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PubMed2003

Paroxysmal nocturnal hemoglobinuria in pregnancy.

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hemolytic anemia in which a defect of glycophosphatidylinositol (GPI)-anchored proteins in the cell membrane of bone marrow stem cells leads to increased sensitivity of the red cells to complement, causing intravascular hemolysis and hemoglobinuria. Other clinical features of this disease are cytopenia and an increased frequency of thrombotic events. We report a case of a pregnant woman with PNH on high-dosage anticoagulation therapy, the follow-up during the pregnancy, the delivery and the postpartum period. The obstetric literature on women with PNH is reviewed, the maternal and fetal risks are evaluated and the management of pregnancies and deliveries in such patients are discussed. During the pregnancy our patient was hypertransfused and used anticoagulation treatment. A healthy child was delivered in week 37 by cesarean section because of premature rupture of the membranes, unsuccessful induction and intrauterine infection. Because of bleeding problems a hysterectomy also had to be performed. In the postpartum period the patient developed her second episode of a liver vein thrombosis. She recovered gradually and 18 months after the delivery her disease is now in a stable phase. The literature shows a high maternal morbidity and mortality among pregnant PNH patients. Fetal wastage and prematurity rate are also high. Pregnancy in patients with PNH represents a high-risk situation for both the mother and the child and should not be recommended. A pregnant PNH woman should be followed closely by both obstetricians and hematologists.

Adult↗
PubMed1999

Different roles of glycosylphosphatidylinositol in various hematopoietic cells as revealed by a mouse model of paroxysmal nocturnal hemoglobinuria.

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have one or a few clones of mutant hematopoietic stem cells defective in glycosylphosphatidylinositol (GPI) synthesis as a result of somatic mutation in the X-linked gene PIG-A. The mutant stem cell clone dominates hematopoiesis by a mechanism that is unclear. To test whether a lack of multiple GPI-anchored proteins results in dysregulation and expansion of stem cells, we generated mice in which GPI-anchor negative cells are present only in the hematopoietic system. We transplanted lethally irradiated mice with female fetal liver cells bearing one allele of the Piga gene disrupted by conditional gene targeting. Because of the X-chromosome inactivation, a significant fraction of the hematopoietic stem cells in fetal livers was GPI-anchor negative. In the transplanted mice, cells of all hematopoietic lineages contained GPI-anchor negative cells. The percentage of GPI-anchor negative cells was much higher in T lymphocytes including immature thymocytes than in other cell types, suggesting a regulatory role for GPI-anchored proteins at an early stage of T-lymphocyte development. However, the proportions of GPI-anchor negative cells in various blood cell lineages were stable over a period of 42 weeks, indicating that Piga mutation alone does not account for the dominance of the mutant stem cells and that other phenotypic changes are involved in pathogenesis of PNH.

Animals↗
PubMed2000

Flow cytometric analysis of glycosylphosphatidyl-inositol-anchored proteins to assess paroxysmal nocturnal hemoglobinuria clone size.

Paroxysmal nocturnal hemoglobinuria (PNH) is characterized by total or partial deficiency of membrane proteins anchored to the cell surface through a glycosylphosphatidyl-inositol (GPI) moiety. The relationship between the size of the PNH clone, determined by the expression of GPI-anchored proteins (AP; CD14, CD48, CD55, CD59, and CD66b) on erythrocytes, lymphocytes, monocytes, and granulocytes using forward and side scatter analysis, and severity of the disease was evaluated in 19 PNH patients. CD55 antigen expression did not delineate abnormal erythrocytes as well as did anti-CD59. The proportion of monocytes deficient in CD55, CD59, CD48, and CD14 (48-97%) and of granulocytes deficient in CD55, CD59, and CD66b (60-99%) was greater than the proportion of erythrocytes deficient in CD59 (24-95%) and the proportion of lymphocytes deficient in CD55 and CD59 (30-98%). There were no significant correlations among reticulocyte, leukocyte, and platelet counts and GPI-AP-deficient immunophenotypes in red and white blood cells. However, high coefficients of determination were seen between hemoglobin levels and granulocytes deficient in CD59 (r(2) = 0.76), CD55 (r(2) = 0.74), and CD66b (r(2) = 0.74) antigens and between hemoglobin and monocytes deficient in CD55 (r(2) = 0.73), CD59 (r(2) = 0.80), and CD14 (r(2) = 0.75) antigens. These results are interpreted as indicating that the size of PNH clone is better assessed by immunophenotypic analysis of monocytes and granulocytes rather than of lymphocytes and erythrocytes.

Adult↗
PubMed1988

Normal polymorphic variations and transcription of the decay accelerating factor gene in paroxysmal nocturnal hemoglobinuria cells.

In paroxysmal nocturnal hemoglobinuria (PNH), an acquired hemolytic anemia, deficiency of decay accelerating factor (DAF) renders blood cells susceptible to increased deposition of autologous complement activation fragments (C3b) and complemented-mediated injury. To investigate the mechanism of the DAF defect, DNA and mRNA from normal and PNH leukocytes were compared in blot hybridization assays by using DAF cDNA and oligonucleotide probes. Southern analyses of DNA from normal cells revealed a single gene spanning approximately equal to 35 kilobases of DNA. Six HindIII banding patterns were distinguishable among normal individuals. In family studies, the patterns segregated as three homozygous and three heterozygous genotypes deriving from three haplotypes: A, B, and C with frequencies of 0.47, 0.36, and 0.17, respectively. Oligonucleotide mapping localized the polymorphic HindIII sites to two noncoding regions in the vicinity of exons encoding (i) the protein oligosaccharide-rich domain and (ii) the mRNA 3'-untranslated region. Analyses of DNA from DAF-negative leukocytes of eight PNH patients demonstrated restriction fragment profiles identical to those of normal individuals for all enzymes studied. Three patients had the BC (normals = 3/32), three patients had the AA (normals = 6/32), and two patients had the AC (normals = 8/32) HindIII genotype. Of the three PNH patients exhibiting the BC genotype, family studies of two demonstrated the expected inheritance patterns, and RNA gel blot analyses of two showed mRNA transcripts indistinguishable from those in normal cells. The absence of DAF gene or mRNA alterations in affected PNH cells that lack other glycolipid-anchored proteins as well as DAF argues that the lesion underlying PNH cells resides in the glycolipid-anchor pathway.

Blood Proteins↗
PubMed1984

Intestinal infarction caused by paroxysmal nocturnal hemoglobinuria.

A patient with paroxysmal nocturnal hemoglobinuria of 14 years duration presented with severe abdominal pain and fever. On admission, his hematocrit had fallen to 19% from his usual level of approximately 30%, and stools were positive for occult blood. Dilated loops of small bowel with air fluid levels were noted on radiographs, and sonography revealed free intraperitoneal fluid. Several sections of gangrenous jejunum and ileum were resected at exploratory laparotomy, and mesenteric venous thromboses were present. This is the second report of pathologically proven intestinal infarction in a patient with paroxysmal nocturnal hemoglobinuria who has survived this abdominal emergency with surgical intervention. Although abdominal pain in patients with paroxysmal nocturnal hemoglobinuria has frequently been attributed to mesenteric venous thromboses, this has rarely been documented either during life or at autopsy.

Hemoglobinuria, Paroxysmal↗
PubMedDate not supplied

Widespread abdominal venous thrombosis in paroxysmal nocturnal hemoglobinuria diagnosed on CT.

Paroxysmal nocturnal hemoglobinuria is a rare disorder characterized by pancytopenia. One of the main manifestations of this disease is development of widespread life-threatening venous thrombosis, which may involve multiple abdominal veins. We describe two patients with paroxysmal nocturnal hemoglobinuria with clinically unsuspected portal, splenic, and mesenteric venous thromboses that were diagnosed on computed tomography. This complication should be clinically suspected in patients suffering from paroxysmal nocturnal hemoglobinuria who present with abdominal pain, and it should be sought by the radiologist on pre- and postcontrast computed tomography.

Abdomen↗
PubMed1985

Thrombolytic therapy for inferior vena cava thrombosis in paroxysmal nocturnal hemoglobinuria.

Two patients with paroxysmal nocturnal hemoglobinuria had increasing abdominal girth and ascites. The Budd-Chiari syndrome or inferior vena cava thrombosis was shown by angiography. After thrombolytic therapy, both patients improved, and thrombolysis was shown by radiography. Neither patient had induction of hemolysis secondary to these agents. These studies suggest that both streptokinase and urokinase are safe and effective in the treatment of intra-abdominal venous thromboses associated with paroxysmal nocturnal hemoglobinuria.

Abdomen↗
PubMed1990

Erythropoiesis in paroxysmal nocturnal hemoglobinuria.

Ten patients with paroxysmal nocturnal hemoglobinuria were studied. The diagnosis was made on the basis of hemolytic anemia, a positive Ham test and hemosiderinuria. Six patients had primary paroxysmal nocturnal hemoglobinuria evolved from aplastic anemia. These four patients also had a milder form of the disease, Over long periods of the follow-up, large variations of hemoglobin values and red blood cell counts were observed. Both absolute and percent reticulocyte counts were increased. Erythroblast counts in the bone marrow were 3-5 times higher than normal. Reticulocyte counts in the bone marrow were 3-5 times higher than normal. Reticulocyte counts showed wide variations but substantially smaller than those in autoimmune hemolytic anemias. Serum iron was either normal or increased, while the bone marrow iron store was high or low. However, the finding of urinary hemosiderin in all cases spoke against depletion of iron stores. The red blood cell life span was moderately shortened. Kinetic studies with 59Fe showed a high red blood cell iron incorporation, while the curves frequently had irregular shapes (broken curve) or an early, abrupt fall. Studies of late erythroid progenitors (CFU-E) indicated that this compartment was preserved. Even after long observation periods was no stem cell pool depletion due to an increased red blood cell demand observed.

Anemia, Aplastic↗
PubMed1977

Renal proximal tubular dysfunction and paroxysmal nocturnal hemoglobinuria.

A patient with paroxysmal nocturnal hemoglobinuria, who required many blood transfusions for hemolytic episodes, had a persistent hyperchloremic metabolic acidosis. Bicarbonate infusion demonstrated a large fractional excretion of bicarbonate (28.6 per cent at a plasma bicarbonate level of 23 meq/liter) which was consistent with proximal renal tubular acidosis. Generalized aminoaciduria and decreased tubular reabsorption of phosphate were also present. Marked deposition of iron in renal proximal tubules was associated with these functional abnormalities. We believe that, as systemic acidosis can promote hemolysis in patients with paroxysmal nocturnal hemoglobinuria, hemolysis can lead, by way of iron deposition in renal tubules, to further acidosis. This cycle should be interrupted with appropriate doses of bicarbonate.

Acidosis, Renal Tubular↗
PubMed1985

Deficiency of the complement regulatory protein, "decay-accelerating factor," on membranes of granulocytes, monocytes, and platelets in paroxysmal nocturnal hemoglobinuria.

Erythrocytes from patients with paroxysmal nocturnal hemoglobinuria are deficient in decay-accelerating factor, a membrane protein that inhibits the complement C3 convertases. We studied the expression of this protein on leukocytes and platelets from four patients with paroxysmal nocturnal hemoglobinuria, using cytofluorographic analysis and antibody to decay-accelerating factor. The granulocytes and monocytes had a bimodal distribution of fluorescence, indicating antigen-deficient and antigen-positive subpopulations of cells. In contrast, granulocytes and monocytes from normal donors and patients with other diseases had no antigen-deficient cells. Platelets from the four patients with paroxysmal nocturnal hemoglobinuria had less fluorescence than normal platelets. Furthermore, surface-radiolabeled granulocytes and platelets from one of the four patients, which were maximally deficient in decay-accelerating factor, also lacked antigen that was immunoprecipitable by specific antibody to this protein. Thus, paroxysmal nocturnal hemoglobinuria is a clonal disorder characterized by deficient membrane expression of decay-accelerating factor on granulocytes, monocytes, and platelets, as well as on erythrocytes.

Adult↗
PubMed1986

Magnetic resonance appearance of the kidneys in paroxysmal nocturnal hemoglobinuria.

A diagnosis of paroxysmal nocturnal hemoglobinuria may be suggested with magnetic resonance imaging, based on the massive renal cortical hemosiderosis that occurs in this disease. A diffuse bilateral depression of renal cortical signal intensity will be observed that is caused mainly by a shortening of the T2 relaxation time of renal cortical protons by the paramagnetic effect of the locally increased ferric ion concentration in the proximal convoluted tubule.

Adult↗
PubMed1994

High-dose recombinant human erythropoietin and low-dose corticosteroids for treatment of anemia in paroxysmal nocturnal hemoglobinuria.

Three patients with paroxysmal nocturnal hemoglobinuria (PNH) and severe anemia were treated with high-dose recombinant human erythropoietin (rHEpo) and low-dose corticosteroids. During therapy their hemoglobin levels gradually improved and no blood transfusions were required. Neither rHEpo nor corticosteroids caused any side effects. This study shows that high rHEpo and low corticosteroid doses may improve the anemia of PNH patients.

Acute Disease↗
PubMed1992

Myeloblastic leukemoid reaction in paroxysmal nocturnal hemoglobinuria associated with myelodysplasia.

Paroxysmal nocturnal hemoglobinuria (PNH) has been observed to evolve into myelofibrosis and acute myeloid leukemia. Myeloblastic leukemoid reaction has not been described in PNH. We described a patient with PNH with myelodysplasia and septicemia. The marrow aspirates showed a picture of myeloblastosis which subsided when sepsis was controlled. The myeloblastic leukemoid reaction in our patient related to overwhelming sepsis, splenectomy and overt hemolysis.

Bone Marrow↗
PubMed1975

Renal impairment in patients with paroxysmal nocturnal hemoglobinuria.

Three patients with paroxysmal nocturnal hemoglobinuria accompanied by chronic renal lesions were studied. All the cases had histories of severe hemolytic anemia and repeated hemoglobinuria. The biopsy specimen of the kidney of two patients (Case 1 and Case 2) showed interstitial nephritis. Renal glucosuria, tubular proteinuria, increased urate clearance (Case 2) and reduced tubular reabsorption of phosphate (Case 3) were revealed in Case 2 and Case 3, suggesting renal tubular impairment. From the nephrological point of view, hemodynamic alteration resulting from intravascular hemolysis and severe persistent chronic anemia may primarily be responsible for the renal impairment.

Adult↗
PubMed1980

HLA antigens in paroxysmal nocturnal hemoglobinuria.

10 patients with paroxysmal nocturnal hemoglobinuria were studied taking 109 normal subjects of the Cuban population as control group. 26 HLA antigens corresponding to loci A and B were studied in both groups. Phenotypical frequency of both groups were compared. No statistically significant increase was found for any of the studied antigens, though there was a nonsignificant increase for antigens HLA-B7 and BW-21. These results might be influenced by the small number of patients studied due to the rareness of the disease.

Gene Frequency↗
PubMed1975

Liver imaging in the diagnosis of hepatic venous thrombosis in paroxysmal nocturnal hemoglobinuria.

Eleven patients with paroxysmal nocturnal hemoglobinuria were studied by serial liver imaging. This disease has a generalized thrombotic tendency, and progressive diffuse hepatic venous thrombosis has been emphasized in recent studies. Radionuclide imaging proved to be of great help in establishing the diagnosis of hepatic venous thrombosis and following the progress of the disease process. Abnormal patterns in hepatic venous occlusion include (a) enlargement of the liver (especially the right lobe), (b) extrahepatic localization of radionuclide, and (c) areas of decreased uptake in the distribution of the involved veins. These findings develop rapidly and are very characteristic in the clinical setting.

Adolescent↗
PubMed2002

Relationship between aplastic anemia and paroxysmal nocturnal hemoglobinuria.

Since aplastic anemia-paroxysmal nocturnal hemoglobinuria syndrome was reported in 1967, the overlap of idiopathic aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH) has been well known. The link between the 2 diseases became even more evident when immunosuppressive therapy improved survival of patients with severe AA. More than 10% of patients with AA develop clinically evident PNH. Moreover, flow cytometric analysis demonstrates that the majority of patients with AA have a subclinical percentage of granulocytes with PNH phenotype. Some of them have clearly recognizable PNH clones. Granulocytes with a PNH phenotype are also often found in normal individuals, though at much smaller percentages of cells. This finding suggests that a PNH clone is expanded in AA. consistent with a hypothesis that blood cells from patients with PNH are more resistant to an autoimmune environment. Survival of PNH clones in pathologic bone marrow may account for limited expansion of PNH clones; however, additional genetic change(s) that confers cells with growth phenotype may be required for the full development of PNH.

Anemia, Aplastic↗