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In contrast to all other intrinsic abnormalities of the erythrocyte, paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder. PNH arises as a consequence of somatic mutation, in one or more hematopoietic stem cells, of PIGA, a gene located on the X chromosome that is required for synthesis of the glycosyl phosphatidylinositol (GPI) moiety that anchors some proteins to 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 clonal disease, it is not a malignant disease, and the extent to which the mutant clones expand varies greatly among patients. Thus, the blood of patients with PNH is a mosaic of abnormal and phenotypically normal cells. The size of the mutant clone is an important determinant of the clinical manifestations of the disease that include thrombophilia and marrow failure in addition to hemolysis. The diagnosis of PNH is straightforward using flow cytometry to detect and quantify the percentage of blood erythrocytes and neutrophils that lack GPI-APs. 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. Eculizumab, however, has no effect on the underlying disease process. The mutant clone can be eradicated and normal hematopoiesis restored by allogeneic hematopoietic stem cell transplant.

Acronyms and Abbreviations

Acronyms and abbreviations that appear in this chapter include: APC, alternative pathway of complement; DAF, decay accelerating factor; EtN, ethanolamine; GLcN, glucosamine; GPI, glycosyl phosphatidylinositol; GPI-APs, glycosyl phosphatidylinositol-anchored proteins; 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 sideroblast; RBCs, red blood cells; RCMD, refractory cytopenias with multilineage dysplasia; RCMD-RS, RCMD with ringed sideroblasts; WHO, World Health Organization.

Although commonly regarded as a type of hemolytic anemia, paroxysmal nocturnal hemoglobinuria (PNH) is actually a hematopoietic stem cell disorder. PNH arises as a result of nonmalignant clonal expansion of one or several hematopoietic stem cells that have acquired a somatic mutation of the X-chromosome gene PIGA (phosphatidylinositol glycan class A). As a consequence of mutant PIGA, progeny of affected stem cells (erythrocytes, granulocytes, monocytes, platelets, and lymphocytes) are deficient in all glycosyl phosphatidylinositol-anchored proteins (GPI-APs) that are normally expressed on hematopoietic cells (and all GPI-APs that are normally expressed on hematopoietic cells are deficient on progeny of PIGA mutant stem cells). The clinical manifestations of PNH ...

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