Disease relevance of Hemoglobinuria

• Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria [1].
• Acquired mutations of the PIG-A gene result in the hemolysis characteristic of paroxysmal nocturnal hemoglobinuria (PNH) [2].
• The spectrum of PIG-A gene mutations in aplastic anemia/paroxysmal nocturnal hemoglobinuria (AA/PNH): a high incidence of multiple mutations and evidence of a mutational hot spot [3].
• Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic disorder characterized by complement-mediated hemolytic anemia, pancytopenia, and venous thrombosis [4].
• Endotoxin binding and elimination by monocytes: secretion of soluble CD14 represents an inducible mechanism counteracting reduced expression of membrane CD14 in patients with sepsis and in a patient with paroxysmal nocturnal hemoglobinuria [5].

High impact information on Hemoglobinuria

• Here we report that PIG-A, which participates in the early step of GPI anchor biosynthesis, is the gene responsible for paroxysmal nocturnal hemoglobinuria [6].
• Deficiency of the GPI anchor caused by a somatic mutation of the PIG-A gene in paroxysmal nocturnal hemoglobinuria [6].
• Paroxysmal nocturnal hemoglobinuria is an acquired hematopoietic disease characterized by abnormal blood cell populations in which the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor is deficient [6].
• Inherited complete deficiency of 20-kilodalton homologous restriction factor (CD59) as a cause of paroxysmal nocturnal hemoglobinuria [7].
• Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria are deficient in decay-accelerating factor, a membrane protein that inhibits the complement C3 convertases [8].

Chemical compound and disease context of Hemoglobinuria

• A 50 percent or greater decrease in the numbers of erythroid and myeloid colonies was noted when marrow cells from the patients with paroxysmal nocturnal hemoglobinuria were exposed to a sucrose solution of low ionic strength in the presence of complement but not in its absence [9].
• A glycoprotein that regulates the deposition of C3b on the erythrocyte surface, called decay-accelerating factor or DAF, is absent from the red blood cells (RBC) of patients with paroxysmal nocturnal hemoglobinuria (PNH), explaining in part their abnormal sensitivity to complement [10].
• A somatic mutation in the X-linked phosphatidylinositol glycan class A (PIGA) gene causes the loss of glycosyl phosphatidylinositol (GPI)-linked proteins on blood cells from patients with paroxysmal nocturnal hemoglobinuria [11].
• Blood from patients with paroxysmal nocturnal hemoglobinuria, whose cells lack mCD14 and other GPI anchored proteins, was unable to enhance LPS activation of HUVEC above the level observed with plasma alone [12].
• Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria (PNH) contained a subpopulation that lacked membrane-associated Factor H-like activity present on normal human erythrocytes [13].

Biological context of Hemoglobinuria

• Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal hematopoietic stem cell disorder resulting from mutations in an X-linked gene, PIG-A, that encodes an enzyme required for the first step in the biosynthesis of glycosylphosphatidylinositol (GPI) anchors [14].
• Resistance to apoptosis caused by PIG-A gene mutations in paroxysmal nocturnal hemoglobinuria [14].
• Effect of heparin on complement activation and lysis of paroxysmal nocturnal hemoglobinuria (PNH) red cells [15].
• Phenotypes and phosphatidylinositol glycan-class A gene abnormalities during cell differentiation and maturation from precursor cells to mature granulocytes in patients with paroxysmal nocturnal hemoglobinuria [16].
• After hemolytic stimulus, Hx-deficient mice presented prolonged hemoglobinuria with a higher kidney iron load and higher lipid peroxidation than control mice [17].

Anatomical context of Hemoglobinuria

• These results suggest that in paroxysmal nocturnal hemoglobinuria, CFU-E, BFU-E, and CFU-GM express a membrane abnormality similar to that on erythrocytes, and that the disease is the result of a change occurring at the level of the pluripotent hematopoietic stem cell [9].
• Deficiency of lymphocyte function-associated antigen 3 (LFA-3) in paroxysmal nocturnal hemoglobinuria. Functional correlates and evidence for a phosphatidylinositol membrane anchor [18].
• Paroxysmal nocturnal hemoglobinuria (PNH) leukocytes fail to express decay-accelerating factor (DAF) but contain DAF mRNA transcripts resembling those in normal cells [19].
• Because NCA-95 and NCA-90 have previously been found to be phosphatidylinositol (PI)-linked, paroxysmal nocturnal hemoglobinuria (PNH) neutrophils (which lack PI-linked surface proteins) were tested as well [20].
• Purified decay-accelerating factor (DAF), from the stroma of normal human erythrocytes, was incorporated into the membranes of erythrocytes of patients with paroxysmal nocturnal hemoglobinuria (PNH), and its effect on the complement sensitivity of the cells was investigated [21].

Gene context of Hemoglobinuria

• The protein encoded by the yeast gene SPT14 shows high sequence similarity to the human protein, PIG-A, whose loss of activity is at the origin of the disease paroxysmal nocturnal hemoglobinuria [22].
• GATA1-Cre mediates Piga gene inactivation in the erythroid/megakaryocytic lineage and leads to circulating red cells with a partial deficiency in glycosyl phosphatidylinositol-linked proteins (paroxysmal nocturnal hemoglobinuria type II cells) [23].
• Furthermore, monocytes from a patient with paroxysmal nocturnal hemoglobinuria, a disease characterized by lack of expression of other PI-linked proteins, failed to express CD14 [24].
• Markedly high plasma erythropoietin and granulocyte-colony stimulating factor levels in patients with paroxysmal nocturnal hemoglobinuria [25].
• In paroxysmal nocturnal hemoglobinuria (PNH), an acquired mutation of the PIGA gene results in the absence of glycosylphosphatidylinositol (GPI)-anchored cell surface membrane proteins in affected hematopoietic cells [26].

Analytical, diagnostic and therapeutic context of Hemoglobinuria

• Oligoclonal and polyclonal CD4 and CD8 lymphocytes in aplastic anemia and paroxysmal nocturnal hemoglobinuria measured by V beta CDR3 spectratyping and flow cytometry [27].
• Longer in vivo survival of CD59- and decay-accelerating factor-almost normal positive and partly positive erythrocytes in paroxysmal nocturnal hemoglobinuria as compared with negative erythrocytes: a demonstration by differential centrifugation and flow cytometry [28].
• This rare complication should be considered in the differential diagnosis when hemoglobinuria develops in a child after administration of ceftriaxone or a similar agent [29].
• Thus, murine Pig-a provides a good animal model to study paroxysmal nocturnal hemoglobinuria, a disease caused by a somatic mutation of PIGA [30].
• Conditioning with high-dose cyclophosphamide may not be sufficient to provide a long-term remission of paroxysmal nocturnal hemoglobinuria following syngeneic peripheral blood stem cell transplantation [31].

References