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PubMed2002

A gel microtyping system for diagnosis of paroxysmal nocturnal hemoglobinuria.

Paroxysmal nocturnal hemoglobinuria (PNH), an acquired stem cell defect, is underdiagnosed because of its atypical symptoms in some patients and because available methods, which are time consuming and complicated, are not widely used. The hemolysis of PNH red blood cells (RBCs) is attributed to their enhanced susceptibility to complement lysis caused by a deficiency in glycosylsphosphatidylinositol (GPI)-anchored complement regulatory membrane proteins, especially membrane inhibitor of reactive lysis (MIRL [CD59]). We evaluated the diagnostic value of a simple hemagglutination test using the gel microtyping system by comparing it with lytic tests (the Ham test and the sucrose lysis test) and with flow cytometry (FC) assessment of expression of GPI-anchored proteins (CD59 and CD55). Examining 51 blood samples from 48 patients, we found that the gel test is useful as a screening test for PNH diagnosis and can replace the Ham test and the sucrose lysis test. The threshold of the gel test is about 10 percent of defective RBCs detected by FC. It should, however, be supplemented with FC so as to analyze precisely the defective RBCs and granulocytes in patients with positive gel test results, and, in case of negative results, to detect a small clone of defective cells in atypical cases. Due to the simplicity of the gel test, its wide use can facilitate the diagnosis of PNH.

Journal Article↗

PubMed2001

[Recurrent acute myocardial infarction in a patient with nocturnal paroxysmal hemoglobinuria].

Paroxysmal nocturnal hemoglobinuria is a form of acquired hemolytic anemia with a high incidence of thrombotic complications, generally in the venous district; arterial thrombosis is rare, and exceptional in the coronary tree. We describe the case of a man who had two episodes of myocardial infarction, both during a hemoglobinuric crisis; this patient was free from cardiovascular risk factors and angiography revealed that there was no coronary stenosis. The clinical course was favorable and the patient's response to thrombolytic and dicumarol therapy was satisfactory. To our knowledge, this is the second case of coronary involvement in paroxysmal nocturnal hemoglobinuria described in the literature.

Hemoglobinuria, Paroxysmal↗

PubMed1987

Acute myeloblastic leukemia in paroxysmal nocturnal hemoglobinuria. Evidence of evolution from the abnormal paroxysmal nocturnal hemoglobinuria clone.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematopoietic stem cell disorder in which the blood cells demonstrate aberrant interactions with serum complement. In part, this is due to the absence of the complement regulatory protein, decay accelerating factor (DAF). A small number of patients with PNH have gone on to develop acute nonlymphocytic leukemia, which is thought to arise from the injured marrow as a second hematopoietic disorder. We have studied a patient with PNH who developed acute myeloblastic leukemia (AML); the blasts from this patient were found to lack DAF as measured by polyclonal antibody binding and fluorescence flow cytometry as well as by immunoblotting. The blasts from 11 other patients with AML bound anti-DAF antibody in amounts similar to normal mononuclear cells from healthy donors. Cells of the human leukemia cell lines HL-60, K562, U937, and HEL also bound anti-DAF antibody. In addition to DAF deficiency, blasts from the PNH patient had undetectable alkaline phosphatase activity, in contrast to human leukemia cell lines. These data suggest that the leukemic cells of the PNH patient arose out of the PNH clone and that AML in the setting of PNH is not a separate disorder.

CD55 Antigens↗

PubMed1979

The membrane abnormalities in paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) cells are characterized by an abnormal membrane which interacts abnormally with normal serum complement. These abnormal reactions occur at two levels of the sequence: 1) All abnormal PNH cells fix more C3 than normal cells for a given activation of complement; 2) PNH III cells are more readily lysed by a given number of assembled terminal complexes. The nature of the lesion yielding these abnormal reactions is not known.

Complement Activation↗

PubMed1989

[Renal failure in paroxysmal nocturnal hemoglobinuria].

UNLABELLED: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare, acquired hemolytic disorder characterized by a membrane abnormality of red cells, and characterized by two major clinical features of gross hemoglobinuria and diffuse venous thrombosis. In Japan, the present report records the first case of acute renal failure complicating PNH with treated by hemodialysis and was almost completely reversible. CASE: A 41 year-old woman was admitted for high fever (39.8 degrees C), dyspnea and clinical signs of a respiratory infection. She was started on Cefotax 1,000 mg 3 times daily. She subsequently developed acute renal failure and which treated by hemodialysis and was almost completely reversible. Following treatment of her renal failure, respiratory infection and anemia, she initially made good progress and was discharged.

Acute Kidney Injury↗

PubMed1997

G-CSF and cyclosporin induce an increase of normal cells in hypoplastic paroxysmal nocturnal hemoglobinuria.

Four paroxysmal nocturnal hemoglobinuria (PNH) patients with severe thrombocytopenia, hemolytic anemia and neutropenia were treated using a combination of filgrastim (G-CSF) and cyclosporin. In all patients a trilineage response of hematopoiesis was achieved. In addition, the proportion of glycosyl-phosphatidylinositol (GPI)-deficient granulocytes decreased. All patients mobilized CD34+ hematopoietic progenitors into peripheral blood after starting treatment with G-CSF. The majority of early progenitors (CD34+ CD38-) after mobilization into peripheral blood was found to be unaffected by the GPI-anchoring defect. No patient developed leukemia while under therapy. We conclude from these data that the combination of G-CSF and cyclosporin represents an efficient option for the treatment of hypoplastic PNH.

Adult↗

PubMed1996

Mechanism of intravascular hemolysis in paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) hemolysis requires both intravascular complement activation and affected erythrocytes susceptible to complement. This susceptibility is explained by a deficiency in complement regulatory membrane proteins that are attached to the membrane by a glycosylphosphatidylinositol (GPI) anchor. Affected cells lack a series of GPI-anchored membrane proteins with various functions. The lack is caused by a synthetic defect of the anchor due to an impaired transfer of N-acetylglucosamine to phosphatidylinositol which is an early metabolic precursor in the anchor synthesis. Moreover, PIG-A gene responsible for the membrane defect was recently cloned. Further, a possible mechanism of complement activation has been proposed, especially for an infection-induced hemolytic precipitation which is clinically crucial. Thus, the molecular events, leading to intravascular hemolysis characteristic of PNH, has been virtually clarified. Next major concern is the nature of PIG-A: How does PIG-A explain the complex pathophysiology of PNH which exhibits various clinical manifestations?

Hemoglobinuria, Paroxysmal↗

PubMed2006

The mutation rate in PIG-A is normal in patients with paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by the presence in the patient's hematopoietic system of a large cell population with a mutation in the X-linked PIG-A gene. Although this abnormal cell population is often found to be monoclonal, it is not unusual that 2 or even several PIG-A mutant clones coexist in the same patient. Therefore, it has been suggested that the PIG-A gene may be hypermutable in PNH. By a method we have recently developed for measuring the intrinsic rate of somatic mutations (mu) in humans, in which PIG-A itself is used as a sentinel gene, we have found that in 5 patients with PNH, mu ranged from 1.24 x 10(-7) to 11.2 x 10(-7), against a normal range of 2.4 x 10(-7) to 29.6 x 10(-7) mutations per cell division. We conclude that genetic instability of the PIG-A gene is not a factor in the pathogenesis of PNH.

Adult↗

PubMed1993

Production and characterization of lymphoblastoid cell lines with the paroxysmal nocturnal hemoglobinuria phenotype.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disorder caused by a somatic mutation in a hematopoietic stem cell. The fact that, in some cases, not only myeloid but also lymphoid cells are affected suggests that the mutation has occurred in a multipotent stem cell. By studying the expression of CD59 antigen (membrane inhibitor of reactive lysis) and of decay accelerating factor (DAF) on the lymphocytes of 16 patients with PNH, we found an abnormal population of lymphocytes (with absent CD59 and DAF) in 10 cases. From 4 of these patients we were able to produce Epstein-Barr virus-immortalized lymphoblastoid cell lines (LCLs) that have a PNH phenotype (absent CD59, DAF, and CD48). PNH LCL cells have apparently normal DAF messenger RNA despite not having DAF on their surface. These cell lines will be a valuable resource for further investigation of the defect or defects underlying PNH.

Adult↗

PubMed1976

Complement-mediated granulocyte dysfunction in paroxysmal nocturnal hemoglobinuria.

In paroxysmal nocturnal hemoglobinuria (PNH), infection, both viral and bacterial, disproportionate to the mild neutropenia seen in many such patients is responsible for significant morbidity. We report impaired granulocyte chemotaxis efficiency which may contribute to the problems induced by bacterial infections. PNH (but not normal) granulocytes, after exposure to very small concentrations of activated serum complement components, migrate poorly, as documented by their inhibited chemotaxis toward bacterial products or activated complement components in Boyden chambers. The granulocytes remain intact, excluding trypan blue, phagocytosing, and killing bacteria, despite this activated complement exposure. It is also suggested that this chemotactic defect may involve only a clone of cells, analogous to the clonal lysis of PNH erythrocytes; those few granulocytes capable of migration after exposure to activated complement contain normal quantities of leukocyte alkaline phosphatase (LAP), in contrast to the LAP deficiency of the overall PNH granulocyte population. Since bacterial infection may initiate or potentiate hemolysis, one of the major symptoms of the disease, these results could explain much of the morbidity of PNH.

Alkaline Phosphatase↗

PubMed1995

Glycosylphosphatidylinositol (GPI)-anchored membrane proteins in clinical pathophysiology of paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which abnormal red blood cells with enhanced susceptibility to complement undergo intravascular hemolysis when complement is activated in vivo, resulting in hemoglobinuria. This enhancement of complement susceptibility appears to involve multipotent stem cells and, in this respect, is thought to closely resemble myelodysplastic syndrome. Recently, it has been reported that the increased susceptibility of PNH cells to complement-mediated lysis is related to a deficiency of complement regulatory membrane proteins, especially CD55 and CD59. Both proteins are glycosylphosphatidylinositol (GPI)-anchored membrane proteins. It was found that a deficiency of GPI-anchored membrane proteins in PNH cells is due to the faulty synthesis of the GPI-anchor which may occur during early synthesis. Moreover, it is suggested that an abnormality of the PIG-A (phosphatidylinositol glycan-class A) gene, which is related to the early stage of GPI-anchor synthesis, is responsible for the pathogenesis of PNH. In conclusion, the clinical expression of PNH is dependent on two factors, complement susceptibility of PNH blood cells and changes in bone marrow function. The search for the ideal treatment of this disease may be aided by resolving the relationship between the two.

Complement Activation↗

PubMed1990

Altered expression of gangliosides in erythrocytes of paroxysmal nocturnal hemoglobinuria.

In paroxysmal nocturnal hemoglobinuria (PNH), impaired glycosyl-phosphatidylinositol (PI)-anchoring of membrane proteins such as decay-accelerating factor has been known to lead to increased susceptibility to complement. Moreover, abnormal expression of non-PI-anchoring glycoproteins such as C3b/C4b receptor (CR1) or glycophorin-alpha also has been shown in PNH. Therefore, we biochemically analyzed glycosphingolipids (GSL) as one of the membrane glycoconjugates of PNH erythrocytes. Erythrocytes of all seven PNH patients showed altered expression of sialosyl GSL (gangliosides) as compared with the control erythrocytes of healthy donors. Both a sialosylparagloboside (IV6NeuAc-nLc4Cer) among four major gangliosides and some minor gangliosides in normal erythrocytes variably disappeared in erythrocytes from the peripheral blood of PNH patients. As one of the possible mechanisms of altered expression of gangliosides in PNH erythrocytes, structural analysis suggested impaired sialylation of GSL. These results suggest not only the altered metabolism of gangliosides in PNH erythrocytes, but also a metabolic disorder of membrane glycoconjugates as a new feature of PNH.

Adult↗

PubMed1990

Synthesis of aberrant decay-accelerating factor proteins by affected paroxysmal nocturnal hemoglobinuria leukocytes.

Paroxysmal nocturnal hemoglobinuria (PNH) leukocytes fail to express decay-accelerating factor (DAF) but contain DAF mRNA transcripts resembling those in normal cells. To further investigate the nature of the DAF defect in affected cells, patients' polymorphonuclear and mononuclear leukocytes (PMN and MNC) were biosynthetically labeled and newly synthesized DAF proteins examined. Analyses of greater than 98% surface DAF-negative PMN and MNC from a patient with PNH III erythrocytes showed precursor DAF protein approximately 3 kD smaller in each cell type than in normal cells. The proportion of precursor to mature (O-glycosylated) DAF protein was increased and soluble DAF protein was detected in the medium. Studies of 70-80% surface DAF-negative PMN and MNC from four patients with type II erythrocytes showed mixtures of the 3 kD smaller and normal DAF precursors. Partitioning with Triton X-114 detergent and biosynthetic labeling with the anchor precursor [3H]ethanolamine indicated that the abnormal peptides lacked glycosyl-inositolphospholipid membrane-anchoring structures. Thus, in PNH cells nascent DAF polypeptides are synthesized. Some of the abnormal pro-DAF molecules are processed in the Golgi and some are released extracellularly.

Amino Acids↗

PubMed2003

Primary prophylaxis with warfarin prevents thrombosis in paroxysmal nocturnal hemoglobinuria (PNH).

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which venous thrombosis is the most common cause of death. Here we address the risk factors for thrombosis and the role of warfarin prophylaxis in PNH. The median follow-up of 163 PNH patients was 6 years (range, 0.2-38 years). Of the patients, 29 suffered thromboses, with a 10-year incidence of 23%. There were 9 patients who presented with thrombosis, and in the remainder the median time to thrombosis was 4.75 years (range, 3 months-15 years). The 10-year risk of thrombosis in patients with large PNH clones (PNH granulocytes > 50%) was 44% compared with 5.8% with small clones (P <.01). Patients with large PNH clones and no contraindication to anticoagulation were offered warfarin. There were no thromboses in the 39 patients who received primary prophylaxis. In comparison, 56 patients with large clones and not taking warfarin had a 10-year thrombosis rate of 36.5% (P =.01). There were 2 serious hemorrhages in more than 100 patient-years of warfarin therapy. Large PNH granulocyte clones are predictive of venous thrombosis, although the exact cut-off for clone size is still to be determined. Primary prophylaxis with warfarin in PNH prevents thrombosis with acceptable risks.

Clone Cells↗

PubMed1987

Relationship between decay accelerating factor deficiency, diminished acetylcholinesterase activity, and defective terminal complement pathway restriction in paroxysmal nocturnal hemoglobinuria erythrocytes.

Paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes exhibit abnormalities in decay accelerating factor (DAF), acetylcholinesterase, and resistance to autologous C5b-9 attack. To investigate the nature of the lesion underlying PNH cells, we examined the relationship of these abnormalities to one another. Analyses of DAF in acetylcholinesterase-negative erythrocytes revealed that these two abnormalities involve functionally independent molecules, coincide precisely in the same cell populations, and are similarly expressed in PNH II and more complement-sensitive PNH III erythrocytes. The DAF and acetylcholinesterase deficiencies contrast with the C3b/C4b receptor (CR1) deficit, which is less profound and similarly distributed in complement-insensitive cell populations. Hemolytic studies showed that defective resistance to autologous C5b-9 attack is mediated by another mechanism. Whereas reconstitution of PNH II erythrocytes with DAF completely corrected their complement sensitivity, DAF reconstitution of PNH III erythrocytes restored their ability to circumvent C3b uptake but had no effect on their heightened susceptibility to reactive lysis. Assays of complement-insensitive (PNH I) erythrocytes surviving after reactive lysis disclosed partial DAF and acetylcholinesterase deficits. These findings indicate that the PNH lesion involves multiple membrane components and that PNH I erythrocytes are also abnormal.

Acetylcholinesterase↗

PubMed1999

Defective TCR signaling events in glycosylphosphatidylinositol-deficient T cells derived from paroxysmal nocturnal hemoglobinuria patients.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic disorder characterized by the presence of abnormal cells of various hematopoietic cell lineages deficient in surface expression of glycosylphosphatidylinositol (GPI)-anchored molecules. By analyzing T cells isolated from patients affected with PNH, it was found that ex vivo GPI-deficient CD4(+) and CD8(+) peripheral T cells display a more naive phenotype as compared to wild-type cells. In addition, in vitro proliferative responses to allogeneic antigen-presenting cells were shown to be reduced in mutant T cells. To investigate the molecular basis responsible for defective T cell activation in GPI-deficient T cells, T cell lines and T cell clones were generated from patients affected with PNH. When stimulated with anti-CD3epsilon mAb, mutant cells displayed a significantly decreased activation of protein tyrosine kinase p56(lck). The decreased kinase activity was accompanied by a delayed TCR capping and internalization. Interestingly, protein tyrosine phosphorylation is not only quantitatively but also qualitatively affected, with one substrate being more intensively phosphorylated in mutant than in wild-type cells. These observations suggest that a defective activation of p56(lck) contributes to the depressed immune responses observed in GPI-deficient T cells derived from PNH patients.

CD4-Positive T-Lymphocytes↗

PubMed2005

Mean fluorescence intensity rate is a useful marker in the detection of paroxysmal nocturnal hemoglobinuria clones.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired disorder of the pluripotent stem cell resulting from the somatic mutation of the X-linked PIG-A gene, involved in the synthesis of the glycosylphosphatidyl-inositol anchor of membrane proteins such as CD55, CD59 and CD14. In the past decade, flow cytometry has become a valuable diagnostic tool in the detection of deficient expression of the GPI-anchored proteins. We report the diagnosis of PNH in four patients confirmed by flow cytometry. Red blood cells, granulocytes and monocytes were classified as PNH types I, II and III according to the mean fluorescence intensities (MFI) of membrane proteins. MFI rate is a numerical data reflecting the severity of decreased antigen expression, and it is obtained by dividing the MFI of the type II or type III cells by the MFI of the respective cells obtained for a normal sample. We found that the investigation of granulocytes and monocytes was more informative than red blood cells when percent negativity was evaluated. In addition, the lowest MFI rate (mean 0.011) was obtained for CD14 on monocytes while CD59 and CD55 gave higher values on all three investigated cell types (0.021-0.34). Thus, CD14 on monocytes seems to be the most reliable marker for establishing the PNH clone size and the severity of antigen deficiency.

CD55 Antigens↗

PubMed1999

Leukemia arising out of paroxysmal nocturnal hemoglobinuria.

In paroxysmal nocturnal hemoglobinuria (PNH), one or more hematopoietic stem cells that are defective in GPI anchor assembly as a result of mutation in the PIG-A gene preferentially expand in the bone marrow and give rise to peripheral blood elements that are deficient in GPI anchored protein expression. According to current concepts, 5-15% of PNH patients develop leukocyte dyscrasias which invariably are acute myelogenous leukemia (AML). In this review, the literature from 1962 to the present is analyzed regarding the type of leukocyte dyscrasia, incidence, and cytogenetic features of the abnormal cells that have been reported. Among a total of 119 cases that are well-documented, 104 myeloid dyscrasias involving several categories in addition to AML, as well as 15 lymphoid dyscrasias are described. Of 1,760 patients in 15 series that contain 20 or more patients, 16 (1%) are reported as having developed "acute leukemia." However, of 288 listed as having died, 13 (5%) are recorded as having had "acute leukemia." In 32 of the patients with hematological dyscrasias where karyotypes were analyzed, 7 were found to be normal and 25 found to harbor various alterations with the +8 abnormality present in 8. In 5 of 7 instances evidence indicates that the dyscratic cell arises from the PNH clone. Processes potentially involved in the evolution of the dyscratic cells from PNH clones are discussed.

Female↗