS/PC clone). The PIGA-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/ravulizumab has tempered enthusiasm for transplantation because of concerns about subjecting patients to the risk of treatment-related morbidity and mortality.

Acronyms and Abbreviations:

APC, alternative pathway of complement; CD55, an antigen encoding DAF; CD59, an antigen encoding MAC-inhibitory protein; DAF, decay accelerating factor; EtN, ethanolamine; GPI, glycosyl phosphatidylinositol; GPI-APs, glycosyl phosphatidylinositol-anchored proteins; GLcN, glucosamine; GVHD, graft versus host disease; HS/PC, hematopoietic stem/progenitor cell; 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; PNH, paroxysmal nocturnal hemoglobinuria; PNH-sc, subclinical PNH; RA, refractory anemia; RAEB, refractory anemia with excess ...

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