scholarly journals Paroxysmal Nocturnal Hemoglobinuria: An Underestimated Cause of Pediatric Thromboembolism

TH Open ◽  
2020 ◽  
Vol 04 (01) ◽  
pp. e36-e39
Author(s):  
Christina Griesser ◽  
Michael Myskiw ◽  
Werner Streif
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clinical Symptoms ◽  
Bone Marrow Failure ◽  
Flow Cytometric Analysis ◽  
Routine Diagnostics ◽  
Glycosyl Phosphatidylinositol ◽  
Vein Thrombosis ◽  
Flow Cytometric ◽  
Appropriate Treatment

AbstractParoxysmal nocturnal hemoglobinuria (PNH) is a chronic disease caused by complement-mediated hemolysis. Clinical symptoms include intravascular hemolysis, nocturnal hemoglobinuria, thromboses, cytopenia, fatigue, abdominal pain, and a strong tendency toward bone marrow failure. It is a rare disease, especially in children, with high mortality rates without appropriate treatment.We here present the case of a 17-year-old girl with unprovoked muscle vein thrombosis. Flow cytometric analysis showed deficiency of glycosyl-phosphatidylinositol-anchored membrane proteins on all three hematopoietic cell lines and confirmed the diagnosis of PNH. Treatment with the monoclonal antibody eculizumab achieved long-term remission.As flow cytometry is normally not part of the routine diagnostics for pediatric thrombosis, awareness is crucial and PNH is important to consider in all children with thrombosis at atypical sites and abnormalities in blood counts with regard to hemolysis and cytopenia.

scholarly journals Update on the diagnosis and management of paroxysmal nocturnal hemoglobinuria

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 208-216 ◽  
Author(s):  
Charles J. Parker
Keyword(s):  
Bone Marrow ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Cell Clone ◽  
Bone Marrow Failure ◽  
Flow Cytometric Analysis ◽  
Disease Process ◽  
Hematopoietic Stem ◽  
Glycosyl Phosphatidylinositol ◽  
Flow Cytometric ◽  
Immune Mediated

Abstract Once suspected, the diagnosis of paroxysmal nocturnal hemoglobinuria (PNH) is straightforward when flow cytometric analysis of the peripheral blood reveals a population of glycosyl phosphatidylinositol anchor protein-deficient cells. But PNH is clinically heterogeneous, with some patients having a disease process characterized by florid intravascular, complement-mediated hemolysis, whereas in others, bone marrow failure dominates the clinical picture with modest or even no evidence of hemolysis observed. The clinical heterogeneity is due to the close, though incompletely understood, relationship between PNH and immune-mediated bone marrow failure, and that PNH is an acquired, nonmalignant clonal disease of the hematopoietic stem cells. Bone marrow failure complicates management of PNH because compromised erythropoiesis contributes, to a greater or lesser degree, to the anemia; in addition, the extent to which the mutant stem cell clone expands in an individual patient determines the magnitude of the hemolytic component of the disease. An understanding of the unique pathobiology of PNH in relationship both to complement physiology and immune-mediated bone marrow failure provides the basis for a systematic approach to management.

Chronic RPS19 Deficiency Leads to Bone Marrow Failure In a Mouse Model for Diamond-Blackfan Anemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 193-193
Author(s):  
Pekka Jaako ◽  
Johan Flygare ◽  
Karin Olsson ◽  
Ronan Quere ◽  
Jonas Larsson ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Bone Marrow Cells ◽  
Bone Marrow Failure ◽  
Flow Cytometric Analysis ◽  
Wild Type ◽  
Erythroid Progenitors ◽  
Hematopoietic Stem ◽  
Flow Cytometric

Abstract Abstract 193 Diamond-Blackfan anemia (DBA) is a congenital erythroid hypoplasia associated with physical malformations and predisposition to cancer. Of the many different DBA disease genes known, all encode for ribosomal proteins, suggesting that DBA is a disorder relating to ribosomal biogenesis or function. Among these genes, ribosomal protein S19 (RPS19) is the most frequently mutated (25 % of the patients). The generation of animal models for DBA is pivotal in order to understand the disease mechanisms and to evaluate novel therapies. We have generated two mouse models for RPS19-deficient DBA by taking advantage of RNA interference (Jaako et al, 2009 ASH meeting abstract). These models contain RPS19-targeting shRNAs expressed by a doxycycline-responsive promoter downstream of the Collagen A1 locus allowing an inducible and dose-dependent regulation of shRNA. As we have previously reported, the induction of RPS19 deficiency results in a reduction in the number of erythrocytes, platelets and white blood cells, and flow cytometric analysis of bone marrow after a short-term induction reveals increased frequencies of hematopoietic stem and progenitor cells reflecting the onset of stress hematopoiesis. In the current study we have analyzed the long-term effect of RPS19 deficiency in bone marrow. In contrast to a short-term induction, flow cytometric analysis of bone marrow after 51 days revealed decreased frequencies of hematopoietic stem and progenitor cells that correlate with a severe peripheral blood phenotype. In addition, we observed a 3–6 fold increase in apoptosis in RPS19-deficient bone marrow compared to controls based on TUNEL assay. Furthermore, transplantation of whole bone marrow cells from transgenic donors into wild type lethally irradiated recipients confirms that the observed phenotype is autonomous to the blood system. To study whether long-term RPS19 deficiency functionally impairs hematopoietic stem cells, we pre-induced mice for 30 days followed by 15 days without doxycycline to restore the RPS19 expression. Mice were sacrificed and total bone marrow cells were transplanted together with wild-type competitor cells (1:1) into wild type lethally irradiated recipients without doxycycline. This experimental setting allows us to assess the functionality of pre-induced hematopoietic stem cells in absence of ribosomal stress. Flow cytometric analysis of peripheral blood one month after transplantation clearly demonstrates decreased reconstitution from pre-induced donors compared to the wild-type competitor. While this time point reflects mainly the function of transplanted progenitors, long-term analysis of hematopoietic stem cell function in these recipients is ongoing. To study the molecular mechanisms underlying the hematopoietic defect we performed comparative microarray analysis. We chose to analyze preCFU-E/CFU-E erythroid progenitors since we have previously located the erythroid defect at the CFU-E – proerythroblast transition based on flow cytometry and clonogenic proliferation cultures of prospectively isolated erythroid progenitors. Microarray analysis of preCFU-E/CFU-E progenitors reveals deregulation of several genetic pathways, including a robust upregulation of p53 pathway genes, and these targets have been confirmed by real-time PCR. Furthermore, many of p53 target genes are also upregulated in the Lineage− Sca-1+ c-Kit+ (LSK) population that contains immature hematopoietic progenitors and stem cells suggesting that the activation of p53 is not restricted to the erythroid lineage. To ask whether increased activity of p53 can solely explain the hematopoietic phenotype, we have crossed our mouse model into a p53-null background. In summary, our data suggest that RPS19-deficient mice fail to uphold stress hematopoiesis for extended periods of time, with chronic RPS19 deficiency causing bone marrow failure. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Persistence of affected T lymphocytes in long-term clinical remission in paroxysmal nocturnal hemoglobinuria

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3925-3928 ◽  
Author(s):  
H Nakakuma ◽  
S Nagakura ◽  
T Kawaguchi ◽  
N Iwamoto ◽  
M Hidaka ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Lymphocytes ◽  
Blood Cells ◽  
Clinical Remission ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Flow Cytometric Analysis ◽  
Regulatory Activity ◽  
Flow Cytometric

Long-term clinical remission of more than 10 years is rarely seen in paroxysmal nocturnal hemoglobinuria (PNH). Affected blood cells in PNH lack glycosylphosphatidylinositol (GPI)-anchored membrane proteins such as decay-accelerating factor (DAF) and CD59. We performed a flow cytometric analysis of circulating blood cells obtained from two patients with PNH who had been in clinical remission for more than 10 and 25 years, respectively. Affected cells with the PNH phenotype were demonstrated only among T-lymphocytes. Persistent affected T cells were negative for the CD52 protein only, this protein being a GPI-anchored lymphocyte marker without complement regulatory activity. The persistence of the affected T cells may be explained either by an inherently long life span after the disappearance of the PNH stem cell or by insidious production at a subclinical level by affected stem cell. In either event, detection of affected T cells, especially CD52- negative T cells, may be useful for the evaluation of long-term clinical remission in PNH.

scholarly journals Mycotoxins in Children’s Food: Problem and Halal Management

2019 ◽  
Vol 1 (1) ◽  
pp. 16-38
Author(s):  
Mosaad A. Abdel-Wahhab ◽  
Aziza A. El-Nekeety ◽  
Soher E. Aly
Keyword(s):  
Indoor Air ◽  
Clinical Symptoms ◽  
Bone Marrow Failure ◽  
Treatment Options ◽  
Pulmonary Hemorrhage ◽  
Childhood Exposure ◽  
Toxicological Effects ◽  
Food Knowledge ◽  
Contaminated Food

Mycotoxins are ubiquitous compounds found in the natural life cycle of food- producing plants. They have a range of diverse chemical and physical properties and toxicological effects on man and animal. Mycotoxins are considered the most important contaminants of the food chain due to their chronic adverse effects on health and the economy. Mycotoxins are known as the 21th century “Great Masquerader” due to its complex natural history involving different tissues and resembling different diseases at each stage in its evolution. Mycotoxins can induce a variety of clinical symptoms including epistaxis, conjunctivitis, coughing, apnea, wheezing, vomiting and nausea. Some mycotoxins induce acute pulmonary hemorrhage, bone marrow failure and pneumonia. Knowledge about these symptoms enables the clinician to ask questions for possible exposure to the main classes of mycotoxins to protect children from sources of such exposure. These sources may include food, clothes, furniture and indoor air at home. Early childhood exposure to mycotoxins may be critical determinants of later health effects. Exposure in utero and through early infancy may additionally be important. Several well-known diseases such as neural tube defects, liver and esophageal cancers are associated with the consumption of mycotoxin-contaminated food. Knowledge of previous short or long term exposure to mycotoxins may help paediatricians to more accurately diagnose and provide treatment options to children and their families. The current review discusses the problems associated with the occurrence of different common mycotoxins in children’s food and the possible halal strategies to counteract these problems.  

scholarly journals Aplastic anemia and paroxysmal nocturnal hemoglobinuria: search for a pathogenetic link

Blood ◽  
1995 ◽  
Vol 85 (5) ◽  
pp. 1354-1363 ◽  
Author(s):  
A Griscelli-Bennaceur ◽  
E Gluckman ◽  
ML Scrobohaci ◽  
P Jonveaux ◽  
T Vu ◽  
...  
Keyword(s):  
Protein Expression ◽  
Aplastic Anemia ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Antithrombin Iii ◽  
Clinical Symptoms ◽  
Flow Cytometric Analysis ◽  
Normal Subjects ◽  
Initial Study ◽  
Pnh Clone

The association of paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia (AA) raises the yet unresolved questions as to whether these two disorders are different forms of the same disease. We compared two groups of patients with respect to cytogenetic features, glycosylphosphatidylinositol (GPI)-linked protein expression, protein C/protein S/thrombomodulin/antithrombin III activity, and PIG-A gene expression. The first group consisted of eight patients with PNH (defined as positive Ham and sucrose tests at diagnosis), and the second, 37 patients with AA. Twelve patients with AA later developed a PNH clone. Monoclonal antibodies used to study GPI-linked protein expression (CD14 [on monocytes], CD16 [on neutrophils], CD48 [on lymphocytes and monocytes], CD67 [on neutrophils and eosinophils], and, more recently, CD55, CD58, and CD59 [on erythrocytes]) were also tested on a cohort of 20 normal subjects and five patients with constitutional AA. Ham and sucrose tests were performed on the same day as flow- cytometric analysis. Six of 12 patients with AA, who secondarily developed a PNH clone, had clinical symptoms, while all eight patients with PNH had pancytopenia and/or thrombosis and/or hemolytic anemia. Cytogenetic features were normal in all but two patients. Proteins C and S, thrombomodulin, and antithrombin III levels were within the normal range in patients with PNH and in those with AA (with or without a PNH clone). In patients with PNH, CD16 and CD67 expression were deficient in 78% to 98% of the cells and CD14 in 76% to 100%. By comparison, a GPI-linked defect was detected in 13 patients with AA, affecting a mean of 32% and 33% of CD16/CD67 and CD14 cell populations, respectively. Two of three tested patients with PNH and 1 of 12 patients with AA had a defect in the CD48 lymphocyte population. In a follow-up study of our patient cohort, we used the GPI-linked molecules on granulocytes and monocytes investigated earlier and added the study of CD55, CD58, and CD59 on erythrocytes. Two patients with PNH and 14 with AA were studied for 6 to 13 months after the initial study. Among patients with AA, four in whom no GPI-anchoring defect was detected in the first study had no defect in follow-up studies of all blood-cell subsets (including erythrocytes). Analysis of granulocytes, monocytes, and erythrocytes was performed in 7 of 13 AA patients in whom affected monocytes and granulocytes were previously detected. A GPI-anchoring defect was detected on erythrocytes in five of six.(ABSTRACT TRUNCATED AT 400 WORDS)

Clinical Course and Flow Cytometric Analysis of Paroxysmal Nocturnal Hemoglobinuria in the United States and Japan

Medicine ◽  
2004 ◽  
Vol 83 (3) ◽  
pp. 193-207 ◽  
Author(s):  
Jun-Ichi Nishimura ◽  
Yuzuru Kanakura ◽  
Russell E. Ware ◽  
Tsutomu Shichishima ◽  
Hideki Nakakuma ◽  
...  
Keyword(s):  
United States ◽  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Clinical Course ◽  
Flow Cytometric Analysis ◽  
The United States ◽  
Flow Cytometric

Characteristics of De Novo Acute Leukemia Patients with Glycosylphosphatidylinositol (GPI) Protein-Negative Population of Leukemic Cells.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4462-4462
Author(s):  
Hideyoshi Noji ◽  
Tsutomu Shichishima ◽  
Masatoshi Okamoto ◽  
Kazuhiko Ikeda ◽  
Akiko Nakamura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Acute Leukemia ◽  
De Novo ◽  
Bone Marrow Failure ◽  
Flow Cytometric Analysis ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Color Flow ◽  
Flow Cytometric ◽  
Number Of Patients

Abstract Paroxysmal nocturnal hemoglobinuria (PNH) is considered to be an acquired stem cell disorder affecting all hematopoietic lineages, which lack GPI-anchored membrane proteins, such as CD59, because of abnormalities in the phosphatidylinositol glycan-class A (PIG-A) gene. Also, PNH is one disorder of bone marrow failure syndromes, including aplastic anemia and myelodysplastic syndrome, which are considered as pre-leukemic states. In this study, to know some characteristics of patients with de novo acute leukemia, we investigated expression of CD59 in leukemic cells from 25 patients (female: male=8: 17; mean age ± standard deviation, 57.8 ± 19.5 years) with de novo acute leukemia by single-color flow cytometric analysis. In addition, the PIG-A gene from CD59− leukemic cells sorted by FACS Vantage in 3 patients with acute leukemia was examined by sequence analysis. All the patients had no past history of PNH. Based on the French-American-British criteria, the diagnosis and subtypes of acute leukemia were determined. The number of patients with subtypes M1, M2, M3, M4, M5, and M7 was 1, 14, 2, 4, 2, and 2, respectively. Two of the patients were classified into acute myeloid leukemia with trilineage myelodysplasia from morphological findings in bone marrow. Chromosomal analyses presented abnormal karyotypes in 14 of 25 patients. Flow cytometric analyses showed that leukemic cells from 16 of 25 patients (64%) had negative populations of CD59 expression and the proportion of the populations was 63.3 ± 25.7%, suggesting the possibility that CD59− leukemic cells from patients with de novo acute leukemia might be derived from PNH clones. In fact, the PIG-A gene analyses showed that monoclonal or oligoclonal PIG-A mutations in coding region were found in leukemic cells from 3 patients with CD59− leukemic cells and all of the clones with the PIG-A mutations were minor. Then, various clinical parameters, including rate of complete remission for remission-induction chemotherapy, peripheral blood, bone marrow blood, and laboratory findings, and results of chromosomal analyses were statistically compared between 2 groups of patients with (n=16) and without (n=9) CD59− leukemic cells. The reticulocyte counts (10.5 ± 13.0 x 104/μl) and proportions of bone marrow erythroblasts (17.5 ± 13.9%) in patients with only CD59+ leukemic cells were significantly higher than those (2.5 ± 1.7 x 104/μl, p<0.05; and 5.6 ± 6.2%, p<0.01, respectively) in patients with CD59− leukemic cells. The proportions of bone marrow blasts (69.3 ± 21.1%) in patients with CD59− leukemic cells were significantly higher than those (45.5 ± 19.3%, p<0.02) in patients with only CD59+ leukemic cells. In conclusion, our findings indicate that leukemic cells derived from PNH clones may be common in de novo acute leukemia patients, suggesting that bone marrow failure may have already occurred in localized bone marrow even in de novo acute leukemia.

Paroxysmal Nocturnal Hemoglobinuria Assessment by Flow Cytometric Analysis

2017 ◽  
Vol 37 (4) ◽  
pp. 855-867 ◽  
Author(s):  
Mike Keeney ◽  
Andrea Illingworth ◽  
D. Robert Sutherland
Keyword(s):  
Paroxysmal Nocturnal Hemoglobinuria ◽  
Flow Cytometric Analysis ◽  
Flow Cytometric
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