Clinical paroxysmal nocturnal hemoglobinuria is the result of expansion ofglycosyl-phosphatidyl-inositol-anchored protein-deficient clone in the condition of deficient hematopoiesis

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal hematopoie tic stem cell disorder in which PIG-A, a gene essential for the biosynthesi s of the glycosyl-phosphatidyl-inositol (GPI) anchor, is somatically mutate d. Absence of GPI-linked proteins from the surface of blood cells is charac teristic of the PIG-A mutant (PNH) clone and is also accountable for certai n manifestations, such as intravascular hemolysis. It is unclear how the PN H clone expands and comes to dominate hematopoiesis. In this study, CD34(+) cells - committed progenitors (colony-forming cells) representing immature hematopoietic stem cells - nd reticulocytes representing the differentiate d erythroid cells were quantitated in peripheral blood of patients with PNH . Compared with normal controls (n = 29), CD34+ cell levels were significan tly lower in PNH patients who did not have preexisting aplastic anemia (AA) (n = 12) (2.47 +/- 1.23 versus 4.68 +/- 1.05 x 10(6)/L mean +/- standard e rror; P = .022). PNH patients with precedent aplastic anemia (AA(+)/PNH) sh owed markedly low CD34+ cell levels compared with normal control subjects ( 0.6 +/- 0.29 versus 4.68 +/- 1.05 x 10(6)/L: P = .0001). In addition, colon y-forming cells from PNH patients were significantly decreased compared wit h those from normal volunteers (erythroid burst-forming units, 2.8 +/- 1.2 versus 25.6 +/- 6.2/5 x 10(5) mononuclear cells; P = .0006: and granulocyte /macrophage colony-forming units, 1.2 +/- 0.5 versus 13.3 +/- 3.0/ 5 x 10(5 ) mononuclear cells: P = .0006). These findings occur in both aplastic and hemolytic types of PNH, suggesting hematopoietic failure in PNH. On the con trary, the numbers of reticulocytes and the reticulocyte production index o f PNH patients were significantly higher than those of normal persons and c omparable to those from patients with autoimmune hemolytic anemia, indicati ng accelerating erythropoiesis in PNH. The degree of reticulocytosis correl ated well with the proportion of CD59(-) (PNH) reticulocytes, All of the fi ndings suggest that in the condition of deficient hematopoiesis, the PNH cl one arising from the mutated hematopoietic stem cell expands and maintains a substantial proportion of the patient's hematopoiesis. (C) 2001 The Japan ese Society of Hematology.