Onset Of Anemia Research Articles

Pharmacokinetics of mycophenolate sodium co-administered with tacrolimus in the first year after renal transplantation.

We assessed the relations between MPA, free MPA (fMPA) and MPA glucuronide (MPAG) pharmacokinetics and the clinical condition of renal transplant recipients treated with EC-MPS and tacrolimus (Tac) in the first post-transplant year. In 18 adult patients blood samples were collected up to 12 h after EC-MPS oral administration. EC-MPS metabolites’ plasma concentrations were determined using validated HPLC methods. All patients reached MPA area under the time–concentration curve (AUC0–12) above 30 µg h/mL. Most of the MPA, fMPA and all MPAG concentrations correlated significantly with respective AUC0–12 values. Some fMPA and all MPAG pharmacokinetic parameters correlated negatively with creatinine clearance and positively with creatinine concentration, whereas no such correlation was observed for MPA. Lower hemoglobin concentrations were observed in patients with higher MPA or fMPA C 0. The significant correlations between MPA C 3 as well as MPA C 4 and MPA AUC0–4 and MPA AUC0–12 may be of importance in further studies including larger number of patients in regard to establishing LSS. In patients treated with EC-MPS and Tac, monitoring MPA C 0 may be important, as too high MPA C 0 may contribute to anemia onset. In EC-MPS treated patients, MPAG concentration is related to renal function as MPAG pharmacokinetics were higher in patients with renal impairment.

Mutant Splicing Factor 3b Subunit 1 (SF3B1) Causes Dysregulated Erythropoiesis and a Stem Cell Disadvantage

Recurrent, heterozygous, somatic mutations in components of the mRNA spliceosome complex were recently identified in over 60% of myelodysplastic syndrome (MDS) patients. Splicing factor mutations are thought to be founding mutations in MDS based on their allele fraction at diagnosis. Splicing factor 3b Subunit 1 (SF3B1) is the most frequently mutated splicing factor in MDS. SF3B1 mutations are highly associated (70 – 85% of cases) with refractory anemia with ring sideroblasts (RARS), a morphologic subtype of MDS characterized by the presence of erythroid precursors with perinuclear iron-laden mitochondria in the bone marrow. The pathophysiological role of SF3B1 mutations in MDS has yet to be elucidated. To explore the biology of SF3B1 mutations, we generated a heterozygous conditional knock-in mouse model of the most common SF3B1 mutation, K700E.Heterozygous conditional knock-in of Sf3b1K700E leads to a progressive macrocytic anemia, with normal absolute neutrophil and platelet counts. Over the course of 15 months, mutant mice developed a statistically significant macrocytic anemia (hemoglobin of 11.4 g/dL vs. 14 g/dL, p = 0.004; MCV of 63.1 fL vs. 58.4 fL, p = 0.008) associated with elevated plasma erythropoietin levels (257.5 pg/mL vs. 101 pg/mL, p = 0.0016). Analysis of hematopoietic stem and progenitor cells at 12 and 65 weeks after induction showed a similar percentage of stem (LT-HSC, ST-HSC, MPP, LSK) and progenitor (LK, CMP, GMP, MEP, pre CFU-E) cells in Sf3b1K700E and wild-type animals. Histopathologic analysis revealed no significant difference in spleen weights, but increased erythroid islands in the red pulp of mutant animal spleens; suggestive of ineffective erythroid maturation. Sf3b1K700E animals have a normocellular bone marrow with rare ring sideroblasts. No ring sideroblasts were identified in wild-type controls. No overt hematological malignancies were identified during the observation period, however two mutant animals succumbed to significant anemia (2 of 11, 18%) compared to zero deaths in the wild-type controls.To further characterize the erythroid-specific phenotype observed in Sf3b1K700E mice, mutant and wild-type animals were treated with phenylhydrazine, a drug that induces intravascular hemolysis. Sf3b1K700E mice had a more rapid onset of anemia and a higher reticulocytosis during count recovery compared to wild-type controls. Analysis of the bone marrow and spleens was notable for a higher percentage of immature erythroid precursors (R2/basophilic erythroblasts) and a lower percentage of more mature erythroid precursors (R4/orthochromatophilic erythroblasts) in mutant animals, consistent with impaired erythroid maturation. An in vitro erythroid differentiation assay using purified ckit+ progenitor cells from Sf3b1K700E mice yielded significantly fewer erythroblasts (p = 0.0226) when compared to cells from wild type mice due to a statistically significant increase in the percentage of mutant cells in G0 (p=0.018). Similarly, noncompetitive transplantation assays highlighted the cell intrinsic nature of these erythroid-specific findings, as mutant cells did not show a defect in repopulating recipients, however Sf3b1K700E recipients developed a progressive macrocytic anemia.Competitive transplantation assays demonstrated a competitive disadvantage in Sf3b1K700E hematopoietic stem cells. Engraftment was lower in Sf3b1K700E compared to wild-type recipients 4 weeks (33.9% vs. 54.4%, p = 0.002) and 16 weeks (29% vs. 62.4%, p = 0.0013) after transplantation. These findings are consistent with the fact that RARS patients have a lower risk of progression to acute myeloid leukemia compared with other MDS subtypes.Taken together, our results demonstrate that heterozygous mutations in Sf3b1 lead to aberrant erythroid maturation and ineffective hematopoiesis in mice. These findings are consistent with the clinical picture seen in RARS patients. The results from the competitive transplantation studies may be consistent with the more favorable prognosis seen in patients with RARS, as our data suggest that additional genetic or epigenetic alterations must be acquired in SF3B1K700E cells to facilitate the development of clonal dominance. DisclosuresNo relevant conflicts of interest to declare.

Occult Iron Deficiency Might be an Important Factor in MPN Patients with Myeloproliferative Neoplasms (MPN) Treated with Ruxolitinib. a Single Centre Experience

Myelofibrosis (MF) is manifested as primary myelofibrosis or post-essential thrombocythemia myelofibrosis (PET-MF), or post-polycythemia vera myelofibrosis (PPVMF). The JAK2 V617F a gain of function somatic mutation is present in approximately 50% of patients (pts) with MF. This and related mutations result in an exaggerated JAK2 signaling and they are the mechanistic cause of Ph(-) myeloproliferative neoplasms (MPN). Ruxolitinib, an oral JAK inhibitor was approved by FDA and EMEA as treatment of myelofibrosis in 201. Clinical trials have demonstrated its effectiveness and that the response rate its independent of the JAK2 mutation status or MPN subtype, , being anemia and thrombocytopenia the most common adverse events that rarely lead to drug discontinuation. In phase I/II clinical trials, in pts who were transfusion independent at baseline, new onset anemia occurred in 23% and was dose dependent, up to 20% of patients required transfusions at higher doses. It was not reported whether any specific MF subtype developed more severe anemia. Hematological toxicity in the placebo-controlled COMFORT-I study revealed grade 3 or 4 anemia in 34.2% and 11.0% of those treated with ruxolitinib and only in 15.9% and 3.3% of placebo-treated patients. The frequency of severe anemia grades 3 and 4 was higher if the initial hemoglobin (Hb) was under 10g/dl. The anemia can be managed effectively with dose modifications, temporary treatment interruptions, as well as red blood cell transfusions and/or erithropoyetin administration Aim: To describe hematological toxicity management on MF pts treated with ruxolitinib Methods: Descriptive, retrospective analysis addressing the anemia safety profile of five MF patients (WHO criteria) treated with ruxolitinib with a median age of 68.2 years. One patient had PMF, 3 had PPV-MF and 1 had PET-MF. One of them required transfusion support, and two of them who had documented iron deficiency, were treated with iron supplementation with marked improvement (Table 1) without requiring dose reduction. Abstract 5564. TableGenderAgeDiagnosisDate of DxDate start TxDose start TxBaseline Hb (gr/dL)Anemia (> 2 gr/dL)Time of tx until anemiaIron SupplementationTransfusion supportAnemia OutcomeFemale79PPV MF04-feb-0522-nov-1220 mg/BID14.4Yes8 weeksYesNoImprovedFemale49PET MF01-Dec-9815-Jan-1320 mg/BID16.6YesYesNoImprovedFemale79PPV-MF07-mar-9613-may-1320 mg/BID14.4NoN/AN/AN/AN/AFemale85PPV-MF01-abr-0902-sep-1315 mg/BID13.3NoN/ANoN/AN/AMale79PMF04-jul-1312-ago-1310 mg/BID8.5Yes16 weeksYesYesImproved Conclusion: Use of ruxolitinib in clinical practice requires careful monitoring of anemia, which is a common side effect that might require dose reduction or hematological support with blood transfusions and erithropoyetin. As PPVMF patients are frequently iron deficient we postulate that the identification and treatment of iron deficiency in patients with secondary myelofibrosis is an important issue as it may ameliorate the anemia, avoiding transfusions, Ruxolitinib discontinuation and therefore improving the treatment outcome. This very provocative observation warrants further investigations addressing this issue. Disclosures No relevant conflicts of interest to declare.

A Case of Idiopathic Colonic Varices Presenting as a Lower Gastrointestinal Bleed

Introduction: Colonic varices remains a rare cause of lower gastrointestinal bleeding in the literature, with an incidence rate of 0.07%. Most commonly, they are secondary to portal hypertension with other less common causes, including congestive heart failure, mesenteric vein thrombosis or compression, splendid vein thrombosis, and adhesions. In a very few reported cases, it has been attributed to being idiopathic. Case Report: A 76-year-old with history of prostate cancer status post robotic surgery but otherwise healthy was admitted with sudden onset left lower quadrant pain, hematochezia, and anemia with hemoglobin 7 requiring blood transfusions. Upon admission, a colonoscopy was performed, which showed large ectopic, colonic varices at the splenic flexure and descending colon region. Similarly, dilated and prominent veins were noted in the rectum as well. No active bleeding was noted at the time of endoscopy, and therefore, no intervention was done. There were very few small diverticula in the left colon as well, but no bleeding stigmata were appreciated. He remained stable post endoscopy, and was eventually discharged home with an outpatient work-up that included complete hepatitis panel, right upper quadrant ultrasound, computed tomography, abdominal and pelvis scan, and also an upper endoscopy, all of which were negative. Subsequently, an interventional radiology-guided mesenteric angiogram was done, which showed no evidence of arterial venous malformation or arteriovenous fistulas. The draining veins were noted to be quite prominent. No intervention was performed. Given that he remained asymptomatic with no evidence of further bleeding or anemia, conservative follow-up was recommended with plan on referral for a surgical evaluation in the future if he re-bleeds. Conclusion: Diagnosing idiopathic colonic varices continues to be a challenge, given its rare presentation. When encountering a patient with lower gastrointestinal bleeding suspected to be from colonic varices on a colonoscopy, a subsequent systemic work-up should be initiated, including a thorough evaluation for causes of portal hypertensive, as well as other vascular abnormalities, before concluding that they are idiopathic in nature. One may have to consider clinical, radiological, and at times, even surgical information collectively for a proper diagnosis. In general, patients with idiopathic colonic varices usually have a better prognosis than patients with colonic varices secondary to portal hypertension.

Diagnosis and treatment of iron deficiency in patients with heart failure: Expert position paper from French cardiologists

The prevalence of iron deficiency is high -even in the absence of anaemia- in patients with chronic heart failure (HF). Although iron deficiency is easily diagnosed with two biomarkers (serum ferritin and transferrin saturation), it is underdiagnosed in patients with HF. Iron is not only necessary for red blood cells, but also for cells in tissues with high-energy demands (heart, muscle, brain). Even before the onset of anaemia, HF patients with iron deficiency have decreased physical and cognitive performances and a poorer quality of life. Moreover, iron deficiency is a risk factor, independent of anaemia, of unfavourable outcome (death or heart transplantation) in patients with chronic HF. Several randomized controlled studies have shown improvement in exercise capacity, New York Heart Association functional class and quality of life after correction of iron deficiency. The results of these clinical trials, which are supported by European guidelines, suggest considering iron deficiency in HF as a possible therapeutic target.

Risk Factors of Anaemia-Development in Patients with Chronic Heart Failure: Results from the Studies Investigating Co-morbidities Aggravating Heart Failure (SICA-HF)

Anaemia and iron deficiency are important co-morbidities and both may lead to reduced exercise capacity. The impact of new onset anaemia in the progression of heart failure needs to be defined. A total of 280 patients with stable chronic HF (mean age: 67±11 y, 21% female, left ventricular ejection fraction [LVEF] 39±13%, body mass index [BMI] 29.3±5.5 kg/m2, New York Heart Association [NYHA] class 2.3±0.6, diabetes mellitus 30%, glomerular filtration rate 53.1±15.6 mL/min) were enrolled from 2010 and followed until April 2014 or until they reached a combined endpoint of death, incident anaemia, or a haemoglobin (Hb) drop >1 g/dL. Anaemia was defined according to World Health Organization criteria [Hb <13 g/dL in men, <12 g/dL in women], microcytic anaemia as mean corpuscular volume (MCV) ≤80fl, macrocytic anaemia as MCV≥96fl. Iron deficiency (ID) was defined as serum ferritin <100 μg/L or ferritin <300 μg/L with transferrin saturation (TSAT) <20%. Exercise capacity was assessed by spiroergometry (peakVO2) and 6-minute walk test (6MWT). A total of 37 (13.2%) Patients died from any cause during a mean follow-up of 26±14 months. At baseline, 88 (31%) patients presented with anaemia, 140 (50%) with ID. Of the anaemic patients 62 were found to have normocytic, 12 macrocytic and 14 microcytic anaemia. Hb levels correlated with peakVO2 (r=0.299, p<0.001). In patients with both ID and anaemia (n=60, 21%) exercise capacity was significantly lower than in patients with ID or anaemia alone. At the first follow-up visit after 8±4 months, 25 patients presented with incident anaemia. A total of 76 patients reached the combined endpoint within 26±14 month. Cox regression analysis showed higher risk with higher NYHA class (hazard ratio [HR]: 1.484, 95% CI:1.03-2.13, p=0.03) and lower risk in patients without artrial fibrillation (HR:0.62, 95%CI:0.39-0.98, p=0.04), without pacemaker devices (HR: 0.59, 95%CI:0.37-0.93, p=0.02), with higher LVEF (HR:0.973, 95%CI: 0.89-1.11, p=0.005). A trend was observed for peak VO2 (HR:0.94, 95%CI:0.889-1.002, p=0.059). Exercise capacity is correlated with haemoglobin values. The impact of anaemia on reduced exercise capacity is stronger than that of ID.

Les anémies hémolytiques immunologiques médicamenteuses : étude rétrospective de 10 observations

PurposeDrug-induced immune haemolytic anemia occurs in one case per million and can be fatal. Our aim was to describe the main characteristics and the type of drug involved. MethodsCases were retrospectively identified using spontaneous notifications collected by our pharmacovigilance centre and the results of immuno-hematological investigations performed by the laboratory of French blood establishment of Lyon between 2000 and 2012. Inclusion criteria were: an immune (positive direct antiglobuline test), hemolytic, anemia (haemoglobin <100 g/L), with at least a plausible causal relationship with drug exposure according to the French method of imputability or the presence of drug-dependent antibodies, and exclusion of other causes of hemolysis. ResultsTen cases (5 men and 5 women, median age 54.4 years) were identified. Causal drugs were ambroxol, beta-interferon, cefotetan, ceftriaxone, loratadine, oxacilline, oxaliplatine, piperacilline-tazobactam, pristinamycine, and quinine. The median time to onset of anemia after starting the culprit drug was 6 days (2 hours to 16 days). The median nadir of hemoglobin was 57.9 g/L (range: 34–78). The direct antiglobulin test was positive in 8 patients: IgG only (n=4), IgG and complement (n=3), and IgA (n=1). Drug-induced immune haemolytic anemia was considered as definite in 5 cases with positive drug-induced antibodies, probable in 4 cases negative for the detection of drug-induced antibodies but with plausible or likely causal relationship with drug exposure, and probable with an autoimmune mechanism in 1 case. ConclusionThe diagnosis of DIIHA is often difficult because of the similarities with autoimmune haemolytic anemia and the inconstant sensitivity of immunologic tests that sometimes required repetitive assessment.

The amount of self‐antigen determines the effector function of murine T cells escaping negative selection

Autoimmune diseases develop when self-specific T cells that escaped negative selection initiate a harmful immune response against self. However, factors, which influence the initiation and progression of an autoimmune response remain incompletely understood. By establishing a double-transgenic BALB/c mouse system in which different amounts of a cell-surface neo-self-antigen are expressed under the CD11c promoter, we demonstrate that antigen dose dramatically influences T-cell tolerance mechanisms. Moderate antigen expression in both hematopoietic and nonhematopoietic cells favors the development of antigen-specific Treg cells and the establishment of a tolerogenic environment. In marked contrast, a high dose of antigen expression results in very stringent negative selection, in poor development of antigen-specific Treg cells and in the early onset of anemia and splenomegaly and the late development of arthritis and high titers of IgG auto Abs. Disease is initiated by autoreactive T cells, which escape negative selection by expressing a second TCR with a different specificity or an altered affinity. Transfer of Ag-specific Treg cells ameliorates the early onset signs of disease but does not prevent the development of long-term chronic pathologies. Altogether, our results suggest that Ag dose directly affects Treg-cell generation and thus, the set-up of T-cell tolerance.

The co-administration of telaprevir increases ribavirin plasma and intra-erythrocytic concentrations, causing higher onset of anemia

The co-administration of telaprevir increases ribavirin plasma and intra-erythrocytic concentrations, causing higher onset of anemia

Susceptibility-weighted imaging is suitable for evaluating signal strength in different brain regions of a rabbit model of acute hemorrhagic anemia.

Susceptibility-weighted imaging is suitable for evaluating signal strength in different brain regions of a rabbit model of acute hemorrhagic anemia.

Feedback Through Dusp6 Modulates Ineffective Erythropoiesis Caused By Mutant Kras

Somatic mutations that activate Ras signaling are common in hematologic malignancies. They are particularly associated with juvenile and chronic myelomonocytic leukemias, which are classified as ‘overlap' myelodysplastic syndromes / myeloproliferative neoplasms (MDS/MPN). These diseases are characterized by myelomonocytic proliferation and dysplasia leading to anemia and thrombocytopenia. We have previously shown that conditional expression of KrasG12D in mice models MDS/MPN, producing a fatal disease with increased granulocyte/macrophage (G/M) progenitors and a reduction in the megakaryocyte/erythroid (Meg/E) lineage. Despite intensive study of Ras signaling, the mechanisms by which oncogenic Ras regulates cell fate decisions in hematopoiesis remain unclear; better understanding of these processes may allow development of novel therapies for MDS/MPN. We found that mRNA and protein levels of dual specificity phosphatase-6 (Dusp6), a negative regulator of MAPK signaling, is elevated in the bone marrow of KrasG12D mice. This suggested that a negative feedback loop generated by Dusp6 might regulate the proliferation and differentiation of hematopoietic progenitors in MDS/MPN. To test this hypothesis, we conditionally expressed KrasG12D from its endogenous locus in the bone marrow of wild type and Dusp6 knockout mice. Interestingly, many characteristics of MDS/MPN were more severe in Dusp6-/-; KrasG12D mice. For example, we observed significantly lower hemoglobin levels in 3-4 week old Dusp6-/-; KrasG12D mice (8.35g/dL, n=4) compared to Dusp6+/+; KrasG12D mice (11.7g/dL, n=10). Moreover, the peripheral blood of Dusp6+/+; KrasG12D mice contained approximately 13% of reticulocytes (n=12), whereas Dusp6-/-; KrasG12D mice had nearly 36% reticulocytes (n=4) in the peripheral blood. Furthermore, we observed acanthocytes, poikilocytes and other structural abnormalities in the red blood cells from Dusp6-/-; KrasG12D mice and not in mice wild type for Dusp6. Thus, Dusp6 loss accelerates the onset of anemia caused by KrasG12D, which suggests an exacerbation of the erythroid differentiation defect. We did not observe any significant differences in white blood count or spleen size attributable to Dusp6 genotype. Differentiation of hematopoietic progenitors was assessed in the bone marrow by flow cytometry. The frequency of pre-Meg/E progenitors (Lin-Sca1-Kit+CD34+FcgR-CD150+CD105-) from Dusp6-/-; KrasG12D mice was reduced by approximately 50% when compared to Dusp6+/+; KrasG12D mice. Consistent with this result, Dusp6-/-; KrasG12D mice possessed a significantly greater percentage of immature red blood cells (proerythroblasts; CD71hi Ter119+) and fewer mature red blood cells (orthochromatic erythroblasts; CD71+ Ter119+) than bone marrow cells from Dusp6+/+; KrasG12D mice. By contrast, Dusp6 expression does not have an effect on the frequency of pre-G/M cells (Lin-Sca1-Kit+CD34+FcgR-CD150-CD105-), which remains unchanged between Dusp6+/+; KrasG12D and Dusp6-/-; KrasG12D mice. Together, these findings demonstrate that negative feedback through Dusp6 functions to maintain erythropoiesis the context of oncogenic Ras signaling. Futher, these data strengthen the association between excessive MAPK activity and dyserythropoiesis, and further support development of inhibitors of MEK and/or ERK to treat MDS/MPN. Disclosures:No relevant conflicts of interest to declare.

Exploring The Relationship Between Autophagy and Mitochondrial Dysfunction In a Mouse Model Of MDS

Although myelodysplastic syndrome (MDS) is uncommon in children, with an annual estimated incidence of 0.5 to 4 cases per million children compared to 20 to 40 cases per million in adults, the incidence of MDS appears to be increasing in the United States with the improvements in survival rates of childhood cancers, at least in part because the intensive chemo- and radiotherapy regimens that cure pediatric patients with cancer may also cause therapy-related MDS. Unlike in other blood-related cancers, the disease-causing mutations in pediatric MDS and t-MDS/AML are unknown. Nevertheless, recent studies have suggested that the mitochondrial dysfunction associated with MDS results from the inability of hematopoietic stem/progenitor cells to appropriately cope with mitochondrial damage andmitochondrial dysfunction appears to be an early event in the development of t-MDS/AML.Autophagy is a catabolic process involved in the sequestration and breakdown of cellular components, including organelles such as mitochondria and long-lived or misfolded proteins. By sequestering and degrading depolarized fragments of mitochondria that result from cycles of mitochondrial fusion and fission, autophagy plays a critical role in the maintenance of healthy pools of mitochondria. Given the importance of autophagy in mitochondrial quality control and increasing evidence that mitochondrial dysfunction plays a role in the pathogenesis of MDS, we sought to explore the role of autophagy in the pathogenesis of MDS associated with mitochondrial dysfunction using the previously established PolgAmt/mt mouse model (a.k.a. mtDNA mutator mice).The mtDNA mutator mice express a proof-reading-deficient mutant of mtDNA polymerase (PolgA-D257A), which results in increased mitochondrial mutation frequencies in multiple tissues, and a decline in respiratory function of mitochondria-encoded complexes. The delayed onset of an MDS-like phenotype in these mice provides a window of time to interrogate the role of autophagy in the progression of disease symptoms. Disruption of autophagy in erythroid progenitors did not cause a significant decrease in hemoglobin or red blood cell count in PolgAwt/wt mice, however, it accelerated the onset of anemia and morbidity significantly in PolgAmt/mt mice, suggesting that autophagy delays the onset of symptoms associated with pathologic mtDNA mutations. Flow cytometric evaluation of peripheral blood of PolgAmt/mt mice and wild-type littermates revealed an unexpected defect in RBC maturation in PolgAmt/mt animals, which became apparent with age or following serial phlebotomy. The defect was similar to that observed in autophagy-defective Ulk1-deficient mice suggesting that pathogenic mtDNA mutations may cause an age-dependent delay in autophagy. Transformed PolgAmt/mt murine embryonic fibroblasts (MEFs) with mitochondrial dysfunction also showed a defect in basal LC3 conversion and p62 accumulation, consistent with impaired flux through the autophagy pathway. Together, our data indicates that although autophagy initially combats accumulation of dysfunctional mitochondria resulting from an increased mtDNA mutation burden, the latter eventually leads to a decline in basal autophagy and impaired clearance of mitochondria, which contributes to the decline in mitochondrial function and progression of MDS-like disease in mice. Disclosures:No relevant conflicts of interest to declare.

Food Fortification to Combat Iron Deficiency Anaemia

Among the various blood disorder anemia is a widespread health problem associated with an increased risk of morbidity and mortality, especially in pregnant women and young children. The major causes for anemia are both nutritional (vitamin and mineral deficiencies) and non-nutritional (infection and hemoglobinopathies). In particular, the major factors that contribute to the onset of anemia are iron deficiency and malaria. The present review focuses on the various intervention programmers for eradicating iron deficiency anaemia.

Significant early higher ribavirin plasma concentrations in patients receiving a triple therapy with pegylated interferon, ribavirin and telaprevir

The new standard of care for treatment for infection with genotype 1a/b of HCV now is the combination of telaprevir (TLV) with ribavirin (RBV) and pegylated interferon (Peg-IFN). Although this new therapy gives a higher response rate than the Peg-IFNα plus RBV treatment, a greatly higher rate of anaemia onset has been reported in all clinical trials. Because haemolysis is a typical concentration-dependent side effect of RBV, modulated by ITPA gene polymorphisms, we aimed to compare the early RBV plasma exposure of nine patients after 2weeks of treatment with triple therapy with RBV concentrations of 187 patients treated with RBV and Peg-IFNα over the same time scale; this comparison was performed also stratifying patients according to ITPA polymorphism genotype and anaemia onset after 1month of treatment. All TLV-treated patients had unfavourable ITPA genetic profile and developed anaemia. Moreover, both the rate of anaemia onset and the haemoglobin loss at 1month were significantly higher in patients treated with TLV. This observation has been confirmed also in patients with the same ITPA genetic profile in double therapy. Strikingly, also early RBV plasma concentrations were significantly higher in patients treated with TLV. These unbiased results confirm the observations recently reported and suggest that the high rate of anaemia onset could be mainly due to the increased RBV exposure, probably caused by a 'boosting effect' by TLV. These data highlight the great importance of early therapeutic drug monitoring of RBV in the management of anaemia in the triple therapy.

Age adjusted Charlson Co-morbidity Index is an independent predictor of mortality over long-term follow-up in infective endocarditis

BackgroundInfective endocarditis (IE) is associated with high morbidity and mortality. The epidemiology of IE is changing, affecting more elderly patients with increased medical comorbidities. We aimed to assess the ability of the age adjusted Charlson Co-morbidity Index (ACCI) to predict early and late outcomes. MethodsBetween 1998 and 2010, adult patients with definite IE according to the modified Duke criteria were identified. The primary outcome was in-hospital and all-cause mortality. The secondary outcome was predictors of the primary outcome incorporating ACCI. Results148 patients with IE were followed up for a mean of 3.8±3years. The mean age was 57±17years and 66% were male. In-hospital mortality and all-cause mortality were 24 and 47% respectively. Comorbid conditions included diabetes mellitus (DM) (21%); ischaemic heart disease (16%); heart failure (HF) (14%); renal failure (eGFR <60ml/min/1.73m2) (19%); and anaemia (64%). The most common causative organism was Staphylococcus aureus (53%). ACCI was >3 in 59% of patients. Cardiac surgery was performed in 45% of patients. On Cox regression analysis, ACCI >3 (HR=3.0 [1.5–6.0], p<0.002), new onset HF (HR=2.2 [1.3–3.6], p<0.003), anaemia (HR=1.8 [1.1–3.2], p=0.04) and age-per decade (HR=1.4 [1.1–1.7]. p=0.004) were independently associated with all-cause mortality. ACCI >3 was the strongest predictor of in-hospital mortality (OR=8.4 [2.8–24], p<0.001). Of the individual ACCI components, prior HF, DM with complications and metastatic disease were independent predictors of all-cause mortality. ConclusionIn-hospital and all-cause mortality of IE remain high. An ACCI >3 was a strong predictor of mortality, in addition to age, new HF and anaemia.

Association of ITPA polymorphisms rs6051702/rs1127354 instead of rs7270101/rs1127354 as predictor of ribavirin-associated anemia in chronic hepatitis C treated patients

Functional variants rs7270101 and rs1127354 of inosine triphosphatase (ITPA) were recently found to protect against ribavirin (RBV)-induced hemolytic anemia. However, no definitive data are yet available on the role of no functional rs6051702 polymorphism. Since a simultaneous evaluation of the three ITPA SNPs for hemolytic anemia has not yet been investigated, we aimed to understand the contribution of each SNPs and its potential clinical use to predict anemia in HCV treated patients.A retrospective analysis included 379 HCV treated patients. The ITPA variants rs6051702, rs7270101 and rs1127354 were genotyped and tested for association with achieving anemia at week 4. We also investigated, using multivariate logistic regression, the impact of each single and paired associated polymorphism on anemia onset.All SNPs were associated with Hb decrease. The carrier of at least one variant allele in the functional ITPA SNPs was associated with a lower decrement of Hb, as compared to patients without a variant allele. In multivariate logistic regression analyses the carrier of a variant allele in the rs6051702/rs1127354 association (OR=0.11, p=1.75×10−5) and Hb at baseline (OR=1.51, p=1.21×10−4) were independently associated with protection against clinically significant anemia at week 4.All ITPA polymorphisms considered were shown to be significantly associated with anemia onset. A multivariate regression model based on ITPA genetic polymorphisms was developed for predicting the risk of anemia. Considering the characterization of pre-therapy anemia predictors, rs6051702 SNP in association to rs1127354 is more informative in order to avoid this relevant adverse event.

Accelerated destruction of erythrocytes in Tie2 promoter-driven STAT3 conditional knockout mice

AimsSTAT3 is a key modulator of activation and differentiation of macrophages. But it is still unknown if deficiency of STAT3 activates macrophages to destroy erythrocytes by phagocytosis. We generated STAT3 conditional knockout mice by crossing floxed STAT3 mice with Tie2 promoter-driven Cre-recombinase transgenic mice and clarified that Stat3 plays a critical role in the formation and activation of macrophages. Main methodsBlood cell count, reticulocyte count, serum lactate dehydrogenase, erythropoietin, iron and ferritin concentration, and life span of the erythrocytes in Tie2 promoter-driven STAT3 conditional knockout mice were analyzed. To explore the erythropoietic function of the mice, we subjected them to brief hemolytic anemia by injecting them intraperitoneally with phenylhydrazine. The fragility of erythrocytes was examined by scanning electron microscopy and osmotic tolerance test. Key findingsThe conditional knockout mice had mild normocytic anemia. They also displayed higher lactate dehydrogenase, ferritin and erythropoietin concentration, higher reticulocyte count, and a shorter lifespan of erythrocytes compared with wild-type controls. These data suggest that destruction of erythrocytes and secondary blood formation were accelerated in the STAT3 conditional knockout mice. It didn't appear due to the fragility of erythrocytes. A few of the conditional knockout mice suddenly developed acute severe anemia, high body temperature and massive splenomegaly, and died within 2weeks after the onset of anemia. SignificanceThis study provided evidence that STAT3 have a critical role in the destruction of erythrocytes by resident macrophages in the spleen.

Anaemia is a predictor of mortality in patients undergoing aortic valve surgery

We read the article ‘Preoperative anaemia is a risk factor for mortality and morbidity following aortic valve surgery (AVS)’ by Elmistekawy et al. [1] with interest. They aimed to investigate the incidence of preoperative anaemia in patients undergoing nonemergency AVS and its association with postoperative outcomes. They concluded that preoperative anaemia is a common finding in patients undergoing AVS and is an important and potentially modifiable risk factor for postoperative morbidity and mortality. We believe that these findings will pave the way for further studies about the relationships between preoperative anaemia and AVS. Thanks to the authors for their contribution. It is actually believed that patients undergoing heart surgery have a lower margin of safety for tolerance of low haemoglobin (Hg) levels. A significant association between anaemia with adverse outcomes (death, stroke and renal impairment) in patients undergoing cardiac and non-cardiac surgery has been demonstrated in previous studies [2]. Blood transfusion is dangerous with regard to in-hospital mortality, morbidity and long-term survival. Blood transfusion is frequently used as a volume expander while simultaneously increasing the haematocrit. Transfusions have been independently associated with increased mortality after cardiac surgery. Transfusion is also dose-dependent risk factor for early mortality after revascularization. Blood transfusions have been linked to postoperative renal dysfunction, pneumonia, wound infections, severe sepsis and hospital mortality [3]. Based on this point of view, because anaemia and need for blood transfusions lead to very significant adverse effects after cardiopulmonary bypass surgery, it is necessary to research the effective methods of anaemia correction to reduce the need for blood transfusions. Nowadays, although anaemia is a predictor of postoperative complications and is a risk factor for mortality in patients after cardiac surgery treatment, red distribution width (RDW) is known as an independent early marker of Hg evolution and independently identified risk of new onset anaemia, providing predictive information for haematological abnormalities beyond Hg concentrations and other known risk factors. RDW has recently been identified as an independent predictor of all-cause long-term mortality in patients with coronary artery disease [4]. So, if the authors had mentioned RDW, the results of the study might be different. Reduced glomerular filtration rate (GFR) may also be associated with adverse outcomes in patients with cardiovascular disease. In previous study, preoperative GFR was predictive of all-cause mortality, cardiovascular mortality and combined cardiovascular mortality and morbidity. GFR may be useful to identify those patients undergoing cardiovascular surgery with subclinical chronic kidney disease [5]. For this reason, it would be better, if the authors mentioned any of these possible conditions. Finally, it would be better if the authors might define how much time they specified on measuring Hg levels, because it can be associated with haemodilutional anaemia [6]. Following cardiac surgery, some factors including longer hospital stays, increased risk of infection, higher rate of pulmonary complications, prolonged ventilation, stroke, renal failure, atrial fibrillation, myocardial infarction, pneumonia, prolonged ventilation and operation time are associated with increased morbidity and mortality rates in patients undergoing AVS [3]. So, the further studies should evaluated these factors in patients with AVS.

The impact of anemia on renal recovery and survival in acute kidney injury

Anemia occurs frequently among patients who develop acute kidney injury likely due to abnormal erythropoietic activity. Anemia has been associated with increased mortality among hospitalized patients, but its impact on renal recovery or survival is poorly characterized among patients with acute kidney injury. We aim to assess if anemia is associated with lower renal recovery and poorer survival. A retrospective cohort of 211 patients was examined. Anemia and other patient characteristics were assessed as potential risk factors for the presence of renal recovery or death. Additionally, renal recovery, dialysis requirement and survival were compared between those with mild versus severe anemia. 86% of patients with acute kidney injury (AKI) developed acute anemia which generally occurred at the time of acute kidney injury. Anemia did not appear to be associated with lack of renal recovery or death, but rather underlying comorbid conditions and severity of illness were more likely to be associated with renal recovery or death, respectively. Neither renal recovery nor survival differed among patients with mild versus severe anemia as measured by fall in hemoglobin or nadir hemoglobin. New onset anemia does not appear to be associated with lack of renal recovery or death among patients with acute kidney injury.

Advantage of Systematic Blood Cell Count 2 Days Post-delivery for the Diagnosis of Postpartum Maternal Anaemia

Aims: To evaluate the advantage of full blood cell count as performed 48h post-delivery for the diagnosis of postpartum maternal anaemia. Study Design: Observational retrospective study. Methodology: According to the usual local protocol, haemoglobin assessment is made in all mothers at entry in the labour room (D0), and 2 days post-delivery (D2). The relationship between haemoglobin decrease, anaemia onset, and obstetrical anamnesis has been evaluated by multiple logistic regression analysis. Results: Four hundred and seven (407) parturient women were included. Of them 13.3% (n=54) had >2g haemoglobin loss and were considered having developed undiagnosed Research Article British Journal of Medicine & Medical Research, 3(4): 1144-1153, 2013 1145 postpartum haemorrhage (UDPPH); 10.3% (n=42) had anaemia with <10g/dL haemoglobin at D2. The identified risk factors for postpartum anaemia onset were episiotomy (OR 11.8; 95%CI 4.71-17.5; P <0.001), foetal distress (OR 5.99; 95%CI 2.2016.3; P <0.001), duration of labour (OR 1.21; 95%CI 1.05-1.40; P<0.008), and presence of perineal and/or vaginal tears (OR 2.9; 95%CI 1.18-7.13; P =0.02). Conclusion: Systematic haemoglobin control in all patients 2 days after vaginal delivery allows the detection and subsequent treatment of UDPPH-related anaemia.