Clinical Course and Flow Cytometric Analysis of Paroxysmal Nocturnal Hemoglobinuria in the United States and Japan

Abstract

: To determine and directly compare the clinical course of white and Asian patients with paroxysmal nocturnal hemoglobinuria (PNH), data were collected for epidemiologic analysis on 176 patients from Duke University and 209 patients from Japan. White patients were younger with significantly more classical symptoms of PNH including thrombosis, hemoglobinuria, and infection, while Asian patients were older with more marrow aplasia. The mean fraction of CD59-negative polymorphonuclear cells (PMN) at initial analysis was higher among Duke patients than Japanese patients. In both cohorts, however, a larger PNH clone was associated with classical PNH symptoms, while a smaller PNH clone was associated with marrow aplasia. Thrombosis was significantly more prevalent in white patients than Asian patients, and was associated with a significantly higher proportion of CD59-negative PMN. For individual patients, CD59-negative populations varied considerably over time, but a decreasing PNH clone portended hematopoietic failure. Survival analysis revealed a similar death rate in each group, although causes of death were different and significantly more Duke patients died from thrombosis. Japanese patients had a longer mean survival time (32.1 yr vs. 19.4 yr), although Kaplan-Meier survival curves were not significantly different. Poor survival in both groups was associated with age over 50 years, severe leukopenia/neutropenia at diagnosis, and severe infection as a complication; additionally, thrombosis at diagnosis or follow-up for Duke patients and renal failure for Japanese patients were poor prognostic factors. These data identify important differences between white and Asian patients with PNH. Identification of prognostic factors will help the design of prospective clinical trials for PNH.

Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP

“…[1][2][3][4] In the last 2 decades, virtually the entire mechanism leading to PNH hemolysis has been elucidated. [5][6][7][8] PNH stem cells acquire PIGA mutations and do not generate glycosylphosphatidylinositol (GPI), resulting in a deficiency of a series of GPI-linked membrane proteins, including complement regulatory molecules such as decay-accelerating factor (DAF) and CD59.…”

“…9 On the other hand, more than half of patients with PNH show various cytopenias and decreased CD34 ϩ hematopoietic cells. [1][2][3][4][10][11][12] PNH closely associates with aplastic anemia and myelodysplastic syndromes (MDSs) that share BM failure and development of leukemia. 1,12,13 It has been indicated that immune-mediated BM injury underlies at least a part of the diseases.…”

The role of paroxysmal nocturnal hemoglobinuria in idiopathic habitual abortion

“…(15). Two large studies have shown that in all patients with thrombosis, the PNH clone in granulocytes was greater than 50% and 61% respectively (15,16). However, in some studies, PNH clones have been reported at much lower levels in patients with thrombosis.…”

“…The association between HA and antiphospholipid antibodies remains a focus of research on AFAS (14). (15). Two large studies have shown that in all patients with thrombosis, the PNH clone in granulocytes was greater than 50% and 61% respectively (15,16).…”

Racial Differences in Paroxysmal Nocturnal Hemoglobinuria Thrombosis and Glycosylphosphatidylinositol-Deficient Granulocytes

“…Eculizumab, an inhibitor of terminal complement C5, provides patients with PNH with a good quality of life by ameliorating hemolysis and thrombosis, and promotes a better understanding of the complement-mediated molecular pathophysiology of PNH [1][2][3]. However, the underlying reasons for distinct differences in the incidences of thrombosis and bone marrow failure between Caucasian and Asian patients with PNH are still unknown (West vs. Japan, 32% vs. 4%) [4]. Racial differences are more evident in PNH thrombosis than in other conventional arterial thromboses (PNH vs. others, 2.4 to 9.8 vs. 1.7 to 3.9-fold increase) [4,5], suggesting that the presence of thrombus formation is characteristic of PNH.…”