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PubMed2001

Reversible renal failure in paroxysmal nocturnal hemoglobinuria.

A Chinese patient with paroxysmal nocturnal hemoglobinuria (PNH) developed acute nonoliguric renal failure with intercurrent urinary tract infection and hemolysis. There was no evidence of renal vein thrombosis. Renal biopsy showed features of acute tubular necrosis (ATN) and hemosiderosis. Magnetic resonance imaging (MRI) showed characteristic features of renal hemosiderosis. The patient was stabilized with temporary hemodialysis and intravenous fluid. The renal function fully recovered 3 weeks later. We review the literature and summarize the clinical features of this disease entity. To our knowledge, this case is the first to report such disorder with thorough investigation including concomitant diagnostic MRI imaging and renal biopsy.

Acute Kidney Injury↗

PubMed1999

Paroxysmal nocturnal hemoglobinuria: An acquired genetic disease.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematopoietic stem cell disorder characterized by an intravascular hemolytic anemia. Abnormal blood cells lack a series of glycosylphosphatidylinositol (GPI)-anchored proteins. The lack of GPI-anchored complement regulatory proteins, such as decay-accelerating factor (DAF) and CD59, results in complement-mediated hemolysis and hemoglobinuria. In the affected hematopoietic cells from patients with PNH, the first step in biosynthesis of the GPI anchor is defective. At least four genes are involved in this reaction step, and one of them, an X-linked gene termed PIG-A, is mutated in affected cells. The PIG-A gene is mutated in all patients with PNH reported to date. Here, we review recent advances in the understanding of the molecular pathogenesis of PNH.

Glycosylphosphatidylinositols↗

PubMed1997

Paroxysmal nocturnal hemoglobinuria as a molecular disease.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired, clonal disorder of hematopoietic cells caused by somatic mutation in the X-linked PIGA gene encoding a protein involved in the synthesis of the glycosylphosphatidylinositol (GPI) anchor by which many proteins are attached to the membrane of cells. About 15 proteins have been found to be lacking or markedly deficient on the abnormal blood cells. These defects result in a clinical syndrome that includes intravascular hemolysis mediated by complement, unusual venous thromboses, deficits of hematopoiesis, and other manifestations. Therapy is presently directed mainly at the consequences of the disorder rather than its basic causes and includes replacement of iron, folic acid, and whole blood; hormonal modulation (prednisone, androgens); anticoagulation; and bone marrow transplantation. PNH is a chronic disease with more than half of adult patients surviving 15 years or more; prognosis is less good in children.

Glycosylphosphatidylinositols↗

PubMed2004

General anesthesia for cesarean delivery in a patient with paroxysmal nocturnal hemoglobinuria and thrombocytopenia.

UNLABELLED: Pregnancy in patients with paroxysmal nocturnal hemoglobinuria (PNH) increases the risk of complement activation, hemolysis, and thrombosis. We describe the anesthetic management of a patient with PNH who underwent general anesthesia for cesarean delivery. Steroids, heparin, and blood products were administered early to minimize the likelihood of a hematologic emergency. IMPLICATIONS: Pregnancy in patients with paroxysmal nocturnal hemoglobinuria increases the risk of hemolysis, thrombosis, anemia, and thrombocytopenia. We describe the anesthetic management of a patient with paroxysmal nocturnal hemoglobinuria and thrombocytopenia who underwent general anesthesia for cesarean delivery.

Adult↗

PubMed1986

Separation of the acetylcholinesterase-deficient red cells in paroxysmal nocturnal hemoglobinuria.

Blood of patients with paroxysmal nocturnal hemoglobinuria (PNH) most often contains two or more populations of erythrocytes--one population with normal sensitivity to lysis by complement (PNH I cells) and a second population of moderately abnormal cells (PNH II cells) or markedly abnormal cells (PNH III cells). PNH II and III cells exhibit moderately and markedly increased sensitivity to lysis by complement, respectively, as well as other membrane defects. We have devised a method for isolating pure, intact PNH II and III cells from mixed populations by use of monoclonal antibodies and cell affinity chromatography. Study of purified cell populations has led to the identification of a further subtype, PNH IIIb, of PNH erythrocytes. PNH IIIb erythrocytes are less sensitive to complement lysis than PNH IIIa cells but are lysed by fluid-phase activation of complement, unlike PNH II erythrocytes.

Acetylcholinesterase↗

PubMed2006

Paroxysmal nocturnal hemoglobinuria superimposed with preeclampsia.

OBJECTIVE: Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematologic disorder characterized by complement-mediated intravascular hemolysis. As maternal complication of PNH is already severe, it becomes much more complex when preeclampsia is superimposed. We present a case of PNH superimposed with severe preeclampsia in the third trimester. CASE REPORT: A 30-year-old, gravida 1, para 0, woman had PNH, diagnosed at the age of 17. Her PNH was stable under medication. In 2004, she conceived and had prenatal care at our hospital. At 35 weeks of gestation, preeclampsia with elevated blood pressure and proteinuria were superimposed and managed with close surveillance. A live male baby was delivered vaginally at 38 weeks of gestation. During parturition, her blood pressure increased to 180/100 mmHg. Thrombocytopenia, hyponatremia, hyperkalemia, hypoalbuminemia, elevated liver enzymes and lactate dehydrogenase were also noted. Preeclampsia continued to postpartum and eventually disappeared. CONCLUSION: The most frequent causes of PNH-related fetomaternal morbidity and mortality are hemolysis and thrombosis. The situation becomes even more complicated when PNH is superimposed with preeclampsia. Appropriate clinical surveillance, awareness of the potential risks of hemolysis and thrombosis, as well as evaluation of fetal wellbeing are essential.

Adult↗

PubMed2006

Recent advances in biological and clinical aspects of paroxysmal nocturnal hemoglobinuria.

The unique feature of paroxysmal nocturnal hemoglobinuria (PNH), a chronic disease with severe hemolytic anemia, is the presence of a population of blood cells that, being deficient in surface proteins tethered to the membrane through a glycosylphosphatidylinositol molecule, are said to have the PNH phenotype. Therefore, the diagnosis of PNH is based on the demonstration that a substantial proportion of red cells and granulocytes have this phenotype. Diagnosis is currently best done by flow cytometry analysis, most appropriately by using anti-CD59 and anti-CD55 antibodies. Flow cytometry can also quantitate these cells and monitor their numbers as a function of time, thereby aiding clinical management. The most important advance in management has been the introduction of a human monoclonal antibody (eculizumab) that is directed against the C5 component of complement. Because hemolysis in PNH is mostly intravascular and complement dependent, periodic administration of anti-C5 produces complement blockade. This agent is the first to substantially reduce the rate of hemolysis in patients with PNH. Because very small PNH clones have been known for some years to exist in healthy people, it is clear that a crucial factor in causing PNH as a clinical disease is a marked expansion of the PNH clones themselves. Several lines of evidence from studies of mouse models and patients suggest that the process of expansion is probably the result of 2 phenomena: (1) damage to normal hematopoietic stem cells and (2) the sparing of PNH hematopoietic stem cells. This process of somatic cell selection may have an autoimmune basis, and the most likely agents are cells belonging to the natural killer-like subset of T-cells.

Animals↗

PubMed1997

Relationship between the phenotypes of circulating erythrocytes and cultured erythroblasts in paroxysmal nocturnal hemoglobinuria.

To investigate erythropoiesis in paroxysmal nocturnal hemoglobinuria (PNH), we studied the expression of glycosylphosphatidylinositol (GPI)-anchored membrane proteins on circulating erythrocytes and erythroblasts obtained by erythropoietic cell culture in nine patients with this disease. One-color and two-color flow cytometric analyses were performed using monoclonal antibodies for decay-accelerating factor (DAF) and/or CD59/membrane attack complex-inhibitory factor (MACIF). In addition, terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) analysis was performed to assess apoptosis of erythroblasts from six patients. On flow cytometric analysis, cases 1 to 6 had positive and negative erythrocyte populations, case 7 intermediate and negative populations, case 8 positive, intermediate, and negative populations, and case 9 a single double-negative population. In addition, cases 1 to 6 and 8 had positive, intermediate, and negative erythroblast populations, while cases 7 and 9 had intermediate and negative populations. The percentage of double-negative erythrocytes showed a significant correlation with that of double-negative erythroblasts (r = .741, P < .05). In seven of nine patients, more erythroblasts than erythrocytes were negative for the two membrane proteins. Also, some patients with an intermediate population of erythrocytes did not necessarily show an increase of PNH II erythroblasts. Apoptosis of PNH erythroblasts was also detected, but the percentage of apoptotic cells in PNH patients showed no difference from that in healthy volunteers. These findings suggest that the final phenotype of mature erythrocytes in PNH is determined during maturation from erythroblasts to erythrocytes by the disappearance or persistence of PNH II erythroblasts. In addition, PNH erythroblasts in vitro may be partly lost by apoptosis, but apoptosis does not play an important role in determining GPI-linked protein expression.

Adult↗

PubMed2000

Impaired growth and elevated fas receptor expression in PIGA(+) stem cells in primary paroxysmal nocturnal hemoglobinuria.

The genetic defect underlying paroxysmal nocturnal hemoglobinuria (PNH) has been shown to reside in PIGA, a gene that encodes an element required for the first step in glycophosphatidylinositol anchor assembly. Why PIGA-mutated cells are able to expand in PNH marrow, however, is as yet unclear. To address this question, we compared the growth of affected CD59(-)CD34(+) and unaffected CD59(+)CD34(+) cells from patients with that of normal CD59(+)CD34(+) cells in liquid culture. One hundred FACS-sorted cells were added per well into microtiter plates, and after 11 days at 37 degrees C the progeny were counted and were analyzed for their differentiation pattern. We found that CD59(-)CD34(+) cells from PNH patients proliferated to levels approaching those of normal cells, but that CD59(+)CD34(+) cells from the patients gave rise to 20- to 140-fold fewer cells. Prior to sorting, the patients' CD59(-) and CD59(+)CD34(+) cells were equivalent with respect to early differentiation markers, and following culture, the CD45 differentiation patterns were identical to those of control CD34(+) cells. Further analyses of the unsorted CD59(+)CD34(+) population, however, showed elevated levels of Fas receptor. Addition of agonist anti-Fas mAb to cultures reduced the CD59(+)CD34(+) cell yield by up to 78% but had a minimal effect on the CD59(-)CD34(+) cells, whereas antagonist anti-Fas mAb enhanced the yield by up to 250%. These results suggest that expansion of PIGA-mutated cells in PNH marrow is due to a growth defect in nonmutated cells, and that greater susceptibility to apoptosis is one factor involved in the growth impairment.

Antigens, CD34↗

PubMed2001

The distribution of PIG-A gene abnormalities in paroxysmal nocturnal hemoglobinuria granulocytes and cultured erythroblasts.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia that is characterized by a deficiency of glycosylphosphatidylinositol-anchored membrane proteins due to phosphatidylinositol glycan-class A (PIG-A) gene abnormalities in various lineages of peripheral blood cells and hematopoietic precursors. The purpose of our study was to clarify the distribution of PIG-A gene abnormalities among various cell lineages during differentiation and maturation in PNH patients. The expression of CD16b or CD59 in peripheral blood granulocytes or cultured erythroblasts from three Japanese PNH patients was analyzed using flow cytometry. PIG-A gene abnormalities in both cell types, including glycophorin A(+) bone marrow erythroblasts, were examined using nucleotide sequence analysis. The expression study of PIG-A genes from each patient was also performed using JY-5 cells.Flow cytometry revealed that the erythroblasts consisted of negative, intermediate, and positive populations in Cases 1 and 3 and negative and intermediate populations in Case 2. The granulocytes consisted of negative and positive populations in all three cases. DNA sequence analysis indicated that all the PNH cases had two or three types of PIG-A gene abnormalities, and that a predominant clone with an abnormal PIG-A gene was different in granulocytes and erythroblasts from Cases 2 and 3. Expression studies showed that all the mutations from the patients were responsible for the null phenotype.PIG-A gene abnormalities result in deficiencies of glycosylphosphatidylinositol-anchored proteins in PNH erythroblasts and granulocytes. The distribution of predominant PNH clones with PIG-A gene abnormalities is often heterogeneous between the cell types, suggesting that a clonal selection of PIG-A gene abnormalities occurs independently among various cell lineages during differentiation and maturation.

Adult↗

PubMed2004

Increased resistance of PIG-A- bone marrow progenitors to tumor necrosis factor a and interferon gamma: possible implications for the in vivo dominance of paroxysmal nocturnal hemoglobinuria clones.

BACKGROUND AND OBJECTIVES: Paroxysmal nocturnal hemoglobinuria (PNH) is a clonal disorder due to a PIG-A gene mutation, resulting in deficient expression of GPI-anchored-proteins. Both immune-mediated suppression of hematopoiesis and cytokine alterations have been reported in aplastic anemia, a disease closely related to PNH whereas no data are available on PNH itself. The aim of this study was to investigate the effect of exogenous cytokines on clonogenic activity in PNH. DESIGN AND METHODS: We evaluated burst-forming units-erythroid (BFU-E) and colony-forming units-granulocyte-macrophage (CFU-GM) in bone marrow mononuclear cells (BMMC) from 5 PNH patients and 5 controls, alone or in the presence of transforming-growth-factor (TGF)-beta, interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, and specific antibodies. Molecular analysis of the PIG-A gene was performed by polymerase chain reaction (PCR) and direct sequencing on every single colony. RESULTS: Patients' cells showed less clonogenic activity than did control cells. In PNH, addition of TGF-beta inhibited both BFU-E and CFU-GM; IFN-gamma and TNF-alpha inhibited BFU-E alone. In patients cytokines modulated normal and mutated clones differently: TGF-b reduced the number of PIG-A- and PIG-A+ colony-forming-cells (CFC), whereas TNF-alpha and IFN-gamma reduced PIG-A+ CFC only. BMMC from patients showed higher TGF-beta production than did BMMC from controls. INTERPRETATION AND CONCLUSIONS: TGF-beta could contribute to the genesis of the unfavorable bone marrow microenvironment but does not seem to play a role in the in vivo dominance of PIG-A deficient cells. Mutated clones were more resistant to the inhibitory effects of IFN-gamma and TNF-alpha, suggesting that PNH cells may have a growth advantage in an unfavorable microenvironment.

Adult↗

PubMed2003

Unusual association between increased bone resorption and presence of paroxysmal nocturnal hemoglobinuria phenotype in multiple myeloma.

Paroxysmal nocturnal hemoglobinuria (PNH) clones deficient in glycosylphosphatidylinositol-anchored molecules, including CD55 and CD59, have been previously described in patients with multiple myeloma (MM). The aim of this study was to investigate the possible association between existence of the PNH phenotype and myeloma bone disease. Forty-three patients with newly diagnosed MM were the subjects of the study. Radiographic evaluation of the skeleton was performed in all patients at diagnosis. The following biochemical markers were measured: bone resorption markers (tartrate-resistant acid phosphatase isoform 5b [TRACP-5b]and N-terminal cross-linking telopeptide of type-I collagen [NTX]), bone formation markers (bone alkaline phosphatase [bALP] and osteocalcin [OC]), osteoprotegerin (OPG), soluble receptor activator of nuclear factor KB ligand (sRANKL), and interleukin 6 (IL-6). Detection of CD55- and/or CD59-deficient red cell populations was performed after diagnosis. Patients with MM had elevated mean baseline NTX, TRACP-5b, sRANKL, and IL-6 levels compared with controls, whereas the mean values of bALP, OC, and OPG were significantly decreased. Four patients had no osteolytic lesions, whereas 8 patients had 1 to 3 lytic lesions, and 31 patients had more than 3 lytic lesions and/or pathologic fractures in the skeletal survey. CD55- and/or CD59-deficient red cell populations were observed in 56% of patients with MM. There was a strong correlation between the presence of PNH-like erythrocytes and increased bone resorption, as measured by NTX, TRACP-5b, and sRANKL/OPG ratio (P < .03, P < .02, and P < .02, respectively). There was also a significant correlation between PNH phenotype and severe bone disease (P < .02). These results suggest that there is a possible link between PNH phenotype and increased osteoclastic activity in MM owing to a potential effect of myeloma microenvironment on a preexisting PNH clone. Further studies are required for clarifying this phenomenon and investigating possible mechanisms of this unusual association.

Aged↗

PubMed1998

[Fatal pulmonary thromboembolism in a patient with paroxysmal nocturnal hemoglobinuria].

A 38 year old woman with paroxysmal nocturnal hemoglobinuria was admitted to our hospital because of hemoptysis. Pulmonary infarction was diagnosed by the perfusion lung scan. In spite of the administration of prednisolone, dextran, low molecular weight heparin, and warfarin, she died of pulmonary infarction and secondary pulmonary hypertension. Autopsy revealed thromboembolism of both pulmonary arteries and hepatic central vein thrombosis. Recent understanding of the pathogenesis and incidence of thromboembolism in paroxysmal nocturnal hemoglobinuria was discussed.

Adult↗

PubMed1981

Paroxysmal nocturnal hemoglobinuria: report of case with odontogenic infection.

Paroxysmal nocturnal hemoglobinuria is characterized by chronic hemolytic anemia, leukopenia, and thrombocytopenia. The increased hemolysis and hemoglobinuria associated with sleep have been observed so frequently that these features have been incorporated into the syndrome's name. Infections, especially of the respiratory and urinary system, can cause hemolytic episodes. Patients with paroxysmal nocturnal hemoglobinuria have increased susceptibility to infections. Some PNH patients are leukopenic, but many are not. It has been reported that leukocyte alkaline phosphatase of granulocytes in patients with PNH is low. As Hartmann and Kohlhouse point out, "The principles of treating infection in PNH seem no different than the therapy of infections in any group. "If major surgery is indicated, preparation should include saline-washed red cells, which would increase the patient's number of circulating normal red blood cells, if necessary. The prognosis is variable. A small percentage of patients with PNH develop leukemia. However, in at least half of all patients, the number of complement sensitive cells decreases, and many of these patients live a fairly normal life.

Adult↗

PubMed1996

Bilateral papilledema with retinal hemorrhages in association with cerebral venous sinus thrombosis and paroxysmal nocturnal hemoglobinuria.

PURPOSE: To report a patient with paroxysmal nocturnal hemoglobinuria who complained of transient obscurations of vision and exhibited bilateral papilledema with retinal hemorrhages. METHODS: Case report. Computed tomography did not demonstrate any abnormality but magnetic resonance imaging disclosed signs of cerebral venous sinus thrombosis. RESULTS: The patient was treated with subcutaneous low molecular weight heparin and intravenous corticosteroids. Symptoms improved within one week and ophthalmoscopic signs resolved within four months. CONCLUSION: Bilateral papilledema with extensive retinal hemorrhages may be a sign of cerebral venous sinus thrombosis, a reported devastating complication of paroxysmal nocturnal hemoglobinuria. Thus, any patient with suspected cerebral venous sinus thrombosis should undergo magnetic resonance imaging, even when results of computed tomography are normal.

Anticoagulants↗

PubMed1995

Mutations in the PIG-A gene causing paroxysmal nocturnal hemoglobinuria are mainly of the frameshift type.

Paroxysmal nocturnal hemoglobinuria is an acquired hemolytic anemia associated with somatic mutations in the X-linked gene PIG-A, which encodes a protein involved in the biosynthesis of glycosyl phosphatidylinositol anchors. To further elucidate the molecular basis of paroxysmal nocturnal hemoglobinuria, we have worked out a systematic and relatively rapid methodology to scan for mutations in the entire coding region of the PIG-A gene. By this methodology, we have identified 15 different somatic mutations in 12 patients. The mutations were spread throughout the entire PIG-A-coding region. Of the mutations, 10 caused frameshifts, 6 caused small deletions, 3 caused small insertions, and 1 caused deletion-insertion. Five single base pair substitutions caused three missense mutations, one nonsense mutation, and one defect in the donor splice site of intron 4. In each of 3 patients, two independent mutations were identified. The predominance of frameshift mutations may reflect selection for somatic mutations giving rise to clones with a completely nonfunctional PIG-A protein.

Amino Acid Sequence↗

PubMed1998

Paroxysmal nocturnal hemoglobinuria: molecular pathogenesis and molecular therapeutic approaches.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal hematologic stem cell disorder classified as an intravascular hemolytic anemia. Abnormal blood cells are deficient in glycosylphosphatidyl inositol (GPI)-anchored proteins. Deficiencies of GPI-anchored complement regulatory proteins, such as decay accelerating factor (DAF) and CD59, render red cells very sensitive to complement and result in complement-mediated hemolysis and hemoglobinuria. In the affected hematopoietic cells from patients with PNH, the first step in biosynthesis of the GPI anchor is defective. Three genes are involved in this reaction step and one of them, an X-linked gene termed PIG-A, is mutated in affected cells. Granulocytes and lymphocytes from the same patient have the same mutation, indicating that a somatic PIG-A mutation occurs in hematopoietic stem cells. The PIG-A gene is mutated in all patients with PNH reported to date. We review these recent advances in the understanding of the molecular pathogenesis of PNH. Furthermore, we present an hypothesis regarding the predominance of the PNH clone, caused by positive selection by hematopoietic suppressive cytokines, such as transforming growth factor (TGF)-beta. In addition, we discuss the possibility of cure for PNH through molecular therapeutic strategy using gene transfer techniques. (Key words: paroxysmal nocturnal hemoglobinuria, glycosylphosphatidylinositol-anchored proteins, PIG-A, clonal dominance, growth advantage, transforming growth factor-beta, gene therapy, molecular therapeutic approach).

Hemoglobinuria, Paroxysmal↗

PubMed1980

Venous thrombosis and splenic rupture in paroxysmal nocturnal hemoglobinuria.

A patient with an 11 year history of paroxysmal nocturnal hemoglobinuria presented with severe abdominal pain. On admission, the hematocrit value was 30 per cent and unchanged from repeated measurements during the previous three years. Abdominal angiography identified extensive thromboses of the splenic and portal venous systems. After initial improvement on heparin therapy, the patient experienced additional abdominal crises. A ruptured and multifragmented spleen was removed at the time of exploratory laparotomy. Postoperatively, after a several days' interval of improvement, the patient experienced additional thrombotic episodes of the abdomen, upper extremities and cerebral cortex. The latter was associated with disabling nerve paralysis. With continuous intravenous heparin plus steroid therapy, the patient's condition improved progressively. Despite the numerous thrombotic episodes during the prolonged hospital course, no hemolytic episodes were observed. This is the first report of documented splenic rupture in a patient with paroxysmal nocturnal hemoglobinuria.

Adult↗