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Mixed Myelodysplastic–Myeloproliferative Neoplasms
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
Granulocytic precursors (promyelocytes, myelocytes, and metamyelocytes) comprise ≥10%, basophils <2%, and monocytes <10% of WBCs. Granulocytic cells display dysplastic features, most often in the form of acquired Pelger–Huët abnormality, clumped nuclear chromatin, bizarrely segmented nuclei, binucleated cells, hypogranularity, and/or abnormal cytoplasmic hypergranularity (Figure 33.10). In a series reported by Xubo et al. [49], the percentage of blasts, nucleated erythrocytes, monocytes, eosinophils, and basophils was 2.45% (±2), 7.8% (±2.9), 1.3% (±1.2), 1.5% (±1.6), and 1.2% (±1), respectively. Megakaryocytes often show atypia in the form of nonlobulated nuclei. Red cell precursors often show dyserythropoiesis.
Physiology and Disorders of Human Bilirubin Metabolism
Published in Karel P. M. Heirwegh, Stanley B. Brown, Bilirubin, 1982
P. Berthelot, Ph. Duvaldestin, J. Fevery
Dyserythropoiesis16,17 can be defined as ineffective erythrocyte production due to abnormalities in the development of erythroblasts together with intramedullary destruction of these abnormal erythroblasts and to rapid destruction of abnormal red blood cells once they are released in the circulation. Apparently, there is a discrepancy between the release of erythrocytes in the blood and the greatly augmented production in the bone marrow. The latter is ineffective because of arrests in one of the phases of the mitotic cycles or of a decreased number of cell divisions. Clinically, the excessive heme breakdown resulting from intramedullary and peripheral destruction of abnormal cells leads to unconjugated hyperbilirubinemia, apparent before the age of 20 years, and to subsequent development of slight hepatomegaly, splenomegaly, gallstones, and iron storage disease (secondary hemochromatosis). Dyserythropoiesis can be primary (congenital dyserythropoiesis, Table 3) or secondary to deficiency of vita-mine B12, folic acid or iron, or to sideroblastic anemia’s. It is also seen in defects of heme or globin synthesis, in hemoglobinopathies and thalassemia, and in other diseases such as paroxysmal nocturnal hemoglobinuria, aplastic anemia, myelosclerosis, etc.
Liver Diseases
Published in George Feuer, Felix A. de la Iglesia, Molecular Biochemistry of Human Disease, 2020
George Feuer, Felix A. de la Iglesia
Minor amounts of bilirubin are derived from direct synthesis and from the degradation of a number of nonhemoglobin tetrapyrrole compounds such as myoglobin and cytochromes. Using labeled precursor of heme synthesis, 15 N-glycine, most of the label appeared in fecal stercobilin at the end of the normal 120 d life of the erythrocytes.220,363 Moreover, two stercobilin components were also present at earlier intervals, at 10 d and between 20 to 100 d after isotope administration. This indicates the contribution of other hemes to the total bile pigment or the de novo synthesis of bilirubin. The amount of stercobilins is twice as much in newborns as compared with adults, and it is highly elevated in various disorders of erythrocyte formation such as pernicious anemia, thalassemia minor and erythropoietic porphyria. In these diseases, the early components take up about 80% of the total excreted stercobilin as compared with 10% of the total in normals. In contrast, the extent of the labeling in the circulating hemoglobin, protoporphyrin, and breakdown products is greatly reduced. These disorders are related to the ineffective production of red blood cells, or dyserythropoiesis.221 In these circumstances, young cells appear in the circulation which are rapidly destroyed and their metabolites probably contribute to the early pigment. In man, when bone marrow activity is stimulated by bleeding, the initial peak is increased. Investigations of a family showing enhanced bile pigment production, but normal erythrocyte formation and breakdown, revealed a large increase of the early fecal stercobilin component. In a patient suffering from the condition of idiopathic dyserythropoietic jaundice, an early labeling of fecal urobilin was apparent with low incorporation rate in hemoglobin protoporphyrin. In general, the more ineffective the erythrocyte formation, the more marked is the disproportion between the increase of early labeled component and the decrease of bile pigment derived from the circulating hemoglobin. This impairment indicates a shift away from the normal erythrocyte toward earlier pathways. This concept is supported by the study of a patient with aplastic anemia. The labeled glycine was not incorporated into the hemoglobin of the circulating red blood cells, although the rate of incorporation into fecal stercobilin was normal or increased, suggesting that the early bile pigment originated outside the bone marrow.
Emerging therapies in β-thalassemia: toward a new era in management
Published in Expert Opinion on Emerging Drugs, 2020
Rayan Bou-Fakhredin, Rami Tabbikha, Hisham Daadaa, Ali T. Taher
Additional data for gene therapy in TDT patients came from the HGB-204 and HGB-205 trials (ClinicalTrials.gov numbers, NCT01745120 and NCT02151526). In these two trials, autologous CD34+ cells were obtained from 22 TDT patients and the cells were transduced ex vivo with LentiGlobin BB305 vector. Patients received a 12.8 mg/kg of myeloablative busulfan followed by 5.2 to 18.1 CD34+ BB305+ cells/kg [52]. The transduction VCN was 0.7 copies. Approximately 26 months after the infusion process, almost all patients with a non-β0/β0 genotype stopped receiving transfusions [52]. Moreover, all biologic markers of dyserythropoiesis were corrected. The median annual transfusion volume decreased by 73% in 9 patients with a β0/β0 genotype, and transfusions were discontinued in 3 patients [52]. Adverse events from the treatment were similar to those associated with autologous stem-cell transplantation. The HGB 212 and HGB 207 trials (ClinicalTrials.gov numbers NCT03207009 and NCT02906202) are currently ongoing phase III studies using the BB305 vector for TDT subjects with a β0/β0 genotype and non-β0/β0 genotypes.
Characteristics of bone marrow cell dysplasia and its effectiveness in diagnosing myelodysplastic syndrome
Published in Hematology, 2018
Chujia Liang, Junxun Li, Jing Cheng, Shaoqian Chen, Zhuangjian Ye, Fan Zhang, Zhe Wang, Fang Wang, Cheng Peng, Juan Ouyang
Combine with the empirical observation, we considered that (1) dyserythropoiesis were relatively common in both MDS and non-clonal anemia. However, some specific dysplastic types possess a relatively higher incidence rate in MDS but relatively low in non-clonal anemia. Therefore, if the dysplastic rate of such kind of specific dysplastic types exceeds a certain threshold; they have a great significance to make a definite diagnosis for MDS. (2) Although the incidence rates of dysgranulopoiesis and dysmegakaryopoiesis were relatively lower either in clonal disorders or non-clonal anemia, such kind of specific dysplastic types as pseudo-Pelger-Huet in dysgranulopoiesis and lymphoid small megakaryocyte in dysmegakaryopoiesis, due to their higher occurrence frequency in MDS, once they occur, they make a great contribution to the diagnosis of MDS. That is, whenever these specific dysplastic types occurred, MDS should be highly considered. Accordingly, we can infer that, if the bone marrow cell of a patient presents any petal nucleus and internuclear bridging in dyserythropoiesis, pseudo-Pelger-Huet in dysgranulopoiesis, or lymphoid small megakaryocyte in dysmegakaryopoiesis, and their corresponding percentages are greater than 0.015, 0.005, 0.025 and 0.005, respectively; it may be considered that the dysplasia does exist, and the patient is more likely to be diagnosed as MDS with a FPR lower than 1 × 10−4.
ZRSR2 mutation in a child with refractory macrocytic anemia and Down Syndrome
Published in Pediatric Hematology and Oncology, 2019
Meghna Srinath, Emily Coberly, Kimberly Ebersol, Kirstin Binz, Katsiaryna Laziuk, William T. Gunning, Barbara Gruner, Richard Hammer, Bindu Kanathezhath Sathi
This is a case of transfusion-dependent macrocytic anemia in a child with Trisomy 21 and ZRSR2 spliceosomal mutation. The exact role of DS in this patient’s disease is not fully understood. It is possible that Trisomy 21 may be necessary for the ZRSR2 mutation to produce the effect seen here.15 There was no evidence of dyserythropoiesis, dysplasia or other clonal cytogenetic changes in the bone marrow, and investigations for known congenital bone marrow failure syndromes, mitochondrial disorders and metabolic derangements were negative. Additionally, the child’s mother was found to have normal blood counts and tested negative for the ZRSR2 mutation. This finding supports that the mutation was likely somatic, not germline, in nature.