Low Transferrin Saturation Research Articles

An association between plasma ferritin concentrations measured 48 h after delivery and postpartum depression

ContextIron deficiency is the most common nutritional problem experienced by childbearing women, and postpartum depression (PPD) is the most common psychiatric disorder seen during the first year after delivery. The possible link between iron deficiency and PPD is not clear. ObjectiveTo evaluate whether iron status 48h after delivery was associated with PPD. Our hypothesis was that iron deficiency would be associated with PPD. DesignThis was a prospective cohort study of depression-free women studied in the postpartum period. SettingWomen who give birth at obstetric units in several general hospitals in Spain. ParticipantsA subsample of 729 women was included in the present study after exclusion of women with high C-reactive protein (CRP) and other diseases known to interfere with iron metabolism. Main outcome measuresWe evaluated depressive symptoms at 48h, 8weeks and 32weeks postpartum and used a diagnostic interview to confirm the diagnosis of major depression. A blood sample obtained 48h after delivery was used to measure the following iron storage parameters: ferritin, transferrin (Tf), free iron and transferrin saturation (TfS) and the inflammatory marker CCRP. ResultsOverall, the women in the study had low iron concentrations (8.8±6.9μmol/L) and low TfS (12.6±9.6%) but normal ferritin and Tf concentrations. A total of 65 women (9%) developed PPD during the 32week postpartum period; these women also had a lower ferritin concentration (15.4±12.7μg/L vs. 21.6±13.5μg/L, P=0.002). A strong association between ferritin and PPD was observed (odds ratio=3.73, 95% CI: 1.84–7.56; P=0.0001 for ferritin cutoff value of 7.26μg/L). In our study, ferritin concentrations have a high specificity but low sensitivity in predicting PPD. ConclusionsThese findings support the role of iron in the etiology of PPD and the use of ferritin as a marker of iron deficiency in the postpartum period. We believe that this topic deserves further investigation.

Risk Factors Associated with Iron Deficiency Among Children Admitted to Paediatric Emergency Unit in Erbil, Iraq

Background and objective: Iron deficiency is the most prevalent and common micronutrient deficiency in the developing world today. The aim is to determine the iron status among 1-5 years old children admitted to emergency department for different reasons and to determine the risk factors associated with iron deficiency in these children. Methods: a cross sectional study was carried out on a total of 106 children aged 1-5 years attended the emergency department of Raparin teaching hospital for children in Erbil from 16th of May to 16th of August 2007 were invited to participate in the study, parent were interviewed for potential risk factors of iron deficiency, blood were taken for analysis of hemoglobin, serum iron, total iron binding capacity and transferrin saturation after a verbal consent. Iron deficiency was defined as serum iron <50 microgram/dl and/or transferrin saturation (TS)<16%. Results: iron deficiency was noted in 51.9% and 48.1% according to serum iron and transferrin saturation respectively. Male have more risk to have lower TS<16% as compared with female ( OR 0.400, 95% CI 0.182-0.879). Age and tea ingestion were significant independent predictor of iron deficiency, family income associated significantly with low serum iron while pica, frequency of meat ingestion, number of sibling and weight percentile have non significant relation with neither low serum iron nor low transferrin saturation Conclusion: iron deficiency is important health problem in this population of children, prevalence of iron deficiency found in 1-2 year age group in this study was alarming, this suggest the need for greater efforts of prevention.

The development of anemia of inflammation during acute myocardial infarction

BackgroundAnemia is associated with an unfavorable outcome in acute myocardial infarction (AMI). An acute phase response could contribute to the development of anemia in AMI patients. MethodsWe have performed a cross-sectional analysis on prospectively collected data at a tertiary hospital catheterization laboratory. Multi-adjusted linear regression models were fitted for hemoglobin as the dependent variable. ANOVA tests were used to determine interactions between time cutoffs of the respective hemoglobin and the concentrations of two inflammatory proteins, namely C-reactive protein and fibrinogen. Anemia indices were analyzed in a subgroup of 138 male AMI patients for whom frozen serum samples were available. ResultsEnrolled were 1017 patients (340 with unstable angina pectoris [UAP] and 677 with AMI). Correlates of hemoglobin in the AMI group included age, male gender, the inflammatory proteins, as well as time from symptom onset to angiography (r2=0.47; p<0.001). A significant decrease in the concentration of hemoglobin with a parallel increase in the inflammatory proteins was observed between the time cutoff from symptom onset to angiography only in the AMI group for males and females, respectively. A pattern suggestive of anemia of inflammation including higher ferritin, lower transferring, lower transferrin saturation, and lower serum iron concentrations has been observed in anemic AMI patients ( all p<0.05). ConclusionsInflammation-sensitive proteins are associated with lower hemoglobin concentrations in AMI patients. We therefore suggest the possibility that at least part of the hemoglobin drop in AMI prior to angiography is related to the anemia of inflammation.

A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA

IRIDA (iron-refractory iron-deficiency anaemia) is a rare autosomal-recessive disorder hallmarked by hypochromic microcytic anaemia, low transferrin saturation and high levels of the iron-regulated hormone hepcidin. The disease is caused by mutations in the transmembrane serine protease TMPRSS6 (transmembrane protease serine 6) that prevent inactivation of HJV (haemojuvelin), an activator of hepcidin transcription. In the present paper, we describe a patient with IRIDA who carries a novel mutation (Y141C) in the SEA domain of the TMPRSS6 gene. Functional characterization of the TMPRSS6(Y141C) mutant protein in cultured cells showed that it localizes to similar subcellular compartments as wild-type TMPRSS6 and binds HJV, but fails to auto-catalytically activate itself. As a consequence, hepcidin mRNA expression is increased, causing the clinical symptoms observed in this IRIDA patient. The present study provides important mechanistic insight into how TMPRSS6 is activated.

Sirolimus is Associated With Impaired Hematopoiesis in Heart Transplant Patients? A Retrospective Analysis

Background Proliferation signal inhibitors may adversely impact bone marrow function. We sought to describe the impact of sirolimus on hemoglobin and erythropoiesis in heart transplant recipients. Methods We have conducted a single-center, retrospective analysis of all heart transplant patients treated with sirolimus. We measured serum hemoglobin (Hb) at baseline and at 3 months to determine the prevalence of anemia and change in Hb after sirolimus initiation. We also characterized hematologic profile of patients to gain insights into the effects of sirolimus on erythropoiesis. Results There were 84 patients included in the study. The prevalence of anemia increased from 71% to 75% after sirolimus initiation. Anemic patients were more likely to be male ( P = .026) and have worse renal function (glomerular filtration rate 49 ± 27 vs 70 ± 42 mL/min; P = .012). A ≥20 g/L drop in Hb was observed in 25% of the overall cohort. Patients investigated for anemia ( n = 67) had a low Hb (111 ± 24 g/L), normal mean corpuscular volume (87 ± 47 FL), and low serum iron levels (10 ± 5 μmol/L) and transferrin saturation (0.22 ± 0.12). Serum ferritin was variable (263 ± 370 μg/L). Bone marrow evaluation in 19 patients revealed adequate marrow iron stores in all cases. Conclusion Anemia is prevalent in heart transplant patients treated with sirolimus and increases over time. Patients have a characteristic hematologic profile suggestive of anemia of chronic disease and functional iron deficiency.

Prevalence of Iron Deficiency in Children with Down Syndrome

To determine the prevalence of iron deficiency (ID) and iron deficiency anemia (IDA) in a sample of children with Down syndrome (DS) and to evaluate the effect of macrocytosis on the diagnosis of ID/IDA in these children. Children with DS ≥ 12 months of age who were followed at the Duke University Medical Center Comprehensive DS Clinic from December 2004 to March 2007 were screened for ID/IDA with a complete blood count, reticulocyte count, iron panel, and erythrocytic protoporphyrins. A total of 114 children were enrolled, with a median age of 4.7 years. ID was identified in 12 subjects (10%), and IDA was identified in 3 subjects (3%). ID/IDA would not have been accurately diagnosed in 13 of 15 subjects (86%) if red blood cell (RBC) indices alone had been used for screening. Abnormal RBC indices with low transferrin saturation were 100% sensitive for ID/ IDA screening. Prevalence of ID/IDA in children with DS was comparable with that in the general pediatric population. Macrocytosis had implications for screening of ID/IDA with only RBC indices. We suggest ID/IDA screening in DS children be done with a laboratory panel at least including complete blood count, reticulocyte count, transferrin saturation, and serum ferritin.

Deficiência de ferro no idoso

Anemia is a common problem in the elderly and is associated with significant morbidity and mortality. More than 10% of all individuals above the age of 65 have anemia. Because an increasing proportion of the world's population is aged 65 and older, it is inevitable that the prevalence of anemia will increase in the future. Thus, early diagnosis of anemia is important to prevent the condition from worsening, to slow disease progression, and improve outcomes in patients. The WHO definition of anemia (hemoglobin concentration <12 g/dL, in women and <13 g/dL, in men) is most often used in epidemiologic studies of older adults. Among older adults with anemia approximately one-third have evidence of iron, folate, and/or vitamin B12 deficiency, another third have renal insufficiency and/or chronic inflammation, and the remaining third have anemia that is unexplained. Anemia due to iron deficiency (IDA) is microcytic and hypochromic. Low serum ferritin levels, high total iron-binding capacity, low transferrin saturation, high concentrations of soluble transferrin receptor, and absent bone marrow iron stores accompany IDA. Iron deficiency in the elderly usually occurs as a result of chronic gastrointestinal blood loss caused by gastritis, ulcers, colon cancer, or angiodysplasia. Gastrointestinal tract abnormalities can be identified in the majority of patients with IDA. In some cases, inadequate intake or inadequate absorption of iron may contribute to the anemia. However, in all cases blood loss should be investigated and excluded before assuming that iron deficiency is due to other causes. Treatment includes stopping blood loss and replacing iron.

Iron deficiency in children with mitochondrial disease

Mitochondrial disease is an energy metabolic disorder with various organ involvement. Iron is widely known to be one of the most important nutriments required for normal brain development and several essential metabolic functions. We retrospectively studied the laboratory data on iron deficiency (ID) in 69 children with mitochondrial respiratory chain complex (MRC) defects by biochemical enzyme assay using muscle tissue. We analyzed the differences between groups of mitochondrial disease based on the presence of ID. ID has higher prevalence in children with mitochondrial disease than in the normal population. There were 6 (9%) patients with low hemoglobin, 12 (17%) with low serum ferrtin, and 22 (32%) with low transferrin saturation levels among children with MRC defects. In comparisons between the ID and the non-ID group of MRC-defect patients, the frequency of MRC I defect was significantly higher in the ID group while that of MRC IV defect was higher in the non-ID group. Abnormal brain magnetic resonance imaging (MRI) findings were more frequently detected in the ID group. The incidence of failure to thrive and gastrointestinal symptoms were significantly higher in the ID group. Early diagnosis and proper treatment of ID are recommended. Especially in cases with risk factors such as failure to thrive or gastrointestinal manifestation, active evaluation of ID should be encouraged.

Negative Iron Balance: Risk Among Female Vegetarian College Students

Iron deficiency anemia is the most common nutrient deficiency, impacting up to 6% of Americans. Given that 5 to 14% of women in the United States between ages 15 and 44 have impaired iron status, depletion may be most prevalent in younger women. Of particular concern is the health impact of iron deficiency anemia among vegetarian women of child bearing age. The objective of this study was to determine if iron deficiency anemia is widespread among college age vegetarian women. A cross sectional analysis of 39 female students at California Polytechnic State University in San Luis Obispo, CA was conducted. Anthropometric data including height, weight and BMI was collected. Three day dietary records were maintained by participants to determine dietary iron intake. A fasting blood sample was obtained and analyzed for white blood cells, red blood cells, hemoglobin, hematocrit, serum iron, serum ferritin, transferrin saturation and total iron binding capacity. Vegetarians tended to eat less iron daily than non vegetarians. Of interest was the tendency for lower serum ferritin status and a greater expression of stage 1V negative iron balance compared to non vegetarians as evidenced by low serum iron, high total iron binding capacity, low transferrin saturation and low serum ferritin. Thus, vegetarian college age women appear to be at higher risk than non vegetarians for developing negative iron balance. Funded by California Polytechnic State University Faculty Support Grant.

Suppression of hepatic hepcidin expression in response to acute iron deficiency is correlated with an increase of matripatase‐2 protein in the liver

Recent studies demonstrate a pivotal role of bone morphogenic protein‐6 (BMP6) and matriptase‐2, a protein encoded by the TMPRSS6 gene, in the induction and suppression of hepatic hepcidin expression, respectively. We examined their expression profiles in isolated liver cells and found an exclusive expression of TMPRSS6 mRNA in hepatocytes. In rats fed an iron deficient (ID) diet for 24 hrs, the rapid decrease of transferrin saturation from 71% to 24% (control versus ID diet) was associated with a marked decrease of hepatic hepcidin mRNA, by approximately 100‐fold in comparison with the corresponding controls. These results indicated a close correlation of low transferrin saturation with the decrease of hepcidin mRNA. The decrease of phosphorylated Smad1/5/8 detected in the ID rat livers suggests that the suppressed hepcidin expression resulted from the inhibition of BMP signaling. qRT‐PCR analysis revealed no significant change in either BMP6 or TMPRSS6 mRNA in the liver. However, an increase of matriptase‐2 protein in the liver from ID rats was detected, suggesting that suppression of hepcidin expression in response to acute iron deficiency is mediated by the increase of matriptase‐2 protein levels.

Usefulness of measuring reticulocyte hemoglobin equivalent in the management of haemodialysis patients with iron deficiency

The evaluation of iron status in dialysis patients provides information essential to the planning of adequate recombinant human erythropoietin treatment. The cellular iron status of the patients can be determined from the recently available measurement of reticulocyte hemoglobin equivalent (RET-He). RET-He is measured on the basis of automated fluorescent flow cytometry which in the reticulocyte channel, using a polymethine dye, also measures the mean value of the forward light scatter intensity of mature red blood cells and reticulocytes. These values equate with reticulocyte hemoglobin content. In this study, to clarify the accuracy of RET-He in diagnosing iron deficiency in dialysis patients, we initially compared RET-He with such iron parameters as serum ferritin levels, transferrin saturation and content of reticulocyte hemoglobin (CHr) which has been established as indicators of functional iron deficiency. Secondly, we investigated the changes in RET-He during iron supplementation for iron-deficient patients to determine whether this marker is a prospective and reliable indicator of iron sufficiency. The participants in this study were 217 haemodialysis patients. Iron deficiency was defined as havsing a transferrin saturation (TSAT) < 20% or serum ferritin < 100 ng/ml. Conventional parameters of red blood cells and RET-He were measured by on a XE-2100 automated blood cell counter (Sysmex). CHr was measured on an ADVIA120 autoanalyser (Siemens). RET-He mean value was 32.4 pg and good correlation (r = 0.858) between RET-He and CHr is obtained in dialysis patients. Receiver operating characteristic curve analysis revealed, values of the area was 0.776 and at a cutoff value of 33.0 pg, a sensitivity of 74.3% and a specificity of 64.9%, were achieved. Iron supplements given to the patients with low TSAT or ferritin, RET-He responded within 2 weeks, and this seemed to be a potential advantage of using RET-He in the estimation of iron status. RET-He is a new parameter, equivalent value to CHr, and is easily measurable on the widely spread and popular blood cell counter and is a sensitive and specific marker of iron status in dialysis patients.

Iron Stores, Periodic Leg Movements, and Sleepiness in Obstructive Sleep Apnea

Most clinical sleep studies are performed for suspected obstructive sleep apnea (OSA), yet one-quarter to one-half show periodic leg movements (PLMs), for reasons that remain unknown. Several other disparate sleep disorders also increase the risk for PLMs. We examined the novel hypotheses that OSA as a representative sleep disorder could promote lower body iron stores, as reflected by serum ferritin levels, and, through downstream effects on dopaminergic transmission, increase PLMs and daytime sleepiness. Subjects were recruited as they underwent laboratory-based polysomnography for suspected OSA. Serum ferritin levels were measured the next morning. Each subject completed an Epworth Sleepiness Scale and a brief questionnaire to assess for restless legs syndrome (RLS). The frequency of apneic events showed no association with serum ferritin levels, before or after adjustment for age, sex, body mass index, and likely RLS (each p value > 0.3). Serum ferritin levels did not predict the frequency of PLMs (p = 0.7) or Epworth scores (p = 0.8). Iron deficiency as a dichotomous variable, determined by ferritin levels less than < 50 microg/L or in combination with low transferrin saturation or mean corpuscular volume, showed similar results. In exploratory analyses, contrary to expectations, lower minimum oxygen saturation and increased sleep-stage shifts predicted increased rather than decreased ferritin levels (p = 0.03 and p = 0.02, respectively). Results of this study, powered to detect small to moderate effect sizes, strongly suggest that OSA does not cause lower serum ferritin levels, which, in turn, cannot explain PLMs or daytime sleepiness in these patients.

Haematologic data, iron parameters and molecular findings in two new cases of iron‐refractory iron deficiency anaemia

Matriptase-2 (Tmprss6), a type II transmembrane serine protease, has an essential role in iron homoeostasis as a hepcidin regulator. Recently, patients with TMPRSS6 mutations and suffering from iron-refractory iron deficiency anaemia (IRIDA) have been reported. We describe two new cases of IRIDA, one patient of Swiss origin and the second of Italian origin. The first case results from a large deletion of 1054 nucleotides corresponding to an in frame deletion of 30 amino acid residues in the low-density lipoprotein receptor-1/-2 (LDLR-1/-2) domains and from a missense mutation in CUB1 (S304L). In the second case, a homozygous G-->C mutation in the last nucleotide of exon 15 and which modified the consensus sequence of the 5' splice donor site of intron 15 (AGgt-->ACgt) was identified. Both patients had a high hepcidin level and low serum iron and transferrin saturation compared to age-matched controls. Continuous perfusion of i.v. iron 4 h/d x 5 d in the first case resulted in a significant rise in haemoglobin. These new cases of IRIDA illustrate the importance of LDLR-1/-2 and CUB1 domains in matriptase-2 function as well as the role of matriptase-2 in hepcidin regulation. Furthermore a deletional form of TMPRSS6 (in LDLR-1/-2 domains) resulting in IRIDA is described for the first time. These cases reinforce the belief that patients suffering from IRIDA have no specific geographical or ethnic distribution and are sporadic secondary to different mutations of the matriptase-2 gene.

Iron, zinc and aluminium ferritin content of hemodialysis hyperferritinemic patients: Comparison with other hyperferritinemic clinical conditions and normoferritinemic blood donors

The present study describes the specific content of ferritin iron, zinc and aluminium in four different groups: 1) hemodialysis hyperferritinemic patients; 2) septic patients; 3) iron overloaded patients with hematologic diseases; and 4) blood donors. In all four groups high levels of aluminium and zinc were found in addition to those of iron. However, the sum of the ferritin ions of the control group is significantly higher than that of the other three groups. Furthermore, while ferritin of hemodialysis patients has the same molecular ratio of metal ions as control group (high Al content vs. Fe and Zn), a lower Al/Fe ratio is found both in septic and hematological patients. The results of the present paper might help to explain the high percentage of hyperferritinemia found in hemodialysis patients also in presence of low transferrin saturation and in absence of inflammatory markers. Moreover, the high content of ions other than iron in the ferritin core leads us to believe that ferritin is not only an iron storage protein but rather a regulator of redox active ions.

Diagnose der Rheuma-Anämie

Anaemia of chronic disease is frequently accompanied by marked disturbances in iron metabolism driven, to a large part, by liver-derived hepcidin. Typically, there is reduced iron resorption from the intestine as well as increased uptake and retention of iron within cells of the reticuloendothelial system, resulting in a diversion of iron from the circulation to storage sites with a subsequent lack of iron for red progenitor cells and iron-deficient erythropoesis. In addition, gastrointestinal blood loss may aggravate the availability of iron. By using biochemical markers and special red blood cell indices, all three compartments of iron metabolism can be readily monitored. Serum ferritin represents storage iron, whereas the transferrin saturation (TSAT) is a measure for the amount of iron bound to transferrin. Determination of red cell indices such as% hypochromic erythrocytes or reticulocyte hemoglobin (CHr) or the soluble transferrin receptor (sTfR) provides direct information on iron availability for erythropoesis. An absolute iron deficiency is characterised by a serum ferritin<30 μg/L and reduced haemoglobin levels (iron deficiency anaemia). A latent iron deficiency is characterised by reduced iron stores with still normal haemoglobin values. Patients suffering from chronic inflammation might become anaemic (Hb reduced) in the presence of adequate iron stores (ferritin normal), due to hepcidin-mediated retention of iron in the reticuloendothelial system and subsequent iron-deficient erythropoesis. Iron-restricted blood formation may also occur during epoetin treatment, when the pharmacologically stimulated erythropoesis needs more iron than transferrin (low TSAT) is able to deliver to the bone marrow. Both scenarios would ultimately lead to iron-deficient erythropoesis, which is also called functional iron deficiency. Normally it is not necessary to determine all iron parameters in each and every case. The simultaneous evaluation of storage iron (ferritin) and iron availability to the bone marrow (% hypochromic red cells, CHr or sTfR) appears to be a rational first step to characterise complex disturbancies of iron homeostasis.

Hyporesponsiveness to Erythropoietin: Causes and Management

In patients with chronic kidney disease, erythropoietin resistance is common, costly, and has implications beyond the management of anemia because the presence of erythropoietin resistance portends mortal outcomes. Exploring the provenance of erythropoietin resistance may be facilitated by the consideration of the pathogenetic triad of iron-restricted erythropoiesis, inflammation, and bone marrow suppression. Challenging to diagnose because of difficulty in interpreting tests of iron deficiency, iron-restricted erythropoiesis should be considered in patients who require high doses of erythropoietin, have low transferrin saturation (eg, <20%-25%), and do not have very high ferritin (eg, <1,200 ng/mL); a therapeutic trial of intravenous iron may be worthwhile. Aluminum intoxication is a rare cause of iron-restricted erythropoiesis that may manifest as microcytic hypochromic anemia. A decrease in serum albumin concentration may signal the presence of inflammation, which may be manifest (such as because of a recent illness or infection) or occult; the latter include clotted synthetic angioaccess, failed renal allograft, dialysis catheter, periodontal disease, underlying malignancy, or uremia per se. Marrow hyporesponsiveness may be improved by increasing the delivered dialysis dose, using ultrapure dialysate, maintaining adequate vitamin B12 and folate stores, or by treating hyperparathyroidism. In summary, improving the outcomes of erythropoietin-resistant patients will require complete patient assessment that goes beyond considerations of iron and erythropoietin dose alone. Given that erythropoietin dose is associated with mortality, mitigating erythropoietin resistance has the potential to improve patient outcomes.

Heme carrier protein 1 (HCP1) genetic variants in the Hemochromatosis and Iron Overload Screening (HEIRS) Study participants

Heme carrier protein 1 (HCP1) has been identified as a possible heme carrier by in vitro analysis. To determine the association of mutations within the HCP1 gene with iron phenotypes, we examined the entire coding region of the HCP1 gene in 788 US and Canadian participants selected from the Hemochromatosis and Iron Overload Screening (HEIRS) Study using denaturing high-performance liquid chromatography. We sequenced the exon and flanking intronic regions if variants were detected. We tested 298 non-C282Y homozygotes from four racial/ethnic backgrounds (White, Black, Asian, and Hispanic) selected because they had high serum ferritin (SF) and transferrin saturations (TS). As controls, we chose 300 other random participants of the same racial/ethnic backgrounds from the same geographic locations. From the 333 HEIRS Study C282Y homozygotes, we selected 75 based on high SF and TS, 75 based on low SF and TS; and 75 were selected randomly as controls. Thirty-five of the randomly selected C282Y homozygotes were also included in the high and the low SF and TS groups due to numerical limitations. We identified eight different HCP1 genetic variants; each occurred in a heterozygous state. Except one, each was found in a single HEIRS Study participant. Thus, HCP1 variants are infrequent in the populations that we tested. Five HEIRS Study participants had non-synonymous, coding region HCP1 variants. Each of these five had TS above the 84th gender- and ethnic/racial group-specific percentile (TS percentiles: 84.7, 91.3, 97.9, 99.5, and 99.9).

Ferric gluconate treatment provides cost savings in patients with high ferritin and low transferrin saturation

A subgroup of hemodialysis patients experience high serum ferritin and low tansferrin saturation for reasons not clearly understood. Here we determined the economic impact of administering sodium ferric gluconate complex to patients with serum ferritin levels higher than 500 ng/ml and a transferrin saturation less than 25% based on the Dialysis Patients Response to IV Iron with Elevated Ferritin (DRIVE) study and its extension, DRIVE II. A cost effectiveness model was developed, consistent with the DRIVE studies, using decision analysis with a 12-week time horizon. The primary effectiveness measure was the mean hemoglobin increase in the intent to treat patient groups comparing epoetin with or without sodium ferric gluconate complex. Costs were computed using projected 2007 US Medicare reimbursements for the treatments and for serious adverse events, with the effectiveness factored by the increase in hemoglobin. The net savings for sodium ferric gluconate complex plus epoetin treatment was $1390 compared to epoetin alone for each g/dl hemoglobin increase over 12 weeks of study. Sensitivity analyses were performed to test the impact of change in the variables (using medians or means and actual 2005 or projected 2007 Medicare reimbursements) and these affirmed the robustness of the model. Our study shows that treatment of patients with high ferritin and low transferrin saturation levels, as defined in DRIVE, with sodium ferric gluconate complex and epoetin resulted in significant savings compared to epoetin alone.

Darbepoetin-Alfa and I.V. Iron Administration after Autologous Hematopoietic Stem Cell Transplantation: A Prospective Randomized Multicenter Trial

Background: We previously reported a retrospective study suggesting that erythropoietin therapy starting on day 28 after autologous HCT was highly effective to improve Hb levels and that i.v. iron might improve response in patients with low transferrin saturation (Baron et al., Clin Cancer Res 2003). This prompted us to conduct a multicenter prospective randomized study analyzing the impact of darbepoetin alfa with or without i.v. iron on erythroid recovery after autologous HCT.Patients and Methods: 127 autologous HCT recipients with lymphoid malignancies were randomized 1:2:2 between no treatment (group 1, n=25), darbepoetin alfa (Aranesp®) 300 μg QOW starting on day 28 after HCT for a total of 7 doses (group 2, n=52), or the same regimen of darbepoetin alfa plus i.v. iron sucrose (Venofer®) 200 mg on days 28, 42 and 56 after HCT (group 3, n=50). Once the target Hb (13 g/dL) was attained, the dose of darbepoetin alfa was reduced to 150 μg, while it was withheld when Hb was ≥ 14 g/dL. Primary endpoints included proportion of complete correctors (i.e. patients reaching Hb □ 13 g/dL) before day 126 post-transplant and median time to achieve Hb correction in each arm. Data were analyzed following the intention-to-treat principle. The proportion of complete correctors by day 126 in each group was compared using the Fisher's exact test, and median times to reach 13 g/dL in each group were compared using the logrank test.Results: The proportion of complete correctors was 24% in group 1, 81% in group 2 (P<0.001 compared with group 1), and 92% in group 3 (P<0.001 compared to group 1, and P=0.099 compared to group 2). Median time to achieve Hb □ 13 g/dL was not reached in group 1, 42 days in group 2 (P<0.001 compared to group 1), and 32 days in group 3 (P<0.001 compared to group 1 and P=0.127 compared to group 2) (Fig 1A). Hb evolution in each group is shown in Fig 1B. Mean ± standard deviation total doses of darbepoetin-alfa administered were 1,445 ± 489 μg in group 2 vs 1,272 ± 443 μg in group 3 (P=0.06). Ferritin levels at the end of study were 477 ± 597, 393 ± 599 and 479 ± 488 in groups 1, 2 and 3, respectively (NS). Eight patients (2 in group 1, 4 in group 2, and 2 in group 3) required red blood cell transfusions on study, including 4 patients following early disease progression. There was no difference in rates of thrombo-embolic events or other complications among the groups. Quality-of-life data will be presented.Conclusions: This is the first prospective randomized trial demonstrating that darbepoetin alfa is safe and highly effective to ensure full erythroid reconstitution after autologous HCT when started on day 28 posttransplant. I.v. iron sucrose tended (not statistically significant) to further fasten erythroid recovery with a lower dose of darbepoetin alfa required. Future studies in this setting should aim at further investigating the impact i.v. iron might have on improving response in patients with low transferrin saturation. [Display omitted]

Mild Pro-Inflammatory State and Anemia in Older Persons.

Abstract Aging is characterized by a progressive dysregulation of homeostatic equilibrium. Inflammation is perhaps the most studied aspect of such homeostatic dysregulation, particularly in the context of anemia. Older persons and even “extremely healthy” older individuals are often affected by a mild pro-inflammatory state marked by high levels of pro-inflammatory markers, such as IL-6 and C-reactive protein (CRP). Patients with overt inflammatory diseases tend to develop anemia, usually of mild severity. Four mechanisms by which inflammation may affect anemia have been hypothesized: inhibition of proliferation and differentiation of erythroid precursors by inflammatory cytokines and/or downregulation of the EPO biological response; blunted EPO production; upregulation of hepcidin synthesis and consequent impairment of intestinal absorption and iron recycling; and reduced erythrocyte survival, not fully compensated by increased erythropoiesis. Studies have shown that the pro-inflammatory state of aging inflammation is associated with EPO levels higher than expected in non-anemic individuals and lower than expected in anemic individuals, suggesting the existence of a pre-anemic state where EPO resistance is compensated by increased EPO levels. Only when this compensatory mechanism fails does anemia become clinically evident. Consistent with this hypothesis, individuals with high EPO and high levels of inflammatory markers are at high risk of developing anemia. The mediating role of hepcidin in the pathogenesis of anemia of inflammation is suggested by an extensive literature. By interacting with the unique iron transporter, ferroportin, hepcidin controls iron intestinal absorption and mobilization from hepatocytes and macrophages, thereby causing low serum iron and ineffective erythropoiesis. Patients affected by disease characterized by overt inflammation, such as rheumatoid arthritis, abscess, and sepsis, show increased hepcidin urinary excretion. There is some evidence that the mild-pro-inflammatory state of aging does not cause hepcidin upregulation, although it is associated with low serum iron, lower transferrin saturation, and higher ferritin concentration. Thus, the iron lowering effect of moderate inflammation may be mediated by some still-unknown mechanism other than hepcidin. Studies are needed to test the hypothesis that the mild inflammation affects erythrocyte lifespan.