Failure Of Red Cell Production Research Articles

The oral iron chelator deferasirox inhibits NF-κB mediated gene expression without impacting on proximal activation: implications for myelodysplasia and aplastic anaemia.

The myelodysplastic syndromes (MDS) are a group of disorders characterized by ineffective haematopoiesis, bone marrow dysplasia and cytopenias. Failure of red cell production often results in transfusion dependency with subsequent iron loading requiring iron chelation in lower risk patients. Consistent with previous reports, we have observed haematopoietic improvement in a cohort of patients treated with the oral iron chelator deferasirox (DFX). It has been postulated that MDS patients have a pro-inflammatory bone marrow environment with increased numbers of activated T cells producing elevated levels of tumour necrosis factor (TNF), which is detrimental to normal haematopoiesis. We demonstrate that DFX inhibits nuclear factor (NF)-κB dependent transcription without affecting its proximal activation, resulting in reduced TNF production from T cells stimulated in vitro. These results suggest that the haematopoietic improvement observed in DFX-treated patients may reflect an anti-inflammatory effect, mediated through inhibition of the transcription factor NF-κB and support the therapeutic targeting of this pathway, which is aberrantly activated in a large proportion of haematological malignancies.

Cells depleted for RPS19, a protein associated with Diamond Blackfan Anemia, show defects in 18S ribosomal RNA synthesis and small ribosomal subunit production

The gene encoding the small subunit ribosomal protein 19 (RPS19) is mutated in about 25% of cases of the bone marrow failure syndrome Diamond Blackfan Anemia (DBA), a childhood disease characterized by failure of red cell production. In these cases DBA is inherited as an autosomal dominant trait and RPS19 haploinsufficiency is thought to cause the disease. To study the molecular pathogenesis of DBA we used siRNA to decrease the level of RPS19 in two human cell lines, HeLa cells and U-2 OS osteosarcoma cells. Cells with reduced RPS19 levels showed a dramatic reduction in the amounts of small 40S ribosome subunits and mature 80S ribosomes and an excess of large 60S subunits. These cells were defective in 18S rRNA production and accumulated 21S and 20S nuclear pre-rRNA molecules, suggesting that RPS19 is required for specific steps in rRNA processing. RPS19 depletion produced a reduction in steady-state levels of RPS6 and RPS16 via a post-transcriptional mechanism while the levels of RPL7 and RPL26 were unaltered, indicating that levels of ribosomal proteins are determined by subunit assembly. This has interesting implications for the pathogenesis of DBA suggesting that deficiency of any of the RPS proteins might have a similar effect and thus may be responsible for causing DBA. Finally in cell lines from DBA patients with mutations we find increased levels of 21S rRNA precursors but no abnormality in the ribosome profile on sucrose gradients or in the steady-state levels of RPS19 suggesting that some cells can partially compensate for the loss of one allele of RPS19. We conclude that defects in ribosome biogenesis may underlie the pathology of Diamond Blackfan Anemia.

Anemia in the newborn.

In neonatal period anemia is a complex problem owing to the unique blood picture. The erythrocytic system undergoes serial adaptation to meet progressively changing demands of oxygen in the embryo, the fetus and neonate. This leads to rapid change in normal hematological change in post-birth period. Definition of anemia is difficult because as described earlier, several important factors influence normal blood in the newborn infants. The etiology of neonatal anemia can be classified into i) hemorrhage (ii) hemolysis (iii) failure of red cell production. Severe fetal hemorrhage may accompany various placental anomalies like placenta praevia, abruptio placenta and accidental incision of placenta during the caesarian section. It is reported that 10% of all infants born following placenta praevia and 4% of infants born following abruptio placenta present with severe anemia. The passage of fetal erythrocytes in maternal circulation occurs commonly during pregnancy. In 50% of pregnancies some fetal cells are passed in maternal circulation sometimes during gestation or during birth process. Treatment of a neonate with anemia due to blood depends on the degree of hypovolemia or anemia and whether the blood loss has been acute or chronic. Newborn with pale skin should be differentiated from an asphyxiated baby.

Investigation of anaemia in dogs

ANAEMIA is a common presenting sign in veterinary practice and is defined as a decrease in red blood cells (erythrocytes) or a decrease in haemoglobin concentration. It can result from...

Physiologic sequelae of prematurity: The nurse practitioner's role Part IV. Anemia

Anemia in the immediate newborn period may be caused by hemolysis, by a failure of red-cell production, or by a combination of both. However, anemia of prematurity often is the result of hemolysis, of a lack of erythropoietin, and/or of nutritional deficits. Transfusion without a search for the cause may obscure the underlying pathology of the anemia. Because severe anemia can be life-threatening, prompt diagnosis and treatment are required. In this article, the fourth of a series of articles on the sequelae of prematurity, a discussion of the pathophysiology, signs and symptoms, data collection, treatment modalities pertinent to the anemia of prematurity, and parental education are discussed.

Effect of Intermittent Hypoxia on Regeneration of Haemopoiesis in Rats Treated with Cyclophosphamide or Total Body Irradiation

Effects of intermittent hypoxia on regeneration of haemopoiesis in rats treated with cyclophosphamide or total body irradiation are described. The rats were exposed to a gas mixture consisting of 10 per cent oxygen and 90 per cent nitrogen within half‐an‐hour after treatment. The exposure to hypoxia lasted for SV2 hours daily. The irradiated and cyclophosphamide treated animals differed markedly in their response to hypoxia. Thus, in the cyclophosphamide treated animals hypoxia induced a steady increase in red cell production following the initial stop in erythropoiesis caused by the treatment. In contrast, in the irradiated rats recovery was more slow and furthermore, a second failure of erythropoiesis occurred during recovery. This second failure of red cell production coincided with the second failure of the myelopoiesis in the same animals. Although total body irradiation and cyclophosphamide treatment caused initially about the same extent of marrow hypoplasia, the present results indicate that irradiation caused more damage to the stem cells than did cyclophosphamide.

RETICULOCYTOPENIA IN SICKLE CELL DISEASE. APLASTIC EPISODES IN THE COURSE OF SICKLE CELL DISEASE IN CHILDREN.

Temporary failure of red cell production has been well documented in hematologically normal persons, usually in association with infection, allergy, or a toxin. 1,2 The brief duration of these episodes (seven to 14 days) in comparison to the relatively long life span of the normal erythrocyte (120 days) results in only a mild, transient, and usually unimportant drop in hemoglobin concentration. The same temporary failure in a patient with a congenital hemolytic anemia, on the other hand, is a dramatic event. In sickle cell disease, where the mean red cell life span has been estimated to range from 6 to 21.5 days 3,4 the same aplastic episode can result in a precipitous fall in hemoglobin to as low as half the steady state level over a two to seven day period. Thus a child who has maintained his hemoglobin at 6 gm% by a continuous brisk reticulocytosis may present with

Anemia in macroglobulinemia

Erythrokinetic and red cell survival studies were performed in ten patients with macroglobulinemia. Inadequate red cell synthesis, decreased erythrocyte survival and iron deficiency, alone or in combination, were responsible for anemia in eight of these patients. In six patients there was a relative failure of red cell production with inadequate compensation for excessive red cell destruction. In two patients there was an absolute failure of erythropoiesis with functional aplasia. No simple correlation between rate of erythropoiesis and serum gamma macroglobulin concentration was evident. Shortened erythrocyte life span was found in eight of the ten patients and was most prominent in those with active disease. Serial studies before and after plasmapheresis in two patients showed that reduction of serum viscosity and macroglobulin level was associated with increased red cell survival. Causes of shortened erythrocyte survival included bleeding disorders, Coombs' positive hemolytic anemia and erythrocyte sequestration by the spleen. Two patients had advanced iron deficiency and four had evidence of early iron deficiency. Depletion of body iron stores usually could be related to external blood loss. The typical features of iron depletion were present when iron deficiency was advanced. Therapy of anemia in these patients consisted of plasmapheresis with or without chemotherapy for disease manifestations associated with high serum viscosity, corticosteroids when immune hemolysis was demonstrable, and iron for iron deficiency.