Iron Overload in an African American Woman with SS Hemoglobinopathy and a Promoter Mutation in the X-Linked Erythroid-Specific 5-Aminolevulinate Synthase (ALAS2) Gene.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3683-3683
Author(s):  
James C. Barton ◽  
Pauline L. Lee ◽  
Luigi F. Bertoli ◽  
Ernest Beutler
Keyword(s):  
Iron Overload ◽  
Promoter Region ◽  
African American Woman ◽  
American Woman ◽  
Erythrocyte Transfusion ◽  
Promoter Mutation ◽  
Ineffective Erythropoiesis ◽  
Sideroblastic Anemia ◽  
Iron Supplements ◽  
Erythroid Precursors

Abstract Iron overload in African Americans unexplained by erythrocyte transfusion has been reported in a woman with sickle cell anemia (Castro et al., Blood (1998) 92 (suppl):13b) and in a woman with undefined mild anemia (Hitender et al., Am J Gastroenterol (2000) 95:2580). We evaluated a 41 year-old African American woman with sickle cell disease referred for management of congestive heart failure and recurrent stroke. She had received four units of erythrocyte transfusion over her lifetime, and had taken oral iron supplements intermittently for many years. Hemoglobin (Hb) was 7.6 g/dL, MCV 94 fL, MCH 20.7 pg, and RDW 23.3%. Erythrocyte MCV histogram revealed a small, distinct subpopulation of microcytes, but was also shifted right due to reticulocytosis (18.2%). Electrophoresis revealed 96.9% Hb S and 3.1% Hb A2. Transferrin saturation (TfSat) was 52%; serum ferritin (SF) was 1,362–3,065 ng/mL (4 measurements) without explanation other than iron overload. Serum transaminase levels were elevated. She declined liver biopsy. A desferrioxamine (DFO) urinary iron excretion test revealed 3,249 μg urinary Fe/24 h (reference range 100–300 μg urinary Fe/24 h). Thereafter, she took subcutaneous infusions of DFO five days weekly with fair compliance; other treatment included exchange transfusions (for management of strokes), hydroxyurea, and folic acid. Supplemental iron use was discontinued. Congestive heart failure improved; serum transaminase levels returned to normal. After 5.5 years of DFO infusions, SF was 561 ng/mL. We evaluated her iron-associated genes for pertinent mutations using denaturing high-performance liquid chromatography (dHPLC) and complete sequencing. She is heterozygous for a proximal promoter region mutation of ALAS2: C to G transversion at nucleotide −206 from the transcription start site, as defined by primer extension. HFE coding region mutations, including C282Y and H63D, were not detected; HFE alleles IVS4-44 C→T and IVS5-46 C→T were present. No single-nucleotide polymorphisms were detected in TFR2 (exons 2, 3; 5-13). This ALAS2 promoter mutation was first described in a Welsh family in which the heterozygous female proband had mild sideroblastic anemia, microcytosis, elevated TfSat and SF, and 87% reduction of ALAS2 mRNA in erythroid precursors, and had taken much supplemental iron (Bekri et al., Blood (2003) 102:698). Peto et al. reported that iron overload due to ineffective erythropoiesis in females heterozygous for X-linked sideroblastic anemia may be severe even when anemia is mild (Lancet (1983) 1:375). In women heterozygous for ALAS2 mutations, we propose that erythroid precursors without an ALAS2 mutation may sustain normal or near-normal levels of circulating erythrocytes and Hb, while erythroid precursors with an ALAS2 mutation stimulate iron absorption due to ineffective erythropoiesis and cause iron overload. In the present case, anemia due to the ALAS2 promoter mutation was partially masked by concurrent SS hemoglobinopathy, and iron overload was likely exacerbated by erythrocyte transfusion and iron supplements. We conclude that an ALAS2 promoter region mutation partly accounts for iron overload in the present patient with SS hemoglobinopathy, and that this or other ALAS2 mutations could explain the occurrence of non-transfusion iron overload in other African Americans with chronic anemia.

The Red Cell: How Erythropoiesis Modulates Hepcidin Expression

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. SCI-24-SCI-24
Author(s):  
Yelena Ginzburg
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Iron Metabolism ◽  
Conflicts Of Interest ◽  
Peptide Hormone ◽  
Well Being ◽  
Iron Loading ◽  
Ineffective Erythropoiesis ◽  
Hepcidin Expression ◽  
Erythroid Precursors

Abstract Abstract SCI-24 Erythroid precursors in the bone marrow require transferrin-bound iron for hemoglobin synthesis. Therefore, it is not surprising that the regulation of erythropoiesis and iron metabolism is interlinked. Iron demand for erythropoiesis is communicated to the iron-regulatory machinery through incompletely understood mechanisms. At the core of systemic iron homeostasis is the peptide hormone hepcidin, restricting cellular iron export to plasma by inducing the endocytosis and proteolysis of ferroportin. Hepcidin, a liver-synthesized peptide hormone, is released in response to increased iron load, and there is early evidence that circulating hepcidin concentrations affect the distribution of iron between the macrophage storage compartment (favored by higher hepcidin concentrations) and parenchymal cells, including cardiac myocytes and hepatocytes (favored by low hepcidin). Furthermore, ferroportin has recently been identified on erythroid precursors. Its purpose in this cell type and its function in the interface between erythropoiesis and iron metabolism are unclear. Additionally, in response to bleeding or the administration of erythropoietin, expansion of erythroid precursors suppresses hepcidin, most likely through one or more mediators released by the bone marrow and acting on hepatocytes. Iron-loading anemias with ineffective erythropoiesis, in particular β-thalassemia, demonstrate the effects of pathological “erythroid regulators” of hepcidin. Although erythrocyte transfusions are the main cause of iron loading in patients who receive them (β-thalassemia major), lethal iron overload is seen also in patients who are rarely or never transfused (β-thalassemia intermedia). Here, iron hyperabsorption is the cause of iron overload and, as in hereditary hemochromatosis, is caused by low hepcidin. Decreased hepcidin expression in β-thalassemia, with concurrent ineffective erythropoiesis and iron overload, indicates that the “erythroid regulator” may play an even more substantial role in iron metabolism than the “stores regulator.” Two members of the bone morphogenetic protein (BMP) family, growth differentiation factor (GDF) 15 and Twisted Gastrulation (TWSG1), have been implicated as candidate bone marrow-derived hepcidin suppressors in β-thalassemia. Neither factor is responsible for the physiologic hepcidin suppression in response to hemorrhage-induced stress erythropoiesis, and the physiologic suppressor is not known. We focus here on the current state of knowledge regarding the regulation of iron metabolism and attempt to elucidate the interface between iron regulation and erythropoiesis using evidence in part derived from animal models of β-thalassemia. A more complete understanding of the coregulation of erythropoiesis and iron metabolism may lay the foundation for improving diagnosis, increasing treatment options, and ultimately impacting the well-being of patients afflicted with different anemias and/or iron overload related-disorders. Disclosures: No relevant conflicts of interest to declare.

Characteristic Macrocytic Anemia, Ineffective Erythropoiesis, and Iron Overload in 5q-Mice and Effect of Exogenous Transferrin

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2846-2846
Author(s):  
Maria Feola ◽  
Tenzin Choesang ◽  
Weili Bao ◽  
Li Huihui ◽  
Huiyong Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Late Stage ◽  
Macrocytic Anemia ◽  
Cellular Damage ◽  
Lower Percentage ◽  
Intermediate Risk ◽  
Ineffective Erythropoiesis ◽  
Transfusion Requirements ◽  
Erythroid Precursors

Abstract Low/intermediate risk myelodysplastic syndromes (MDS) is associated with relatively longer survival and high transfusion requirements, resulting in secondary iron overload. Iron overload is an independent variable associated with poor prognosis, impacting survival, and iron chelation therapy is associated with prolonged survival in transfusion-dependent MDS patients. We have previously shown that exogenous transferrin (Tf) results in more circulating red blood cells (RBCs), increased hemoglobin (Hb), reversal of splenomegaly, and improvement in ineffective erythropoiesis in β-thalassemic mice (Li Nat Med 2010) and recently demonstrate that erythroferrone (ERFE), a newly described physiologic erythroid regulator of hepcidin, is normalized in Tf-treated β-thalassemic mice (Chen, manuscript in review). We postulate that ineffective erythropoiesis in β-thalassemia shares many characteristics with that of low risk MDS, such as defective erythroid differentiation, anemia, splenomegaly, and systemic iron overload, suggesting that similar effects of exogenous Tf may be relevant also in MDS. Partial deletion of chromosome 5, 5q-syndrome, is the most common cytogenetic abnormality in low/intermediate risk MDS. We characterize a mouse model of 5q-syndrome, Cd74+/lox Nid67+/lox, Lmo2Cre+ mice (5q-mice) (Barlow Nat Med 2010). Our findings reveal that 5q-mice exhibit macrocytic anemia (Hb 6 vs. 12 g/dL, P<0.0001; MCV 61 vs. 48 fL, P<0.0001), splenomegaly (0.007 vs. 0.003 spleen/body weight, P<0.0001), extramedullary hematopoiesis in the liver (Fig 1A), expanded erythropoiesis in spleen (Fig 1B), and a lower percentage of erythroid precursors in the bone marrow (Fig 1C) despite increased serum erythropoietin (79 vs. 0.4 pg/L, P=0.04). Furthermore, 5q-mice exhibit evidence of iron overload relative to WT mice with increased Tf saturation (70 vs. 39%, P=0.004) and liver iron stores (1.0 vs. 0.3 mg iron/g liver weight, P=0.001). Although no difference in liver hepcidin expression or serum hepcidin concentration is evident (Fig 2A and 2B), bone marrow ERFE expression is increased (14-fold, P=0.002) and a trend toward decreased hepcidin:liver iron is observed in 5q- relative to WT mice (Fig 2C). We hypothesize that the effect of exogenous Tf applies to 5q- as β-thalassemic mice in light of similarities in disease characteristics. Using bone marrow transplantation to generate a cohort of 5q- mice with similar disease severity, 8x10^6 cells from 2 month old 5q- mice were transplanted into a cohort of sub-lethally irradiated 8 week old WT mice. Transplanted mice were allowed to recover and started Tf injections IP (10mg/day or equal volume PBS (200 uL) 2 weeks post-transplant. After completing 20 days of injection, mice were sacrificed and all erythroid- and iron-related parameters analyzed. Tf-treated 5q- mice exhibit statistically increased RBC count (10 vs. 8 x10^6 cells/uL, P<0.0001) and lower MCV (41 vs. 53 fL, P<0.0001) and MCH (12 vs. 16 pg, P<0.0001) compared to PBS injected 5q- mice. Results demonstrate an increase in reticulocyte count (676 vs. 477 x 10^9 cells/L, P=0.003) and platelet count (549 vs. 364 x 10^3 cells/ul, P=0.02) in the circulation and an increase in orthochromatophilic erythroblasts (19.3 vs. 16.1%, P=0.04) and reticulocytes (32.8 vs. 26.6%, P=0.04) in the bone marrow, without changes in Erfe expression. Although TfR1 mRNA expression is unchanged, membrane TfR1 MFI is increased in late stage erythroid precursors in both bone marrow (11 vs. 7 x 10^3 MFI, P=0.01) and spleen (16 vs. 12 x 10^3 MFI, P<0.05) from Tf-treated relative to PBS injected 5q-mice. Interestingly, intracellular ROS is increased in late stage splenic erythroid precursors from Tf-treated relative to PBS injected 5q-mice. Although increased ROS levels result in cellular damage, emerging evidence suggests that ROS is required for normal hematopoiesis, such that high ROS states are associated with differentiating HSCs. Taken together, our data demonstrates erythropoiesis- and iron-related characteristics of 5q- mice consistent with human disease. Although these preliminary experiments using exogenous Tf reveal no increase in Hb, improved ineffective erythropoiesis, or reversal of iron overload, our data suggests that TfR1 and ROS are intimately involved in the effect of exogenous Tf in erythropoiesis. Disclosures No relevant conflicts of interest to declare.

Down-Regulation of TfR1 Increases Erythroid Precursor Enucleation and Hepatocyte Hepcidin Expression in ß-Thalassemic Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 754-754
Author(s):  
Huihui Li ◽  
Tenzin Choesang ◽  
Weili Bao ◽  
Lionel Blanc ◽  
Huiyong Chen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Critical Role ◽  
Nuclear Fraction ◽  
Double Heterozygote ◽  
Ineffective Erythropoiesis ◽  
Liver Iron ◽  
Erythroid Precursor ◽  
Erythroid Precursors ◽  
Serum Hepcidin

Abstract Transferrin-bound iron binding to transferrin receptor 1 (TfR1) is essential for erythropoiesis, and TfR1 is found in highest concentrations on erythroid precursors due to high iron requirement for hemoglobin (Hb) synthesis. Diseases of ineffective erythropoiesis such as β-thalassemia, are characterized by anemia, expanded and extramedullary erythropoiesis, and iron overload. Iron overload results from insufficient hepcidin, a peptide hormone secreted by hepatocytes in response to iron load. In β-thalassemia, hepcidin is relatively suppressed as a consequence of erythroid expansion. Erythroferrone (ERFE), a recently described erythroid-derived hepcidin suppressor, has been proposed as the mechanism and found in higher concentration in bone marrow of β-thalassemic mice. We previous demonstrate that exogenous transferrin (Tf) ameliorates anemia in β-thalassemic mice, reversing splenomegaly, hepcidin suppression, and iron overload and recently confirmed a decrease in Erfe expression in erythroid precursors from Tf-treated β-thalassemic mice. We observed that although Tf-treated β-thalassemic mice exhibit a further decrease in MCV and MCH, suggesting a relatively more iron restricted erythropoiesis, TfR1 expression is decreased. We hypothesize that TfR1 is central to Tf's effect on erythropoiesis in β-thalassemic mice. Last year, we presented our analysis of th3/+ TfR1+/- double heterozygote mice which exhibit reversal of all erythropoiesis- and iron-related pathology in th3/+ mice, confirming our observations in Tf-treated β-thalassemic mice and further supporting our hypothesis. To evaluate the mechanism involved, we observed that despite suppressed TfR1 concentration in reticulocyte (P=0.006) and sorted bone marrow erythroid precursors (P=0.0004) from Tf-treated th1/th1 mice, cell surface TfR1 expression decreased on reticulocytes (P=0.003) but was surprisingly increased on late stage erythroid precursors (P=0.007) (Figure 1A), suggesting that exogenous Tf influences erythroid precursor enucleation. Because we previously demonstrate decreased serum soluble TfR1 in Tf-treated th1/th1 mice [Liu J Blood 2013], we hypothesize that exogenous Tf alters TfR1 shedding from erythroid precursor membranes, promoting enucleation and improved terminal differentiation. We observed decreased enucleation using syto60 in flow cytometry of fetal liver cells (FLC) from th3/+ relative to wild type (WT) embryos (35 vs. 51%, P=0.03) which is normalized by exposure of th3/+ FLCs to Tf in vitro (58 vs. 41%, P=0.001) (Figure 1B). Tf-treated th3/+ FLCs shed more TfR1 to the nuclear fraction relative to reticulocyte during enucleation (P=0.0001) (Figure 1C). Furthermore, enucleation isdecreased in vivo in th3/+ relative to WT FLCs and peripheral blood at E14.5 and normalized in th3/+ TfR1+/- double heterozygote mice (45 vs. 35%, P=0.002) (Figure 1D). Interestingly, we analyzed iron status in TfR1+/- mice revealing that serum hepcidin is increased relative to WT (323 vs. 190 ng/ml, P=0.04) despite minimally decreased serum and liver iron concentrations (no statistically significant differences) and increased Erfe expression in erythroid precursors (5-fold, P=0.04). Relative to th3/+ mice, double heterozygote mice exhibit decreased serum iron (94 vs. 133 ug/dl), non-heme liver iron (0.31 vs. 0.74 mg iron/g dry weight, P=0.02), and Erfe expression (0.3-fold, P=0.04). Although no difference is observed between double heterozygote mice and th3/+, serum hepcidin is significantly increased in double heterozygote mice compare to WT (392 vs. 190 ng/ml, P=0.01), suggesting a more appropriate hepcidin response to iron overload (Figure 1E). Taken together, we postulate that decreased TfR1 expression plays a critical role in reversing ineffective erythropoiesis by increasing enucleation and influences hepcidin regulation in an ERFE independent manner. Disclosures No relevant conflicts of interest to declare.

Apotransferrin Injection Leads to More Effective Erythropoiesis in β-Thalassemic Mice.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 276-276
Author(s):  
Yelena Z. Ginzburg ◽  
Anne C. Rybicki ◽  
Sandra M. Suzuka ◽  
Leni von Bonsdorff ◽  
Mary E. Fabry ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Iron Overload ◽  
Binding Capacity ◽  
Globin Gene ◽  
Transferrin Saturation ◽  
Dry Weight ◽  
Ineffective Erythropoiesis ◽  
Erythroid Precursor ◽  
Hepcidin Expression ◽  
Erythroid Precursors

Abstract β-thalassemia is a disease resulting from a β-globin gene mutation which leads to less β-globin, expanded and ineffective erythropoiesis, and anemia. Additionally, mature red blood cells have a shortened survival. Although the degree of anemia varies, from severe transfusion-dependence to only an increase in iron absorption in the gut to maintain hemoglobin levels, all thalassemic patients develop some degree of iron overload. In a previous study using β-thalassemic mice, we were able to induce iron overload using iron dextran injections and demonstrated an increase in hemoglobin with increased reticulocytosis and an expansion of extramedullary erythropoiesis in the liver and spleen. The fact that iron administration reduced anemia in β-thalassemic mice was surprising. Since patients with β-thalassemia have ample iron supply, we hypothesized that part of the anemia in β-thalassemia may result from a maldistribution of iron as a consequence of insufficient circulating transferrin to deliver iron for erythropoiesis. In the present study, we analyzed the effect of intraperitoneal human apotransferrin injections on markers of hematopoiesis and iron metabolism in thalassemic mice. We used three different doses of apotransferrin - 5mg, 10mg, and 30mg - daily, for a 10 day course. Mice with β-thalassemia intermedia (Hbbth1/th1) were compared with age and gender matched control C57BL/6J mice. Although no increase in hemoglobin was observed, the reticulocyte count decreased after apotransferrin injections (2975±125 x 109 vs. 1636±130 x 109 cells/L, P=2.29 x 10−5). The efficiency of erythropoiesis, as measured by red cell to reticulocyte ratio, increased after apotransferrin injections (0.029±0.002 vs. 0.007±0.0007, P=0.0002), confirming that more red cells circulate as a result of each maturing erythroid precursor. We were able to demonstrate that apotransferrin is effective in increasing transferrin iron binding capacity (TIBC) (739.5±98.4 vs. 419.1±18.3 mg/dL, P=0.002) without changing the transferrin saturation (23.0±7.1 vs. 34.9±4.2%, P=0.15) in our mice. Apotransferrin injections also resulted in a reduction of iron deposition in the liver (5.49±0.48 vs. 11.08±1.24 mg/g dry weight, P=0.003) and heart (1.25±0.18 vs. 2.26±0.26 mg/g dry weight, P=5.7 x 10−5) of Hbbth1/th1 mice without changes in labile plasma iron levels. Using flow cytometry, we demonstrated an increase in erythroid precursors in the bone marrow of Hbbth1/th1 mice (68.7±1.5 vs. 56.5±3.96% ter119+ precursors, P=0.01) but a decrease in the spleen (41.05±3.16 vs. 60.95±8.3% ter119+ precursors, P=0.03) compared to baseline. Lastly, liver hepcidin expression was progressively suppressed with increasing transferrin dose in our mice. Taken together, this data strongly suggests that exogenous apotransferrin is able to mobilize stored iron for production of erythroid precursors in the bone marrow; this process leads to hepcidin suppression. Diseases of ineffective erythropoiesis, in which expanding erythropoiesis may be limited by the iron delivery system to maintain hemoglobin production, may be a result of insufficient transferrin and relative iron deficiency. The significance of our current findings has potential broad implications for the mobilization of stored iron for use in erythropoiesis in many diseases in which iron overload co-exists with anemia such as β-thalassemia, sideroblastic anemia, and the myelodysplastic syndromes.

scholarly journals Natural history of idiopathic refractory sideroblastic anemia

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 305-312 ◽  
Author(s):  
M Cazzola ◽  
G Barosi ◽  
PG Gobbi ◽  
R Invernizzi ◽  
A Riccardi ◽  
...  
Keyword(s):  
At Risk ◽  
Natural History ◽  
Iron Overload ◽  
Bone Marrow Failure ◽  
Blood Transfusions ◽  
Ineffective Erythropoiesis ◽  
Sideroblastic Anemia ◽  
Monosomy 7 ◽  
Risk Of Death ◽  
History Of

Abstract We analyzed the natural history of idiopathic refractory sideroblastic anemia (IRSA) in 37 patients studied between 1969 and 1986. Although erythroid abnormalities were prominent in all, 12 patients also showed involvement of the granulocytic and/or megakaryocytic cell lines, and nonrandom chromosomal aberrations were observed in five of 23 patients studied for such defects. Measurements of erythroid marrow function showed in most cases erythroid expansion with ineffective erythropoiesis. In seven patients, however, the erythroid activity was found to be inappropriately low for the degree of anemia. Transfusion dependence occurred in 26 of 37 cases. Iron overload was a common feature at presentation but produced clinical manifestations of hemochromatosis only in those patients who subsequently had a regular need for blood transfusions. Five patients progressed to bone marrow failure, and another five patients (two of whom had monosomy 7) evolved into acute nonlymphocytic leukemia (ANLL). The median survival was 72 months, with a high transfusion requirement, multilineage defects, and inappropriately low erythroid proliferation being associated with a poor prognosis. The most common causes of death were complications of iron overload and evolution into ANLL. We conclude that (a) the natural history of IRSA is characterized by an initial phase of erythroid hyperplasia and ineffective erythropoiesis, which is usually stable for many years but in a subset of patients may be followed by a phase of marrow failure with or without the later emergence of leukemic blasts; (b) peripheral blood counts, measurement of erythroid marrow function, and chromosomal analysis are useful for identifying subjects at risk of evolution into marrow failure or ANLL; and (c) IRSA patients with no need for blood transfusions are very likely to be long survivors, whereas those who become transfusion dependent are at risk of death from the complications of secondary hemochromatosis.

scholarly journals Natural history of idiopathic refractory sideroblastic anemia

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 305-312 ◽  
Author(s):  
M Cazzola ◽  
G Barosi ◽  
PG Gobbi ◽  
R Invernizzi ◽  
A Riccardi ◽  
...  
Keyword(s):  
At Risk ◽  
Natural History ◽  
Iron Overload ◽  
Bone Marrow Failure ◽  
Blood Transfusions ◽  
Ineffective Erythropoiesis ◽  
Sideroblastic Anemia ◽  
Monosomy 7 ◽  
Risk Of Death ◽  
History Of

We analyzed the natural history of idiopathic refractory sideroblastic anemia (IRSA) in 37 patients studied between 1969 and 1986. Although erythroid abnormalities were prominent in all, 12 patients also showed involvement of the granulocytic and/or megakaryocytic cell lines, and nonrandom chromosomal aberrations were observed in five of 23 patients studied for such defects. Measurements of erythroid marrow function showed in most cases erythroid expansion with ineffective erythropoiesis. In seven patients, however, the erythroid activity was found to be inappropriately low for the degree of anemia. Transfusion dependence occurred in 26 of 37 cases. Iron overload was a common feature at presentation but produced clinical manifestations of hemochromatosis only in those patients who subsequently had a regular need for blood transfusions. Five patients progressed to bone marrow failure, and another five patients (two of whom had monosomy 7) evolved into acute nonlymphocytic leukemia (ANLL). The median survival was 72 months, with a high transfusion requirement, multilineage defects, and inappropriately low erythroid proliferation being associated with a poor prognosis. The most common causes of death were complications of iron overload and evolution into ANLL. We conclude that (a) the natural history of IRSA is characterized by an initial phase of erythroid hyperplasia and ineffective erythropoiesis, which is usually stable for many years but in a subset of patients may be followed by a phase of marrow failure with or without the later emergence of leukemic blasts; (b) peripheral blood counts, measurement of erythroid marrow function, and chromosomal analysis are useful for identifying subjects at risk of evolution into marrow failure or ANLL; and (c) IRSA patients with no need for blood transfusions are very likely to be long survivors, whereas those who become transfusion dependent are at risk of death from the complications of secondary hemochromatosis.

Merle’s travel: A Quest For Completeness In Paule Marshall’s The chosen place, the timeless people.

2019 ◽  
Vol 5 (4) ◽  
pp. 36-42
Author(s):  
Dr. K. Radah ◽  
G. Gayathri
Keyword(s):  
African American ◽  
Social Context ◽  
African American Women ◽  
African American Woman ◽  
American Woman ◽  
Community Level ◽  
Dominant Culture ◽  
True Self ◽  
American Women ◽  
Human Need

African American women have been silenced and kept ignorant by the dominant culture and it is the human need to create and maintain a true self in a social context. However, such an endeavor becomes an ordeal for those who are doubly oppressed, for those who are muted and mutilated physically and psychically through the diabolic crossfire of caste/race, sex and colonialism. This paper focuses on, an African American Woman, throughout her journey of life, seeking completeness in terms of family, society and community level.

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