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PubMed1989

Paroxysmal nocturnal hemoglobinuria. A complement-mediated disease.

Paroxysmal nocturnal hemoglobinuria (PNH) is a hemolytic disease characterized by an increased sensitivity of erythrocytes to the hemolytic action of complement. Two membrane proteins, the decay-accelerating factor and the C8-binding protein, which protect normal erythrocytes from the hemolytic action of complement, are deficient on the abnormal blood cells from patients with PNH. Other membrane proteins unrelated to complement regulation, but which share with the decay-accelerating factor and the C8-binding protein a common post-translational modification, namely a glycan-phosphatidylinositol linkage to the cell membrane, are also missing from PNH cells. In the present review, clinical, biological, and molecular aspects of PNH are discussed. In addition, diagnostic tests in clinical use are discussed, and new tests using indirect immunofluorescent assays are proposed.

Complement System Proteins↗
PubMed2003

Fibrinolytic therapy with rt-PA in a patient with paroxysmal nocturnal hemoglobinuria and Budd-Chiari syndrome.

Paroxysmal nocturnal hemoglobinuria (PNH) is associated with a high risk of thrombosis, particularly in the peripheral, cerebral, and abdominal veins. We report a patient with an occlusion of the hepatic veins and a slit shape narrowing of the cava inferior consistent with the Budd-Chiari syndrome in whom intravenous fibrinolytic therapy with recombinant tissue plasminogen activator (rt-PA) was applied. Systemic rt-PA was given in a dose of 25 mg rt-PA over 3 h and 25 mg rt-PA as constant intravenous infusion over the next 21 h leading to an incomplete recanalization. The same protocol was applied again 2 days later, resulting in a complete recanalization of the hepatic veins and the vena cava inferior. Our case shows that exclusive systemic application of rt-PA can result in full anatomic and clinical restoration.

Adult↗
PubMed1993

Deficiency of glycosyl phosphatidylinositol-anchored proteins in polymorphonuclear leukocytes from patients with paroxysmal nocturnal hemoglobinuria with low-grade hemolysis.

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder characterized by the deficiency of glycosyl phosphatidylinositol (GPI)-anchored proteins in blood cell membranes. We experienced a patient with PNH whose grade of hemolysis was reduced during the course of the disease. An analysis of the expression of GPI-anchored proteins on blood cells revealed typical PNH defects in polymorphonuclear leukocytes (PMN), but not in red blood cells (RBC). Accordingly, we investigated the expression of CD59 on RBC and of CD59 and CD16 on PMN in PNH patients, using immunofluorocytometry. We examined the cells of 8 PNH patients with different grades of hemolysis. PNH-affected PMN deficient in CD16 and CD59 were clearly demonstrated in every patient, including those with low-grade hemolysis. We conclude that demonstration of PNH-affected PMN deficient in GPI-anchored proteins has diagnostic values even in PNH patients with low-grade hemolysis.

Aged↗
PubMed1994

Characterization of alternatively spliced PIG-A transcripts in normal and paroxysmal nocturnal hemoglobinuria cells.

The genetic lesion in paroxysmal nocturnal hemoglobinuria (PNH) cells resides in a DNA element that 1) encodes a product required for assembly of GlcNAc-inositol phospholipid and 2) is commonly affected in different patients. In this study, three alternative mRNA transcripts (1600, 1200, and 950 bp) that derive from this genetic element in normal cells were characterized. The 1200-bp transcript was found to arise from splicing out of 374 bp of exonic sequence extending from positions 407-780. The 950-bp transcript was found to arise from removal of this and 284 bp of additional exonic sequence beginning further upstream at position 123. Analyses of transcripts expressed in Epstein-Barr virus (EBV)-transformed B lymphocytes prepared from two PNH patients showed that both failed to express normal 1600-bp transcripts. One expressed truncated transcripts of 1000 and 800 bp generated by an alternate splice which utilized a downstream signal in place of the normal intronic splice signal. The other expressed a 1600-bp transcript with multiple nucleotide changes but normal 1200- and 950-bp "spliced" transcripts.

Alternative Splicing↗
PubMed2006

[Paroxysmal nocturnal hemoglobinuria--consequences of a missing anchor].

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematological disorder characterized by the clonal expansion and differentiation of a multi-potent hematopoietic stem cell carrying a somatic mutation in the X-linked PIG-A gene. As a consequence of this mutation, glycosylphosphatidylinositol (GPI)-anchored proteins are lacking on the surface of blood cells derived from the mutated stem cell. This may result clinically in hemolytic anemia and a tendency for venous thrombosis and serious infection. Bone marrow failure is a frequently observed phenomenon associated with PNH. Reliable diagnosis of PNH is currently best achieved by flow cytometric analysis of GPI-anchored proteins on peripheral blood cells. Both the clinically relevant size of the PNH clone and type of GPI deficiency (complete or partial) can be reproducibly determined by this method. Most patients will benefit from supportive measures, albeit that allogeneic hematopoietic stem cell transplantation is currently considered the only potentially curative therapy. The development of a new therapeutic monoclonal antibody that reduces intravascular hemolysis and progress in diagnostic flow cytometry using a new GPI-specific marker may provide further benefit for PNH patients in the future.

Clinical Trials as Topic↗
PubMedDate not supplied

Labor analgesia in a patient with paroxysmal nocturnal hemoglobinuria with thrombocytopenia.

BACKGROUND AND OBJECTIVES: Paroxysmal nocturnal hemoglobinuria (PNH) is a form of acquired hemolytic anemia in which a defect of glycophosphatidylinositol anchor proteins in the cell membrane of bone marrow stem cells leads to activation of the complement system and consequent destruction of defective cells. The characteristics of this disease are an increased frequency of thrombotic events, anemia, and thrombocytopenia. METHODS: We report a case of a pregnant patient with PNH with thrombocytopenia who delivered vaginally after receiving epidural labor analgesia. Prophylaxis of thromboembolism was performed with heparin 1 hour after the removal of the epidural catheter, and repeated at 12-hour intervals. Sensory changes or motor changes and pain were monitored every 10 minutes for 8 hours after delivery. RESULTS: During analgesia, the patient reported complete pain relief. Delivery and the immediate postpartum period were without any untoward events. CONCLUSIONS: Four major factors influenced the anesthetic conduct used for the present patient: (1) the risk of an acute hemolytic crisis, (2) the need to perform prophylaxis for thromboembolism, (3) the need to reduce labor stress, and (4) minimizing the risk of missing an epidural hematoma. We also present a survey of the literature about PNH and discuss the anesthetic conduct in this patient.

Adult↗
PubMed1991

[Successful cholecystectomy in a patient with paroxysmal nocturnal hemoglobinuria].

We report a case of paroxysmal nocturnal hemoglobinuria (PNH) and review the literature regarding transfusion of red blood cells in PNH patients. A 42-year-old woman with myelodysplastic syndrome (MDS) complaining of right hypochondralgia and high fever was admitted to the hospital for acute cholecystitis with gall stone. Blood examination revealed bicytopenia (leukocytes, 1,700/microliters and hemoglobin, 8.5 g/dl) and bone marrow examination showed normocellular but hypererythroid bone marrow and dyshematopoiesis, which suggested MDS. Laboratory data revealed obstructive jaundice and hemolytic anemia. Positive sucrose and Ham tests, which were compatible with the diagnosis of PNH. Cholecystectomy was successful, and the patient showed no postoperative complications of increased hemolysis or thrombosis. As hemoglobin level gradually decreased for the first two postoperative weeks, filtrated white cell-depleted red blood cells (total, 1,000 ml) were transfused instead of washed red blood cells. No side effects of the transfusion were noted. On the basis of findings in this case and those reported in the literature, it is concluded that in some case of PNH, the use of washed red blood cells is unnecessary, and that the use of white cell-depleted red blood cells is indicated.

Adult↗
PubMed1986

Characterization of the hematopoietic defect in paroxysmal nocturnal hemoglobinuria.

We studied the relationship between paroxysmal nocturnal hemoglobinuria (PNH) and bone marrow failure using in vitro hematopoietic colony culture assays. Most of 17 patients with PNH showed decreased colony formation, by erythroid burst-forming cells (BFU-E) and granulocyte-macrophage colony-forming cells (CFU-C) in methylcellulose, disproportionate to their degree of bone marrow biopsy cellularity. Only a minority of the hematopoietic progenitors were sensitive to complement-mediated lysis in vitro. In contrast, normoblasts from maturing erythroid bursts removed from culture and exposed to acidified serum were sensitive to complement-mediated lysis. The size of bursts and the sensitivity of their progeny correlated strongly, suggesting that the PNH defect was acquired in culture as a function of the generational age of erythroid precursor cells. In addition, BFU-E of PNH patients were very sensitive to 3H-thymidine suicide, in comparison with normal individuals and patients with other hemolytic anemias, indicating that a large proportion of primitive erythroid progenitors in PNH bone marrow were in cell cycle. All of these results imply that acquisition of the PNH defect during erythropoiesis may lead to intramedullary destruction of developing erythroid cells. The increased demand that results on the progenitor pool may lead to stem cell depletion and bone marrow failure.

Adolescent↗
PubMed2001

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).

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have blood cells deficient in glycosyl phosphatidylinositol (GPI)-linked proteins owing to a somatic mutation in the X-linked PIGA gene. To target Piga recombination to the erythroid/megakaryocytic lineage in mice, the Cre/loxP system was used, and Cre was expressed under the transcriptional regulatory sequences of GATA-1. Breeding of GATA1-cre (G) transgenic mice with mice carrying a floxed Piga (L) allele was associated with high embryonic lethality. However, double-transgenic (GL) mice that escaped early recombination looked healthy and were observed for 16 months. Flow cytometric analysis of peripheral blood cells showed that GL mice had up to 100% of red cells deficient in GPI-linked proteins. The loss of GPI-linked proteins on the cell surface occurred late in erythroid differentiation, causing a proportion of red cells to express low residual levels of GPI-linked proteins. Red cells with residual expression of GPI-linked proteins showed an intermediate sensitivity toward complement and thus resemble PNH type II cells in patients with PNH. Recombination of the floxed Piga allele was also detected in cultured megakaryocytes, mast cells, and eosinophils, but not in neutrophils, lymphocytes, or nonhematopoietic tissues. In summary, GATA1-Cre causes high-efficiency Piga gene inactivation in a GATA-1-specific pattern. For the first time, mice were generated that have almost 100% of red cells deficient in GPI-linked proteins. These animals will be valuable to further investigate the consequences of GPI-anchor deficiency on erythroid/megakaryocytic cells.

Animals↗
PubMed2003

[Proliferation and anti-tumor activity of lymphocytes and their effect on normal phenotype of autologous bone marrow hematopoietic cells in patients with paroxysmal nocturnal hemoglobinuria].

There is a hypothesis that paroxysmal nocturnal hemoglobinuria (PNH) hematopoitic stem cells are resistant to the cytotoxic effect of T cells because they lack glycosylphosphatidylinositol (GPI)-linked proteins. The aim of this study is to investigate proliferation and anti-tumor activity of lymphocytes in patients with PNH, and also to assay the effect on normal cell (CD59(+)) phenotype in bone marrow of PNH patient by autologous lymphocytes in vitro. MTT assay for detection of lymphocytes proliferation and its anti-tumor effect was driven to delineate T cell reactive function. The CD34(-) and CD34(+) bone marrow cells (selected by means of immunomagnetic method) as well as unsorted marrow cells in PNH patients were cultured together with autologous CD59(+) or CD59(-) lymphocytes, their cultured supernatant, extrinsic IFN-gamma and IL-2 in a liquid culture system. CD59(+) cells were counted by flow cytometry after 10 day culture in vitro. The results showed that there were no differences in the proliferation ability of lymphocytes between each group: controls 1.42 +/- 0.46, unsorted PNH lymphocytes 1.40 +/- 0.35, CD59(-) 1.30 +/- 0.40, and CD59(+) PNH lymphocytes 1.40 +/- 0.42. Anti-tumor effect of lymphocytes declined in PNH patients when compared with control [(50.00 +/- 28.67)% vs. (76.13 +/- 10.15)%]. The proportion of CD59(+) cells diminished significantly after culture with autologous lymphocytes, their supernatant, extrinsic IFN-gamma or IL-2 (P < 0.01) in groups of unsorted, CD34(+) and CD34(-) bone marrow cells. No significant difference was found between groups of CD59(-) and CD59(+) lymphocytes, or CD34(-) and CD34(+) marrow cells. It is concluded that turbulences of immune regulations may be involved in pathogenesis of PNH.

Adult↗
PubMed1994

Differences in the regulation of specific glycosylation in the pathogenesis of paroxysmal nocturnal hemoglobinuria and the Tn-syndrome.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematologic disorder that resembles in several aspects the Tn-syndrome, in which bone marrow-derived cells are deficient in mucin-type beta 1,3 galactosyltransferase (beta 1,3Gal-T) due to the persistent repression of an intact allele. In the present study, we have investigated phytohemagglutinin (PHA)-activated T cells from the peripheral blood of an individual with the well-established clinical diagnosis of PNH. Only 10% of T cells were deficient in surface expression of the glycosylphosphatidylinositol (GPI)-linked CD48 antigen; in contrast, 95% of the patient's polymorphonuclear leukocytes harbored the defect. The cell-surface density of CD48 on unaffected T cells from this patient was two- to three-fold higher when compared to PHA-activated normal donor T cells. CD48-negative T cells were cloned and shown to belong to the CD4+ or the CD8+ antigenic subset. To test for the possibility that in PNH, as in Tn syndrome, gene repression may be responsible for the deficiency, CD48- T cell clones were treated with 5-azacytidine (5-azaC) and sodium n-butyrate (NaB). While such treatment reproducibly led to reexpression of a sialylated CD43 epitope on affected Tn-syndrome T cell clones, these drugs failed to induce reexpression of CD48 on affected PNH T cell clones. Our data suggest that despite many similarities, different pathogenetic mechanisms are responsible for PNH and Tn-syndrome. These CD48- T cell clones are the first to be described and may be useful to define the PNH lesion at a biochemical and genetic level.

Adult↗
PubMed1985

Characterization of the complement sensitivity of paroxysmal nocturnal hemoglobinuria erythrocytes.

The affected erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH II and PNH III cells) are abnormally sensitive to complement-mediated lysis. Normal human erythrocytes chemically modified by treatment with 2-amino-ethylisothiouronium bromide (AET) have been used as models for PNH cells inasmuch as they also exhibit an enhanced susceptibility to complement. To investigate the bases for the greater sensitivity of these abnormal cells to complement-mediated lysis, we compared binding of C3 and constituents of the membrane attack complex to normal, PNH II, PNH III, and AET-treated cells after classical pathway activation by antibody and fluid-phase activation by cobra venom factor complexes. When whole serum complement was activated by antibody, there was increased binding of C3 and C9 to PNH II, PNH III, and AET-treated cells, although the binding of these complement components to PNH II and PNH III cells was considerably greater than their binding to the AET-treated cells. In addition, all of the abnormal cell types showed a greater degree of lysis per C9 bound than did the normal erythrocytes. PNH III and AET-treated cells were readily lysed by fluid-phase activation of complement, whereas normal and PNH II erythrocytes were not susceptible to bystander lysis. The greater hemolysis of PNH III and AET-treated cells in this reactive lysis system was due to a quantitative increase in binding of constituents of the membrane attack complex. This more efficient binding of the terminal components after fluid-phase activation of whole serum complement was not mediated by cell-bound C3 fragments. These investigations demonstrate that the molecular events that characterize the enhanced susceptibility of PNH II, PNH III, and AET-treated erythrocytes to complement-mediated lysis are heterogeneous.

Cobra Cardiotoxin Proteins↗
PubMed2002

HLA class II haplotype and quantitation of WT1 RNA in Japanese patients with paroxysmal nocturnal hemoglobinuria.

It is unclear how a paroxysmal nocturnal hemoglobinuria (PNH) clone expands in bone marrow, although immune mechanisms involving cytotoxic T lymphocytes, autosomal proliferation, and apoptosis resistance have been hypothesized. To clarify aspects of immune mechanisms and proliferation of PNH cells, we investigated HLA-DRB1, -DQA1, and -DQB1 alleles by polymerase chain reaction (PCR)-based genotyping and expression of the Wilms' tumor gene, WT1, by real-time reverse transcriptase-PCR (RT-PCR) in 21 PNH and 21 aplastic anemia (AA) patients. HLA genotyping indicated that the frequency of DRB1*1501, DQA1*0102, and DQB1*0602 alleles in PNH patients and of DQB1*0602 allele in AA patients was significantly higher than in 916 Japanese controls, and that the HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotype, found in 13 of 21 PNH patients, 5 of 7 AA-PNH syndrome patients, and 7 of 21 AA patients showed significant differences compared with healthy individuals. RT-PCR analysis showed that the mean values of WT1 RNA were 3413, 712, and 334 copies/microg RNA in PNH, AA, and healthy individuals, respectively. The values for PNH patients were significantly higher than for AA patients and healthy volunteers and were correlated with the proportion of CD16b(-) granulocytes. The high frequency of HLA-DRB1*1501-DQA1*0102-DQB1*0602 haplotype in PNH, including AA-PNH syndrome, and AA patients suggests that linkage exists between the disorders and that immune mechanisms in an HLA-restricted manner play an important role in the pathogenesis of these disorders. In addition, high expression of WT1 RNA in PNH patients is related to a PNH clone, but it remains unclear whether this causes expansion of a PNH clone.

Adult↗
PubMed1996

Paroxysmal nocturnal hemoglobinuria: the price for a chance.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic blood disease. The dramatic symptoms that gave the disease its name and the unique nature of the underlying cellular abnormality made the disease for many years a curiosity amongst human blood disorders. Clinical manifestations of PNH are chronic hemolytic anemia with acute exacerbations, bone marrow failure, an increased tendency to thrombosis, and episodes of severe abdominal pain. PNH has a close although not yet fully understood relationship to aplastic anemia (AA), and probably also to acute myeloid leukemia (AML). Blood cells in patients with PNH have a defect in the biosynthesis of a complex glycolipid structure which is a glycosyl phosphatidylinositol (GPI) molecule and serves as an anchor for many surface proteins. Red cells, granulocytes, monocytes, lymphocytes and platelets are therefore deficient in all proteins which are anchored to the cell membrane by such a molecule. Biochemical analysis pinpointed the metabolic block in PNH cells to an early step in the anchor biosynthesis. The block in the biosynthetic pathway is due to the deficiency of a protein called PIG-A. The PIG-A gene maps to the X-chromosome. Cloning of the gene and analysis of the gene in PNH patients lead to the identification of a number of somatic mutations which occur on the active X-chromosome in an early hematopoietic stem cell. All mutations identified thus far inactivate or impair the function of the PIG-A protein and therefore fully explain the deficiency of the missing surface proteins, which in turn explain some of the clinical features of the disease. However, the characterization of the molecular lesion does not explain how the PNH clone can expand to the extent of contributing a substantial proportion of the patient's hematopoiesis. Thus a second factor is needed to explain the pathogenesis of PNH. We hypothesize that this is most likely the coexistence of bone marrow failure that produces paradoxically a growth or survival advantage for the PNH clone. The coexistence of more than one PNH clone in many patients supports this hypothesis and suggests that bone marrow failure is the primary event. The occurrence of the PIG-A mutation causing the absence of GPI-linked proteins on blood cells allows the PNH clone to flourish and to maintain hematopoiesis; thus it seems that the PIG-A mutation is nature's own gene therapy and the price that these patients have to pay is PNH.

Adult↗
PubMedDate not supplied

Paroxysmal nocturnal hemoglobinuria and the risk of venous thrombosis: review and recommendations for management of the pregnant and nonpregnant patient.

BACKGROUND: Paroxysmal nocturnal hemoglobinuria is a rare, clonal primitive hematopoietic cell disorder, often affecting middle-aged adults, including women of reproductive age. Major morbidity and mortality with this disease are often ascribed to the development of venous thromboembolism. We reviewed the current literature on the risk of venous thrombosis among nonpregnant and pregnant patients, and generated recommendations for the prevention of venous thromboembolism, as well as duration of treatment for affected patients who develop thrombotic disease. METHODS: We searched Medline for papers published between January 1966 and April 1999. We also requested relevant unpublished data from speakers who attended a recent international workshop of paroxysmal nocturnal hemoglobinuria. References from all primary data and review publications were also examined. Only English language publications were included. Event rates for venous thromboembolism and death were pooled using a random effect technique. Reports of paroxysmal nocturnal hemoglobinuria during pregnancy were summarized using descriptive statistics only. RESULTS: Thirteen retrospective studies of paroxysmal nocturnal hemoglobinuria in nonpregnant individuals were found. The rates of venous thrombosis varied considerably, but were reported to affect 14.4% of all individuals [95% confidence interval (CI) 7.6-25.5]. Among patients from western nations, venous thromboembolism seemed to develop at a higher rate (30.3%, 95% CI 26. 1-34.9). The majority of venous thromboembolic events were intra-abdominal, principally within the hepatic and mesenteric veins. The likely cause of death among patients with paroxysmal nocturnal hemoglobinuria was described in nine studies: 22.2% of fatalities were due to venous thrombosis (95% CI 11.8-38.0), more commonly in western countries (event rate 37.2%, 95% CI 21.6-56.0). Another 20 published reports described the outcome of 33 pregnant women with paroxysmal nocturnal hemoglobinuria. Two women developed venous thromboembolism during pregnancy and another 2 during the postpartum state for a combined event rate of 12.1% (95% CI 3.4-25.2), three of which resulted in death. The all-cause mortality rate was 20.8% (95% CI 7.3-39.0). Both anemia (event rate 72.7%, 95% CI 56.5-86.3), and thrombocytopenia (event rate 27.3%, 95% CI 13.7-43.5) were common, often necessitating red cell or platelet transfusions. Almost half of all infants (54.8%, 95% CI 36.1-72.7) were delivered preterm, and had a mean live birth weight of 2,800 g. Three of 34 reported births ended in death (perinatal mortality rate 8.8%, 95% C 1.9-23.7). CONCLUSION: In accordance with the apparently high rate of venous thrombosis among pregnant and nonpregnant individuals with paroxysmal nocturnal hemoglobinuria, especially for fatal thrombosis, we developed practical recommendations for the prevention and treatment of venous thromboembolic disease in these groups.

Adolescent↗
PubMed2003

[Paroxysmal nocturnal hemoglobinuria associated with intestinal ischemia leading to small bowel perforation].

Paroxysmal nocturnal hemoglobinuria is rarely associated with intestinal complications. We report a case of paroxysmal nocturnal hemoglobinuria with small bowel ischemia leading to ileal perforation. In the literature, an ulcerative jejuno-ileitis has been reported in 6 cases of intestinal ischemia, due to thrombosis of mucosal small vessels. This disease is usually revealed by abdominal pain. Based on published cases and our observation of intestinal ischemia leading to small bowel perforation, surgery should be considered as the first-line treatment, especially when small bowel lesions are limited.

Adult↗