Frascati , a Mitochondrial Solute Transporter, and Its Role in Vertebrate Erythropoiesis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 49-49
Author(s):  
Barry H. Paw ◽  
George C. Shaw ◽  
John J. Cope ◽  
Kenneth Corson ◽  
Candace Hersey ◽  
...  
Keyword(s):  
Positional Cloning ◽  
Heme Biosynthesis ◽  
Developmental Expression ◽  
Deficiency Anemia ◽  
Congenital Defects ◽  
Iron Dextran ◽  
Erythroid Progenitors ◽  
Over Expression ◽  
Transporter Family ◽  
Solute Transporter

Abstract Acquired and congenital defects in iron metabolism from either deficiency or excess are one of the most common human diseases. Here we present the characterization of the zebrafish frascati mutation, which results in a profound hypochromic anemia and a developmental arrest at the pro-erythroblast stage. Using a positional cloning strategy, we have identified the gene disrupted frascati in mutants as a novel member of the mitochondrial solute transporter family. Members of this family of solute carriers have related tripartite sequence and structure. They function in transporting various metabolites and substrates across the inner mitochondrial membrane. We have verified the identity of the gene in zebrafish by the following criteria: (a) tissue-restricted expression in erythroid progenitors, (b) identification of missense mutations from the frascati five alleles, (c) rescue of anemia by over-expression frascati of cRNA in mutant embryos, and (d) mimicry of anemia using inactivating antisense morpholinos in wildtype embryos. We have also identified the functional ortholog in the mouse which has an analogous tissue and developmental expression pattern. The frascati ortholog in the mouse is highly expressed in fetal liver and adult bone marrow and spleen. The murine frascati transcript and protein are induced during terminal erythroid differentiation in MEL cells treated with either DMSO or HMBA. The over-expression of the mouse frascati cRNA in zebrafish frascati mutant embryos rescued their anemia with equal efficacy as the zebrafish clone. Given the identity of the gene and the requirement for iron in heme biosynthesis in the mitochondria of the developing erythron, we injected exogenous iron-dextran into frascati embryos. The embryos injected with iron-dextran were allowed to develop to 3 days post-fertilization, then stained for hemoglobinized cells with o-dianisidine and genotyped. Using this assay, the anemia caused by frascati the mutation could be partially rescued with exogenous iron supplementation. We therefore propose that the frascati gene functions as the essential transporter for iron importation into the mitochondria for heme biosynthesis and subsequent hemoglobin production in developing erythroid progenitors. Insight into the function of frascati the gene will be directly relevant to our understanding of human disorders of iron deficiency anemia and iron-overload sideroblastic anemia.

scholarly journals Elucidating the Role of IL6 in Stress Erythropoiesis and in the Development of Anemia Under Inflammatory Conditions

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 940-940
Author(s):  
Sayantani Sinha ◽  
Ritama Gupta ◽  
Jianbing Zhang ◽  
Amaliris Guerra ◽  
Ping La ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Bone Marrow ◽  
Inflammatory Cytokines ◽  
Reticulocyte Count ◽  
Erythroid Cell ◽  
Deficiency Anemia ◽  
Iron Dextran ◽  
Erythroid Cells ◽  
Second Wave

Anemia of inflammation, also known as anemia of chronic disease is the second most common anemia after iron deficiency anemia. The predominant regulators of AI are the cytokine-interleukin-6 (IL6) and the hormone hepcidin (Hamp). IL6 has been implicated in inducing expression of hepcidin. Published data from our lab have shown that lack of IL6 or hepcidin in knockout mouse models (IL6-KO and Hamp-KO) injected with the heat-killed pathogen Brucella abortus(BA) results in recovery from anemia but interestingly the pattern of the recovery was different in IL6-KO and Hamp-KO mice, suggesting that the two proteins contribute independently to AI. Here, we validated the independent role of IL6 and Hamp in AI by generating a double-knockout (DKO) mouse model lacking the expression of both. In the first few days following BA administration, we observed severe reduction in the total number of BM cells in each model followed by a slow recovery in erythroid and multilineage hematopoietic cells. The recovery, initially, was more sustained in the BA-treated-DKO model. In particular, in the first week, BA-treated-DKO mice showed an increased number of erythroblasts in the bone marrow (BM) and spleen as seen in comparison to IL6-KO and Hamp-KO. IL6-KO mice showed an intermediate recovery profile when compared to DKO and Hamp-KO, the last one showing the worst profile in the BM. Interestingly, when the reticulocyte count in the DKO mice was compared to that of IL6-KO and Hamp-KO mice, it showed a biphasic trend, with a significant increase in number during the 2nd week, followed by a significant reduction during the 3rd week. We hypothesized that the initial surge in reticulocyte count in DKO was due to lack of hepcidin, which increases iron availability to erythroid cells, and concurrent lack of IL6, which favors BM erythropoiesis in presence of inflammatory stimuli. However, we also speculated that the excess of iron (as NTBI), which accumulates during the first two weeks, leads to oxidative stress and erythroid cell death in presence of inflammatory cytokines, despite the absence of IL6. We also surmised that, during the second week, a second wave of inflammatory cytokines is triggered by the adaptive response in response to the BA that would explain the negative effect on erythropoiesis after the initial recovery. To assess this hypothesis, we utilized an inflammation panel to analyze the cytokine expression in WT animals treated with PBS or BA at 6 hours, 24 hours and then around ~2 weeks. The cytokine levels were normalized after 24 hours. However, around two weeks, we observed a novel surge of cytokines such as IFN-g and TNFa in the BA treated mice, indicating their role in innate (immediate effect; 6 hours) and adaptive immune response, which activated a second wave of inflammation (around 2 weeks, during the recovery of hematopoiesis in the BM). Interestingly, while we observed oxidative stress and defective erythropoiesis in the bone marrow, this was not seen in the spleen, where increased and extramedullary erythropoiesis sustained some level of RBC production. Since the BA-treated-IL6-KO did not show any major defect in the BM after two weeks, we challenged them with administration of iron dextran. Upon treatment, also the IL6-KO mice treated with both BA and iron dextran shown increased production of reactive oxygen species as well as a defect in bone marrow erythropoiesis, similarly as in DKO or Hamp-KO mice, thereby explaining the plausible reason of reduced erythropoiesis in the bone-marrow. Furthermore, to identify mechanisms leading to oxidative stress, we established an in-vitro culture system where primary murine bone marrow cells were cultured for 18-20 hours in presence of serum isolated after 6hrs from either PBS treated or BA treated C57BL/6 mice. With the help of confocal microscopy, we observed an increase in mitochondrial superoxide in the cells treated with BA serum; interestingly we have also seen a decrease in Ter 119 population in the cells cultured with BA treated serum implicating that the erythroid cells are dying. To further investigate the downstream players related to the death of erythroid progenitors we are currently investigating the role caspase 1 (a major regulator in pyroptosis) and Gata-1. In conclusion, this study is elucidating some of the mechanisms associated with the anemia triggered by inflammation with the potential to identify new targets and treatments. Disclosures Rivella: Disc medicine, Protagonist, LIPC, Meira GTx: Consultancy; Meira GTx, Ionis Pharmaceutical: Membership on an entity's Board of Directors or advisory committees.

scholarly journals A Study Examining the Efficacy of Ferric Carboxymaltose in a Large Pediatric Cohort

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 17-18
Author(s):  
Chandni Dargan ◽  
David Simon ◽  
Nathan Fleishman ◽  
Alka Goyal ◽  
Mukta Sharma
Keyword(s):  
Pediatric Population ◽  
Demographic Data ◽  
Deficiency Anemia ◽  
Ferric Carboxymaltose ◽  
Iron Dextran ◽  
Pediatric Hospital ◽  
Inclusion Criteria ◽  
Short Bowel ◽  
Time Period ◽  
Iv Iron

Background: Iron deficiency anemia (IDA) is common in the pediatric population with high risk factors such as nutritional deficiency, inflammatory bowel disease (IBD) and other bowel inflammatory disorders, menorrhagia, blood loss, poor absorption and anemia of chronic disease. Intravenous (IV) iron supplementation has become a more desirable mode of treatment in patients with moderate to severe anemia and in patients who are either unresponsive to or have undesirable side-effects secondary to oral iron. Iron sucrose and Iron dextran have been traditionally used in pediatrics as they both are FDA approved for use in this population. Ferric carboxymaltose (FCM) has only been FDA approved for use in adults however is currently used in pediatrics as well. One of the major advantages of Ferric carboxymaltose is the ease of dosing and efficacy. Though FCM was approved for adults in 2013 and there have been no safety concerns, it is not yet FDA approved for pediatric patients despite a few pediatric studies demonstrating its safety and efficacy (Laass, et al., 2014; Powers et al., 2017; Tan et al., 2017, Carman et al., 2019). The purpose of this study is to examine the utilization of different IV iron formulations in a large pediatric hospital as well as evaluate the safety and efficacy of ferric carboxymaltose in comparison to other IV iron formulations. At this time, we present data regarding the use of different forms of IV iron. Methods: This is a retrospective chart review study of all patients who met inclusion criteria in a large pediatric hospital who received Iron dextran, Iron sucrose, and/or FCM between the dates of 8/1/2018 through 9/30/2019. Anonymized data from eligible patients was entered into a secure electronic database. Once our population of interest was isolated, based on the proposed criteria, we reviewed charts individually and collected data including demographics and details about each IV iron administration. Demographic data encompassed race and gender. We also recorded the patients' underlying diagnosis (or diagnoses) contributing to iron deficiency anemia. In addition to compiling demographic data, we also wanted to analyze the trend of IV iron usage in our institution. This was done by tallying the number of each type of IV iron infusion monthly for the allotted time period. Results: A total of 120 patients met inclusion criteria and were included in this study with details regarding diagnosis in Figure 1. Fifty-six (46.7%) patients were male and 64 (53.3%) were female. We also analyzed the underlying diagnoses leading to IDA of patients who received IV iron infusions. Most patients had an underlying IBD diagnosis (Crohn's Disease 49.2%, Ulcerative colitis 15.8%, and Indeterminate colitis 5.8% of all included patients). Additional diagnoses included 18 patients (15%) with nutritional IDA and 8 patients (6.7%) with heavy menses. Examples of "other" diagnoses are blood loss secondary to immune thrombocytopenia, short bowel secondary to complex gastroschisis, gastrointestinal bleed secondary to Helicobacter pylori, short bowel secondary to bowel resection due to graft versus host disease after hematopoietic stem cell transplant, TMPRSS6 mutation, protein losing enteropathy, short bowel secondary to midgut volvulus and intestinal atresia, among other diagnoses. We also analyzed the overall usage of IV iron in our institution during this same time period. The number of IV iron infusions has steadily increased since August 2018. The average number of IV iron infusions was 18 per month in 2018 and 22.67 per month in 2019. As shown in figure 3, the utilization of iron dextran has decreased over time. The graph also displays that the usage of FCM at our institution continues to increase as time progresses. Conclusion: Analysis of demographic data reveals that an underlying gastrointestinal diagnosis is the most common reason for receiving IV iron likely due to decreased absorption of enteral iron. Our data has also shown that the overall usage of IV iron is increasing in the pediatric population as well as specifically FCM. This study is the first retrospective pediatric review comparing the utilization of different IV iron formulations including FCM. Preliminary data demonstrates an increase in hemoglobin after treatment with FCM, however further analysis of the data is ongoing. Figure 1 Disclosures No relevant conflicts of interest to declare.

scholarly journals Management of postpartum iron deficiency anemia: review of literature

2018 ◽  
Vol 8 (1) ◽  
pp. 338
Author(s):  
Mohamed Saber ◽  
Mohamed Khalaf ◽  
Ahmed M. Abbas ◽  
Sayed A. Abdullah
Keyword(s):  
Iron Deficiency ◽  
Blood Transfusion ◽  
Iron Deficiency Anemia ◽  
Iron Sucrose ◽  
Deficiency Anemia ◽  
Ferric Carboxymaltose ◽  
Allogenic Blood Transfusion ◽  
Iron Dextran ◽  
Peripheral Tissues ◽  
Iv Iron

Anemia is a condition in which either the number of circulating red blood cells or their hemoglobin concentration is decreased. As a result, there is decreased transport of oxygen from the lungs to peripheral tissues. The standard approach to treatment of postpartum iron deficiency anemia is oral iron supplementation, with blood transfusion reserved for more server or symptomatic cases. There are a number of hazards of allogenic blood transfusion including transfusion of the wrong blood, infection, anaphylaxis and lung injury, any of which will be devastating for a young mother. These hazards, together with the national shortage of blood products, mean that transfusion should be viewed as a last resort in otherwise young and healthy women. Currently, there are many iron preparations available containing different types of iron salts, including ferrous sulfate, ferrous fumarate, ferrous ascorbate but common adverse drug reactions found with these preparations are mainly gastrointestinal intolerance like nausea, vomiting, constipation, diarrhoea, abdominal pain, while ferrous bis-glycinate (fully reacted chelated amino acid form of iron) rarely make complication. Two types of intravenous (IV) preparations available are IV iron sucrose and IV ferric carboxymaltose. IV iron sucrose is safe, effective and economical. Reported incidence of adverse reactions with IV iron sucrose is less as compared to older iron preparations (Iron dextran, iron sorbitol), but it requires multiple doses and prolonged infusion time. Intramuscular iron sucrose complex is particularly contraindicated because of poor absorption. It was also stated that when iron dextran is given intravenously up to 30% of patients suffer from adverse effects which include arthritis, fever, urticaria and anaphylaxis.

scholarly journals Effects of Iron Deficiency Anemia and Its Rapid Correction on the Serum Metabolomic Profile of Rhesus Infants

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1070-1070
Author(s):  
Brian Sandri ◽  
Gabriele Lubach ◽  
Eric Lock ◽  
Michael Georgieff ◽  
Pamela Kling ◽  
...  
Keyword(s):  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Acid Production ◽  
Iron Status ◽  
Deficiency Anemia ◽  
Iron Dextran ◽  
Metabolomic Profile ◽  
Intramuscular Injections ◽  
Iron Deficient ◽  
Rapid Correction

Abstract Objectives To determine whether rapid correction of iron deficiency using intramuscular iron dextran normalizes serum metabolomic changes in a nonhuman primate model of iron deficiency anemia (IDA). Methods Blood was collected from naturally iron-sufficient (IS; n = 10) and IDA (n = 12) male and female infant rhesus monkeys (Macaca mulatta) at 6 months of age. IDA infants were treated with intramuscular injections of iron dextran, 10 mg/weekly for 4–8 weeks. Iron status was reevaluated following treatment using hematological measurements and sera were metabolically profiled using HPLC/MS with isobaric standards for identification and quantification. Results Early-life iron deficiency anemia negatively affects many cellular metabolic processes, including energy production, electron transport, and oxidative degradation of toxins. Slow iron repletion with dietary supplementation restores iron deficient monkeys from a hematological perspective, but the serum metabolomic profile remains differed from monkeys that had been iron sufficient their entire life. Whether rapid iron restoration through intramuscular injections of iron dextran normalizes serum metabolomic profile is not known. A total of 654 metabolites were measured with differences in 53 metabolites identified between IS and IDA monkeys at 6 months (P 0.05). Pathway analyses provided evidence of altered liver function, hypometabolic state, differential essential fatty acid production, irregular inosine and guanosine metabolism, and atypical bile acid production in IDA infants. After treatment, iron-related hematological parameters had recovered, but the formerly IDA infants remained metabolically distinct from the IS infants, with 225 metabolites differentially expressed between the groups. Conclusions As with slow iron repletion, rapid iron repletion does not normalize the altered serum metabolomic profile in rhesus infants with IDA, suggesting the need for iron supplementation in the pre-anemic stage. Funding Sources National Institutes of Health.

Optimizing Clinical Status and Quality of Life With Iron Dextran in Gynecologic Patients With Iron Deficiency Anemia [8L]

2019 ◽  
Vol 133 (1) ◽  
pp. 130S-131S
Author(s):  
Ghadear Shukr ◽  
Haleema Saeed ◽  
Marian Girgis ◽  
Aparna Basu ◽  
Phillip Kuriakose ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Iron Deficiency ◽  
Iron Deficiency Anemia ◽  
Clinical Status ◽  
Deficiency Anemia ◽  
Iron Dextran ◽  
Gynecologic Patients

scholarly journals Impaired erythropoietin response to anemia after bone marrow transplantation

Blood ◽  
1992 ◽  
Vol 80 (10) ◽  
pp. 2677-2682 ◽  
Author(s):  
CB Miller ◽  
RJ Jones ◽  
ML Zahurak ◽  
S Piantadosi ◽  
WH Burns ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Marrow Transplantation ◽  
Deficiency Anemia ◽  
Erythroid Progenitors ◽  
Graft Versus Host ◽  
Human Erythropoietin ◽  
Iron Deficient ◽  
Oncology Center ◽  
Marked Suppression

Abstract Delayed erythroid recovery is common after bone marrow transplantation (BMT), with some patients continuing to require red blood cell (RBC) transfusion support for as long as 1 year. While the etiology is multifactorial, inadequate stimulation of erythroid progenitors by the erythroid growth factor, erythropoietin, may play a role. In this study, the erythropoietin response to anemia of 70 consecutive patients undergoing BMT at the Johns Hopkins Oncology Center was compared with the erythropoietin response in uncomplicated iron deficiency anemia. Erythropoietin levels were elevated for the degree of anemia early after BMT; however, at the time of marrow recovery, erythropoietin levels were significantly suppressed in both allogeneic and autologous BMT patients compared with the iron-deficient patients. Patients with acute graft-versus-host disease (GVHD) had a more marked suppression of the erythropoietin response to anemia. In the patients who remained anemic for extended periods of time (up to 12 months after BMT), an inadequate erythropoietin response to anemia persisted. Delayed erythroid recovery after BMT is associated with inadequate erythropoietin levels. Therefore, recombinant human erythropoietin may be useful in the treatment of the anemia associated with both autologous and allogeneic BMT.

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