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Anemia and chronic kidney disease (CKD), which worsen bidirectionally, are associated with mortality in older adults. This study aimed to examine the association between CKD and the type of anemia and its impact on mortality in the general population. Data from a nationwide database of 203,280 individuals who participated in the annual "Specific Health Check and Guidance in Japan" evaluation between 2008 and 2011 were used. Over a follow-up period of 4 years, 2,819 all-cause, 1,595 cancer-related, 523 cardiovascular, and 128 infectious disease deaths were recorded. Macrocytic anemia was detected in 2.3% of participants. The prevalence of normocytic and macrocytic anemia increased with advancing CKD stage. Multivariate Cox proportional hazards regression analysis revealed significant associations between macrocytic anemia and the all-cause, cancer, and cardiovascular mortality rates. Including the anemia type improved the prediction accuracy for all-cause deaths. The participants were divided into eight groups based on the anemia type and CKD. Macrocytic anemia of CKD had the highest hazard ratio for all-cause mortality in the general population. A correlation was observed between macrocytic anemia and CKD. Macrocytic anemia predicted mortality in the general population, suggesting that it could serve as an early indicator of premature death in high-risk individuals., Competing Interests: Declarations. Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Background: Pre-operative anaemia is common and associated with adverse outcomes. We hypothesised that pre-operative anaemia would be evident more than 1 month pre-operatively, and that peri-operative changes in haemoglobin and post-operative outcomes differed between red cell size-based subsets of anaemia., Methods: A retrospective single-centre cohort study, including all patients 18 years and older undergoing their first surgery at Landspitali between January 2006 and December 2018 with available measurement of haemoglobin (Hb) within 30 days preceding surgery. Clinical data were compared between patients with subgroups of anaemia classified by mean corpuscular volume (MCV) into microcytic (MCV < 80 fl), normocytic (MCV 80-100 fl), and macrocytic (MCV > 100 fl) anaemia. The development of haemoglobin measurements from a nationwide database was plotted from 1 year pre-operatively to 2 years post-operatively., Results: Of 40,979 patients, 10,505 (25.6%) had pre-operative anaemia, of which 1089 (10.4%) had microcytic anaemia, 9243 (88.0%) had normocytic anaemia, and 173 (1.6%) had macrocytic anaemia. Patients within all subgroups of pre-operative anaemia had a higher degree of comorbidity and frailty burden and a low haemoglobin evident for more than 100 days pre-operatively and similar changes post-operatively. Post-operative prolonged recovery of haemoglobin was slower for macrocytic anaemia than other types of anaemia. All groups of patients with anaemia had a higher incidence of 30-day mortality, acute kidney injury, and rate of readmission compared with patients without anaemia., Conclusions: Pre-operative anaemia is evident long prior to the procedure and its association with worse outcomes is similar regardless of red cell size., (© 2023 Acta Anaesthesiologica Scandinavica Foundation.)

Introduction: Anemia frequently occurs during course of clinical thyroid diseases. Without proper diagnosis & effective treatment of underlying thyroid disease, it is often difficult to achieve complete correction of anemia., Aim: The present study was conducted to assess prevalence & types of anaemia in patients with thyroid disorders., Materials: A cross sectional study was conducted on 160 patients including both hypothyroid & hyperthyroid patients at OPD/IPD in SRN Hospital affiliated to MLN Medical college Prayagraj between July 2021 & August 2022. Blood samples were taken to estimate CBC, GBP with Retic count, S. ferritin, S. folate, S. Vitamin B12, Thyroid profile. Data was entered in MS Excel Spreadsheet & appropriate statistical package applied., Result: Out of 144 hypothyroid patients, 102 (70.83%) were found to be anaemic & out of 16 hyperthyroid patients, 6 (37.5%) were found to be anaemic. In 102 anaemic hypothyroid patients, 56 (54.9%)had normocytic normochromic, 25 (24.5%) had microcytic and 21 (20.5%) had macrocytic anaemia. In 6 anaemic hyperthyroid patients, 3 (50%) had normocytic normochromic, 2(33.33%) had microcytic and 1 (16.67%) had macrocytic anaemia., Conclusion: High prevalence of anaemia was found in patients with thyroid disorders. Anaemia is an uncommon finding in hyperthyroidism but when present may be similar to that present in hypothyroidism. The most common type of anaemia in both hyperthyroidism & hypothyroidism was found to be normocytic normochromic, followed by microcytic & least common being macrocytic. References Suhail N, Abu Alsel BT, Batool S. Prevalence and association of thyroid dysfunction with anemia/body iron status among northern border Saudi population. Int J Med Res Health Sci 2020;9(3):1-7. Peraka SA, Karre S, Ravuri S, et al., To evaluate prevalence of anemia in hypothyroid patients. J Diagn Pathol Oncol 2019;4(2):110-113., (© Journal of the Association of Physicians of India 2011.)

Justification: Anemia in children is a significant public health problem in our country. Comprehensive National Nutrition Survey 2016-18 provides evidence that more than 50% of childhood anemia is due to an underlying nutritional deficiency. The National Family Health Survey-5 has reported an increase in the prevalence of anemia in the under-five age group from 59% to 67.1% over the last 5 years. Clearly, the existing public health programs to decrease the prevalence of anemia have not shown the desired results. Hence, there is a need to develop nationally acceptable guidelines for the diagnosis, treatment and prevention of nutritional anemia., Objective: To review the available literature and collate evidence-based observations to formulate guidelines for diagnosis, treatment and prevention of nutritional anemia in children., Process: These guidelines have been developed by the experts from the Pediatric Hematology-Oncology Chapter and the Pediatric and Adolescent Nutrition (PAN) Society of the Indian Academy of Pediatrics (IAP). Key areas were identified as: epidemiology, nomenclature and definitions, etiology and diagnosis of iron deficiency anemia (IDA), treatment of IDA, etiology and diagnosis of vitamin B12 and/or folic acid deficiency, treatment of vitamin B12 and/or folic acid deficiency anemia and prevention of nutritional anemia. Each of these key areas were reviewed by at least 2 to 3 experts. Four virtual meetings were held in November, 2021 and all the key issues were deliberated upon. Based on review and inputs received during meetings, draft recommendations were prepared. After this, a writing group was constituted which prepared the draft guidelines. The draft was circulated and approved by all the expert group members., Recommendations: We recommend use of World Health Organization (WHO) cut-off hemoglobin levels to define anemia in children and adolescents. Most cases suspected to have IDA can be started on treatment based on a compatible history, physical examination and hemogram report. Serum ferritin assay is recommended for the confirmation of the diagnosis of IDA. Most cases of IDA can be managed with oral iron therapy using 2-3 mg/kg elemental iron daily. The presence of macro-ovalocytes and hypersegmented neutrophils, along with an elevated mean corpuscular volume (MCV), should raise the suspicion of underlying vitamin B12 (cobalamin) or folic acid deficiency. Estimation of serum vitamin B12 and folate level are advisable in children with macrocytic anemia prior to starting treatment. When serum vitamin B12 and folate levels are unavailable, patients should be treated using both drugs. Vitamin B12 should preferably be started 10-14 days ahead of oral folic acid to avoid precipitating neurological symptoms. Children with macrocytic anemia in whom a quick response to treatment is required, such as those with pancytopenia, severe anemia, developmental delay and infantile tremor syndrome, should be managed using parenteral vitamin B12. Children with vitamin B12 deficiency having mild or moderate anemia may be managed using oral vitamin B12 preparations. After completing therapy for nutritional anemia, all infants and children should be advised to continue prophylactic iron-folic acid (IFA) supplementation as prescribed under Anemia Mukt Bharat guidelines. For prevention of anemia, in addition to age-appropriate IFA prophylaxis, routine screening of infants for anemia at 9 months during immunization visit is recommended.

Background/purpose: Our previous study found 284 gastric parietal cell antibody (GPCA)-positive atrophic glossitis (AG) patients (so-called GPCA + AG patients in this study) in a group of 1064 AG patients. This study evaluated whether high-titer (GPCA titer ≥ 160) GPCA + AG patients had greater frequencies of anemia, vitamin B12 deficiency, macrocytosis, and hyperhomocysteinemia than low-titer (GPCA titer < 160) GPCA + AG patients., Methods: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 117 high-titer GPCA + AG patients, 167 low-titer GPCA + AG patients, and 532 healthy control subjects were measured and compared., Results: We found that 12.0%, 29.1%, 23.1%, 16.2%, 1.7%, and 23.1% of 117 high-titer GPCA + AG patients and 5.4%, 17.4%, 17.4%, 7.2%, 1.2%, and 14.4% of 167 low-titer GPCA + AG patients were diagnosed as having macrocytosis, blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, and hyperhomocysteinemia, respectively. Moreover, both 117 high-titer and 167 low-titer GPCA + AG patients had significantly greater frequencies of macrocytosis, blood hemoglobin, serum iron and vitamin B12 deficiencies, and hyperhomocysteinemia than 532 healthy control subjects (all P-values < 0.05). In addition, 117 high-titer GPCA + AG patients also had greater frequencies of anemia (P = 0.029, statistically significant), serum vitamin B12 deficiency (P = 0.027, statistically significant), macrocytosis (P = 0.075, marginal significance), and hyperhomocysteinemia (P = 0.085, marginal significance) than 167 low-titer GPCA + AG patients., Conclusion: For GPCA + AG patients, high-titer GPCA + AG patients have greater frequencies of anemia, serum vitamin B12 deficiency, macrocytosis, and hyperhomocysteinemia than low-titer GPCA + AG patients., (Copyright © 2019 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Hypocupremia is a rare and under-recognised cause of bone marrow dysplasia and myeloneuropathy. A 47-year-old Caucasian woman had progressive ascending peripheral neuropathy and gait ataxia over 3 months and fatigue, dyspnoea and unintentional weight loss over 8 months. She had profound macrocytic anaemia and neutropenia. Initial workup included normal serum vitamin B 12 Bone marrow biopsy was suggestive of copper deficiency. Serum copper levels were later confirmed to be undetectable. The patient received oral copper repletion which resulted in complete normalisation of haematological abnormalities 16 weeks later. However, neurological deficits persisted. This case describes a delayed diagnosis of hypocupremia as initially suggested through invasive testing. Associating myeloneuropathy with cytopenia is imperative for accurate and prompt diagnosis of hypocupremia, which can be confirmed by serum analysis alone. Developing an accurate differential diagnosis can help prevent unnecessary procedures. Furthermore, initiating prompt copper repletion prevents further neurological impairment. Neurological deficits are often irreversible., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background/purpose: Macrocytosis is defined as having the mean corpuscular volume (MCV) ≧ 100 fL. This study evaluated whether 41 atrophic glossitis (AG) patients with macrocytosis had significantly higher frequencies of anemia, hematinic deficiencies, hyperhomocysteinemia, and serum gastric parietal cell antibody (GPCA) positivity than 532 healthy control subjects or 1064 AG patients., Methods: Complete blood count, serum iron, vitamin B12, folic acid, homocysteine, and GPCA levels in 41 AG patients with macrocytosis, 1064 AG patients, and 532 healthy control subjects were measured and compared., Results: We found that 73.2%, 22.0%, 73.2%, 4.9%, 80.5%, and 56.1% of 41 AG patients with macrocytosis were diagnosed as having blood hemoglobin, iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity, respectively. Moreover, 41 AG patients with macrocytosis had significantly higher frequencies of blood hemoglobin and serum vitamin B12 deficiencies, hyperhomocysteinemia, and serum GPCA positivity than 532 healthy control subjects or 1064 AG patients (all P-values < 0.001). In addition, 41 AG patients with macrocytosis also had significantly higher frequencies of serum iron and folic acid deficiencies than 532 healthy control subjects (both P-values < 0.001). Pernicious anemia was found in 22 AG patients with macrocytosis., Conclusion: There are significantly higher frequencies of anemia and serum iron, vitamin B12, and folic acid deficiencies, hyperhomocysteinemia, and serum GPCA positivity in AG patients with macrocytosis than in healthy control subjects. AG patients with macrocytosis also have significantly higher frequencies of blood hemoglobin and serum vitamin B12 deficiencies, hyperhomocysteinemia, and serum GPCA positivity than AG patients., (Copyright © 2019 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

We report here the case of a 62-year-old patient with Child-Pugh stage C ethylic cirrhosis associated with severe macrocytic anaemia, refractory to iterative transfusions and withdrawal. After a haemorrhagic, deficiency-related, or sideroblastic etiology was ruled out, haemolytic anaemia was suspected. A blood smear allowed diagnosis of haemolytic anaemia with acanthocytes. This offers the opportunity to discuss anaemia in patients with alcoholic cirrhosis, a frequent complication spanning a broad severity range and having the potential to be life-threatening. Its origin can be multifactorial : acute haemorrhage, dilution, haemolysis (here due to acanthocytosis), marrow insufficiency caused by direct alcohol toxicity, malnutrition, iron deficiency, vitamin B9 or B12 deficiency, chronic inflammation, splenic sequestration induced by portal hypertension...

A patient with a diagnosis of myelodysplastic syndrome (MDS) with isolated 5q deletion underwent repeat bone marrow biopsy to assess haematological response after 6 months of initial lenalidomide therapy. Subsequent bone marrow biopsies revealed persistent MDS with del(5q) in addition to a small atypical mast cell population with >25% of mast cells with spindle-shaped morphology and immunohistochemistry characteristics consistent with mastocytosis. Molecular testing on the bone marrow was positive for cKIT D816V and the patient was diagnosed with systemic mastocytosis (SM) with an associated haematological neoplasm. MDS with SM is well known to be associated; however, to the best of our knowledge, only one prior case report identifies MDS with del(5q) and associated cKIT D816V positive mastocytosis. While the exact clonal origin of both chromosomal aberrations is unclear, this case illustrates the therapeutic efficacy of lenalidomide in a patient with MDS with del(5q) and rarely associated cKIT positive SM., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Macrocytic anemia is common in liver disease. However, its role in hepatitis B virus (HBV)-related decompensated cirrhosis remains unknown. The aim of the present study was to determine the association between macrocytic anemia and the severity of liver impairment in patients with HBV-related decompensated cirrhosis according to the Model for End Stage Liver Disease (MELD) score., Methods: A total of 463 participants who fulfilled our criteria were enrolled in this cross-sectional study. Patients were classified into three groups according to anemia types, diagnosed based on their mean corpuscular volume level. Multivariate linear regression analyses were used to determine the association between macrocytic anemia and the MELD score for patients with HBV-related decompensated cirrhosis., Results: Patients with macrocytic anemia had evidently higher MELD scores (10.8 ± 6.6) than those with normocytic anemia (8.0 ± 5.5) or microcytic anemia (6.3 ± 5.1). The association remained robust after adjusting for age, gender, smoking, drinking, and total cholesterol (β = 1.94, CI: 0.81-3.07, P < 0.001)., Conclusions: Macrocytic anemia was found to be associated with the severity of liver impairment and might be a predictor for short-term mortality in patients with HBV-related decompensated cirrhosis.

Backgorund: Sanjad-Sakati syndrome (SSS) is a rare autosomal recessive disease caused by a deletion mutation (155-166del) in exon 3 of the TBCE gene on chromosome 1q42-43. The syndrome is characterized by primary hypoparathyroidism, typical dysmorphic features and severe growth retardation., Case Presentation: We encountered a 2-year-old boy with hypocalcemia, failure to thrive and macrocytic anemia. The patient had the characteristic features of SSS and genetic testing confirmed that he was homozygous for the TBCE mutation. Although malabsorption was initially considered the cause of his symptoms, the results did not confirm that diagnosis. Our patient had cow milk protein allergy and folic acid deficiency, which has not been described in previous SSS cases. It was difficult to treat the patient's hyperphosphatemia and we ultimately selected sevelamer treatment, which was tolerated well and improved his hypocalcemia., Conclusions: SSS should be considered in the differential diagnosis of any infant with hypocalcemia, dysmorphism and failure to thrive.

Background: Hemolytic features in patients with pernicious anemia have not been emphasized., Methods: Seven Japanese patients at 60 - 88 years of age with vitamin B12 deficiency-related hemolytic anemia were assessed., Results: Serum vitamin B12 levels in these cases were 46 - 89 pg/mL (normal reference range: 233 - 914 pg/mL). Clinically, the patients presented with thrombotic microangiopathy (TMA)-like hemolytic features (including macrocytic anemia, schistocytes on blood smears, high serum lactate dehydrogenase, hyperbilirubinemia, and low serum haptoglobin). Six cases had type A gastritis (assessed by esophagogastroduodenoscopy with hypergastrinemia) with additional laboratory data of high plasma homocysteine levels and anti-intrinsic factor/anti-parietal cell antibodies. One case was in post-gastrectomy condition. Following treatment with vitamin B12, anemia resolved within 4 weeks in five of the seven cases except for two cases of delayed response., Conclusions: In elderly patients exhibiting hemolytic features in association with macrocytic anemia, vitamin B12 deficiency should be considered in the differential diagnosis.

Introduction: Nutritional deficiency is frequent in patients with an alcohol use disorder (AUD). We aimed to analyze serum and erythrocyte folate deficiency in a case series of patients that initiated treatment of AUD., Patients and Methods: A cross-sectional study in patients admitted for detoxification between 2007 and 2015 was performed. Sociodemographic characteristics, history of alcohol consumption, type of alcohol, and medical co-morbidity were assessed at admission. Blood samples for biochemistry and hematological parameters were collected at admission. Logistic regression models were used to establish predictors of folate deficiency., Results: 211 patients (79.1% men) were eligible; age at admission was 46 years [IQR:40-51], and the amount of alcohol consumption was of 160g/day [IQR:120-200]. Thirty four percent of patients had macrocytosis (MCV>100fL), 12.8% had anemia, 23% of cases presented with serum folate deficiency and 7% presented with erythrocyte folate deficiency. Most (69%) of the patients with serum folate deficiency had normal erythrocyte folate levels. In univariate analysis, macrocytosis (OR=3.4, 95%CI:1.7-6.6), alcohol-related liver disease (ARLD) (OR=2.5, 95%CI:1.0-6.1) and drinking alcoholic beverages other than beer (OR=3.3, 95%CI:1.5-7.3) were associated with folate deficiency. However, only macrocytosis was significantly associated with serum folate deficiency in multivariate analysis (OR=3.1, 95%CI:1.1-8.9). Macrocytosis (P<0.001), ARLD (P=0.01) and the type of alcohol consumption (P<0.001) were factors associated with erythrocyte folate deficiency in univariate analysis. In multivariate analysis only macrocytosis remained significantly associated to erythrocyte folate deficiency (P=0.037)., Conclusion: Folate deficiency is a relatively frequent finding in contemporary, middle-aged patients with AUD, and macrocytosis is significantly associated with the deficiency., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Microcystic stromal tumor (MST) is a rare tumor of presumed sex-cord stromal differentiation. We present a case of MST arising within a patient with constitutional 5q deletion syndrome, whose deletion encompassed the APC gene. Genomic analysis of the MST revealed a point mutation in the remaining APC allele, predicted to result in abnormal splicing of Exon 7. Subsequent clinical investigation revealed multiple gastrointestinal polyps qualifying for a diagnosis of familial adenomatous polyposis. This case emphasizes the importance of an aberrant Wnt/β-catenin pathway in the development of MST and adds credence to the inclusion of MST as a rare phenotype of familial adenomatous polyposis. In a search for additional genetic aberrations which may contribute to the development of this rare tumor, genomic analysis revealed a frameshift mutation in FANCD2, a protein which plays a key role in DNA repair. This protein is expressed in human ovarian stromal cells and FANCD2-knockout mice are known to develop sex cord-stromal tumors, factors which further support a possible role of aberrant FANCD2 in the development of MST.

Background: Serum free light chain (FLC) analysis with ratio and urine immunofixation electrophoresis (IFE) are both available for routine use in helping to detect plasma cell dyscrasia and related diseases., Cases: Case reports showing one serum positive for serum FLC but that showed a hook effect and overestimated the amount of monoclonal FLC while urine IFE was negative for Bence Jones protein, and a second serum that showed elevated FLC κ and λ but a normal κ/λ ratio, while urine IFE was positive for Bence Jones protein., Conclusions: These two techniques complement one another. Neither of the techniques is truly quantitative, and both exhibit methodological defects.

5q-syndrome is a distinct form of myelodysplastic syndrome (MDS) where a deletion on chromosome 5 is the underlying cause. MDS is characterized by bone marrow failures, including macrocytic anemia. Genetic mapping and studies using various models support the notion that ribosomal protein S14 (RPS14) is the candidate gene for the erythroid failure. Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis, similar to what is observed with other ribosomal proteins. However, due to the higher risk for cancer development in patients with ribosome deficiency, targeting the p53 pathway is not a viable treatment option. To better understand the pathology of RPS14 deficiency in 5q-deletion, we generated a zebrafish model harboring a mutation in the RPS14 gene. This model mirrors the anemic phenotype seen in 5q-syndrome. Moreover, the anemia is due to a late-stage erythropoietic defect, where the erythropoietic defect is initially p53-independent and then becomes p53-dependent. Finally, we demonstrate the versatility of this model to test various pharmacological agents, such as RAP-011, L-leucine, and dexamethasone in order to identify molecules that can reverse the anemic phenotype., (Copyright © 2016 Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, and Genetics Society of China. Published by Elsevier Ltd. All rights reserved.)

Sweet syndrome (SS) was described over 50 years ago as a distinctive form of neutrophilic dermatosis. It may be idiopathic, drug-induced or paraneoplastic, and in the last of those subtypes, myeloproliferative diseases are prominently represented. A peculiar variant of SS is termed 'histiocytoid' SS (HSS), and early accounts of that condition asserted that it showed no linkage to hematological disorders. We herein report two additional cases of HSS--both of which were associated with myeloid dyscrasias--together with a review of the pertinent literature. Along with our observations, the latter process appears to contradict the contention that HSS has no relationship to hematopoietic diseases; between 35 and 55% of reported cases have indeed shown such an association, usually with myelogenous leukemia or myelodysplastic syndromes., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The National Institute for Health and Care Excellence (NICE) invited the manufacturer of lenalidomide (Celgene) to submit evidence of the clinical and cost effectiveness of the drug for treating adults with myelodysplastic syndromes (MDS) associated with deletion 5q cytogenetic abnormality, as part of the Institute's single technology appraisal (STA) process. Kleijnen Systematic Reviews Ltd (KSR), in collaboration with Erasmus University Rotterdam, was commissioned to act as the Evidence Review Group (ERG). This paper describes the company's submission, the ERG review, and the NICE's subsequent decisions. The ERG reviewed the evidence for clinical and cost effectiveness of the technology, as submitted by the manufacturer to the NICE. The ERG searched for relevant additional evidence and validated the manufacturer's decision analytic model to examine the robustness of the cost-effectiveness results. Clinical effectiveness was obtained from a three-arm, European, randomized, phase III trial among red blood cell (RBC) transfusion-dependent patients with low-/intermediate-1-risk del5q31 MDS. The primary endpoint was RBC independence for ≥26 weeks, and was reached by a higher proportion of patients in the lenalidomide 10 and 5 mg groups compared with placebo (56.1 and 42.6 vs 5.9 %, respectively; both p < 0.001). The option of dose adjustments after 16 weeks due to dose-limiting toxicities or lack of response made long-term effectiveness estimates unreliable, e.g. overall survival (OS). The de novo model of the manufacturer included a Markov state-transition cost-utility model implemented in Microsoft Excel. The base-case incremental cost-effectiveness ratio (ICER) of the manufacturer was £56,965. The ERG assessment indicated that the modeling structure represented the course of the disease; however, a few errors were identified and some of the input parameters were challenged. In response to the appraisal documentation, the company revised the economic model, which increased the ICER to £68,125 per quality-adjusted life-year. The NICE Appraisal Committee (AC) did not recommend lenalidomide as a cost-effective treatment. Subsequently, the manufacturer submitted a Patient Access Scheme (PAS) that provided lenalidomide free of charge for patients who remained on treatment after 26 cycles. This PAS improved the ICER to £25,300, although the AC considered the proportion of patients who received treatment beyond 26 cycles, and hence the ICER, to be uncertain. Nevertheless, the AC accepted a commitment from the manufacturer to publish, once available, data on the proportion of patients eligible for the PAS, and believed this provided reassurance that lenalidomide was a cost-effective treatment for low- or intermediate-1-risk MDS patients.

Constitutional trisomy 8 mosaicism (CT8M) is a rare chromosomal abnormality. The phenotype varies from normal features to severe malformations. CT8M increases the risk of developing leukemia and myelodysplastic syndrome. As CT8M is very rare, its diagnosis can easily be overlooked, especially in cases with mild phenotypes. Here, we report the diagnostic process of a 40-year-old female patient with CT8M and discuss the importance of follow-up in monitoring for hematological malignancies., (© 2016 S. Karger AG, Basel.)

Background: Although other blood dyscrasias are known to cause sudden sensorineural hearing loss, macrocytosis has not previously been implicated in the absence of another causative agent., Case Report: We present a case of bilateral sequential sudden sensorineural hearing loss in a patient with significant macrocytosis (mean corpuscular volume at presentation 124 fl) secondary to alcohol-induced liver dysfunction., Conclusion: A possible pathophysiological mechanism linking macrocytosis and sudden sensorineural hearing loss was identified, suggesting areas for further investigation.

Pernicious anaemia is an autoimmune disease caused by intrinsic factor antibody; it leads to vitamin B12 deficiency and is marked by ineffective erythropoiesis. Haematological features reveal macrocytosis, hyperchromasia and hypersegmented neutrophils. Schistocytes are typically seen in microangiopathy, such as in thrombotic thrombocytopaenic purpura (TTP)/haemolytic uraemic syndrome or disseminated intravascular haemolysis (DIC). We report a case of a patient with severe anaemia who presented to the emergency room. Peripheral smear revealed macrocytosis, hypersegmented neutrophils and marked schistocytosis. The patient also had high reticulocyte count with high serum lactate dehydrogenase, elevated D-dimer, low fibrinogen and low haptoglobin. Vitamin B12 level came back low and the presence of intrinsic factor antibody confirmed pernicious anaemia. ADAMTS13 level was noted to be mildly reduced, which raised the suspicion of the association of acquired TTP with pernicious anaemia. Acquired TTP is another autoimmune disorder and its association with pernicious anaemia needs further evaluation., (2015 BMJ Publishing Group Ltd.)

Background/purpose: Folic acid deficiency (FAD) may result in macrocytic anemia. This study assessed the hematinic deficiencies and anemia statuses in oral mucosal disease patients with FAD (defined as folic acid ≤ 6 ng/mL)., Methods: The blood hemoglobin (Hb), iron, vitamin B12, and folic acid concentrations, serum gastric parietal cell antibody level, and mean corpuscular volume (MCV) in 198 oral mucosal disease patients with FAD were measured. Based on World Health Organization (WHO) criteria, anemia or Hb deficiency was defined as having an Hb concentration of <13 g/dL for men and <12 g/dL for women. In this study, macrocytic anemia due to FAD was defined as having an MCV ≥100 fL and folic acid ≤6 ng/mL; pernicious anemia as having MCV ≥100 fL, vitamin B12 < 200 pg/mL, and serum gastric parietal cell antibody positivity; iron deficiency anemia as having MCV <80 fL and iron <60 μg/dL; and thalassemia trait as having MCV <74 fL, red blood cell (RBC) count > 5.0 × 10(12)/L, and Mentzer index (MCV/RBC) < 13., Results: We found that by WHO definitions, 73 (36.9%), 41 (20.7%), and 10 (5.1%) of our 198 FAD patients had concomitant Hb, iron, and vitamin B12 deficiencies, respectively. Of 73 anemic FAD patients, three had macrocytic anemia due to FAD, one had pernicious anemia, 14 had iron deficiency anemia, eight had thalassemia trait, and the resting 47 had normocytic anemia., Conclusion: In addition to macrocytic anemia (2.0%), FAD patients may have concomitant normocytic (23.7%) or microcytic (11.1%) anemia., (Copyright © 2015. Published by Elsevier B.V.)

Background: Folate deficiency is rare in western countries and therefore blood tests for folate level have limited indications. One such indication is red cell macrocytosis, however it is unclear if the association of macrocytosis with folate deficiency is robust enough to serve as a risk marker. Our objective is to determine whether macrocytosis is a useful marker for folate deficiency., Findings: Paired data from the Calgary Laboratory Services Information System was analyzed using receiver operating characteristic (ROC) curves to determine strength of association between mean corpuscular volume and serum folate. Strength of association was analyzed for serum folate cut-off values of 12, 10, 8, and 6 nmol/L. Overall, 0.2% of individuals were folate deficient (<6 nmol/L serum folate). Based on ROC curves, at each cut-off level, mean corpuscular volume was a poor predictive marker for serum folate level., Conclusions: Folate deficiency is rare in Calgary, Alberta. Macrocytosis is not a strong predictor for folate deficiency.

Pearson disease is a rare, usually fatal, mitochondrial disorder affecting primarily the bone marrow and the exocrine pancreas. We report a previously healthy 10-week-old girl who presented with profound macrocytic anemia followed by pancytopenia, synthetic liver dysfunction with liver steatosis, and metabolic acidosis with high lactate levels. She had no pancreatic involvement. Multiple cytoplasmic vacuoles in myelocytes and monocytes were seen upon microscopic evaluation of the bone marrow. Genetic analysis of the mitochondrial genome revealed a 5 kbp deletion, thus establishing the diagnosis of Pearson disease.

A 72-year-old woman was diagnosed with 5q- myelodysplastic syndrome in the course of an indolent multiple myeloma (MM). Bone marrow (BM) cytogenetics disclosed two unrelated clones: 46,XX,del(5)(q13q33), and [47,X,-X,der(1;21)(q10;q10),-4,-4,+5,del(5)(q13q31),+7,der(7)t(1;7)(p34.2;p22),add(8)(p23),-13,+15,der(16) t(1;16)(q23;q12.2),+19,-21,+mar1,+mar2]. The last complex karyotype belonged to malignant plasma cells. FISH and SKY techniques demonstrated different 5q deletions. EGR1 gene (on 5q31) lost in 5q- syndrome remained in 5q- plasma cells. Biclonal evolution was noted: myeloid 5q- cells added a deletion 13q and plasma cells showed monosomy 13. Patient achieved complete cytogenetic response of 5q- syndrome with low-dose of lenalidomide, and a partial remission of MM with high-dose of lenalidomide/dexamethasone combination., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Lenalidomide (Revlimid(®)), a thalidomide analogue, is an orally administered second generation immunomodulator with anti-angiogenic, antineoplastic, anti-inflammatory and pro-erythropoietic properties. It is approved for the treatment of patients with transfusion-dependent anaemia due to International Prognostic Scoring System low- or intermediate-1-risk myelodysplastic syndrome (MDS) associated with either chromosome 5q deletion [del(5q)] with or without additional cytogenetic abnormalities (US, Japan and Switzerland etc.), or with an isolated del(5q) cytogenetic abnormality when other therapeutic options are insufficient or inadequate (EU) [featured indication]. In a randomized, double-blind, multicentre, registrational trial (MDS-004; n = 205) in this patient population, a significantly higher proportion of lenalidomide recipients than placebo recipients achieved red blood cell transfusion independence for ≥26 consecutive weeks (primary endpoint for efficacy) and cytogenetic responses. The erythroid response to lenalidomide was accompanied by an increase in the haemoglobin levels. These efficacy outcomes are generally consistent with those seen in an earlier noncomparative registrational trial (MDS-003; n = 148). In MDS-004, lenalidomide also significantly improved health-related quality of life compared with placebo at 12 weeks. Retrospective analyses that compared outcomes between lenalidomide-treated patients with low- or intermediate-1-risk del(5q) MDS and multicentre registry cohorts showed that lenalidomide treatment did not appear to increase the risk of progression to acute myeloid leukaemia. Lenalidomide had a manageable safety profile in the registrational trials, with ≤20 % of patients discontinuing treatment because of adverse events. The most common adverse events (incidence ≥20 %) occurring in lenalidomide recipients were thrombocytopenia and neutropenia, which were generally managed by dosage reductions and/or interruptions, and/or pharmacotherapy. Thus, lenalidomide is a useful option for the treatment of patients with transfusion-dependent anaemia due to low- or intermediate-1-risk del(5q) MDS, with or without additional cytogenetic abnormalities.

We report health-related quality of life (HRQL) outcomes assessed using the Functional Assessment of Cancer Therapy-Anemia (FACT-An) among 167 RBC transfusion-dependent patients with IPSS Low-/Intermediate-1-risk del5q31 MDS treated with lenalidomide versus placebo in a randomized phase 3 clinical trial, MDS-004. Mean baseline to 12 week changes in FACT-An Total scores improved following treatment with lenalidomide 5 and 10mg (+5.7 and +5.7, respectively) versus placebo (-2.8) (both p<0.05). Clinically important changes in HRQL from baseline were observed at weeks 12, 24, 36, and 48 among RBC-TI≥26 week responders in both treatment groups. Lenalidomide treatment may be effective in improving HRQL outcomes., (Copyright © 2012 Elsevier Ltd. All rights reserved.)

Objectives: Macrocytosis is a relatively common finding in adult patients undergoing blood cell counting. Approximately 10% of patients will have unexplained macrocytosis after laboratory evaluation. Data on the approach to patients with unexplained macrocytosis are limited., Methods: To investigate this topic and help delineate an approach to this condition, the records of 9779 patients diagnosed in our institution between 1995 and 2005 as having macrocytosis were reviewed. Patients with evidence of liver disease, alcohol abuse, hypothyroidism, folate or vitamin B12 deficiency, hemolysis, or use of any drugs known to cause macrocytosis were excluded., Results: Forty-three patients were found to have unexplained macrocytosis. The median follow-up was 4 years. A total of 11.6% patients developed a primary bone marrow disorder (two B-cell lymphomas, two with myelodysplastic syndrome, one plasma cell disorder), 16.3% developed worsening cytopenias, 69.7% had stable disease, and 2.3% resolved. The median time to first cytopenia was 18 months, and the mean time to diagnosis of bone marrow disorder was 31.6 months. The outcomes were not significantly different when comparing patients with or without anemia upon diagnosis. The probability of a bone marrow biopsy to establish a diagnosis of a primary disorder was 33.3% in patients with macrocytosis without anemia compared with 75% in patients with macrocytosis with anemia., Conclusions: Patients with unexplained macrocytosis still require close follow-up. We suggest a strategy of follow-up with blood cell counting every 6 months. Bone marrow biopsy should be performed when cytopenias are present because this approach may provide a higher yield of diagnosis and aid with therapeutic decisions.

Case 1. The laboratory findings of a hematological analysis of a 53-year-old woman with palpitations and dyspnea revealed the following: red blood cell (RBC) count: 9.4×10(5)/μL with 60.0‰ reticulocytes; Hb: 3.7 g/dL; mean corpuscular volume (MCV): 124.5 fL; white blood cell (WBC) count: 2,800/μL with 10.0% myeloblasts. Case 2. Similarly, a 42-year-old man with dizziness had a RBC count of 1.63×10(6)/μL with 24.0% reticulocytes, an Hb level of 6.0 g/dL, an MCV of 120.2 fL and a WBC count of 3,100/μL with 4.0% myeloblasts. Bone marrow aspirates in both patients confirmed a diagnosis of acute erythroid leukemia (AEL), which can present as marked macrocytic anemia with an MCV in excess of 120 fL and hemolysis.

We report a successful third complex heart operation without the transfusion of any allogeneic blood or blood products in a female Jehovah's Witness patient who had pronounced preoperative anaemia with a haemoglobin value of 6.9 mg/dl. The report shows that such a procedure is possible without any transfusion of allogeneic blood or blood products in extreme conditions with a very low preoperative haemoglobin level.

Myelodysplastic syndromes (MDS) are clonal hematopoietic stem cell disorders primarily seen in the elderly that are characterized by ineffective hematopoiesis and a propensity to develop AML. Clinicians may be hesitant to refer older patients with unexplained cytopenias and/or macrocytosis for a bone marrow biopsy (BM), and consequently undiagnosed patients may be deprived access to effective treatments. Previously, we described factors which were independently predictive of a diagnosis of MDS at time of bone marrow: age ≥65, mean cell volume (MCV), red cell distribution width (RDW), and lactate dehydrogenase (LDH), and suggested a scoring system to calculate the post-test probability of MDS [1]. In this study we validate this scoring system in a cohort of 313 individuals who underwent bone marrow examinations for the investigation of unexplained cytopenias and or macrocytosis over a 3 year period at our institution (2006-2008). Thirty-two percent of all patients were diagnosed with MDS and 9% had suspected MDS. The post-test likelihood of a diagnosis of MDS increased from 12% when none of the four identified factors were present to 48% when 3 or more factors were present. This scoring system can be used to guide the diagnostic testing of patients presenting with unexplained cytopenias or macrocytosis., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Serotonin (5-HT) has long been recognized as a neurotransmitter in the central nervous system, where it modulates a variety of behavioral functions. Availability of 5-HT depends on the expression of the enzyme tryptophan hydroxylase (TPH), and the recent discovery of a dual system for 5-HT synthesis in the brain (TPH2) and periphery (TPH1) has renewed interest in studying the potential functions played by 5-HT in nonnervous tissues. Moreover, characterization of the TPH1 knockout mouse model (TPH1(-/-)) led to the identification of unsuspected roles for peripheral 5-HT, revealing the importance of this monoamine in regulating key physiological functions outside the brain. Here, we present in vivo data showing that mice deficient in peripheral 5-HT display morphological and cellular features of ineffective erythropoiesis. The central event occurs in the bone marrow where the absence of 5-HT hampers progression of erythroid precursors expressing 5-HT(2A) and 5-HT(2B) receptors toward terminal differentiation. In addition, red blood cells from 5-HT-deficient mice are more sensitive to macrophage phagocytosis and have a shortened in vivo half-life. The combination of these two defects causes TPH1(-/-) animals to develop a phenotype of macrocytic anemia. Direct evidence for a 5-HT effect on erythroid precursors is provided by supplementation of the culture medium with 5-HT that increases the proliferative capacity of both 5-HT-deficient and normal cells. Our thorough analysis of TPH1(-/-) mice provides a unique model of morphological and functional aberrations of erythropoiesis and identifies 5-HT as a key factor for red blood cell production and survival.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal neoplasms with the median age at diagnosis being in the seventh decade. If left untreated, the disease progresses to acute myeloblastic leukemia (AML). There are many options for the management of MDS, but the only potentially curative treatment is allogenic hematopoietic stem cell transplantation (allo-HSCT), which is often not an option because of advanced age or comorbidities at diagnosis or lack of a human leukocyte antigen-identical donor. MDS in the elderly should be managed similar to that in young patients, but the fact that many advanced age patients cannot undergo allo-HSCT precludes any chance of cure. Despite the main objective of prolonging overall survival and the time to progression to AML, the key is to improve quality of life for the longest possible time. To achieve these objectives, supportive care is essential. Likewise, immunomodulatory drugs, such as lenalidomide, can reduce transfusion requirements and reverse cytologic and cytogenetic abnormalities in patients with MDS with chromosome 5q deletion. Elderly patients with high-risk MDS can benefit from 5-azacitidine (5-AZA), with efficacy and safety profiles comparable with those found in patients under 75 years of age. In any patient, predictive drug response scores are required in order to ensure more rational use of these medications.

Objectives: Our aim was to assess the incidence of all-cause mortality in patients with anemia undergoing percutaneous coronary intervention (PCI) receiving drug-eluting stents (DES) or bare-metal stents (BMS)., Background: Anemia has been associated with poor clinical outcomes in patients undergoing PCI. However, it is unknown whether stent selection (DES or BMS) has a differential outcome in this high-risk group., Methods: Anemia was defined as a hematocrit below 36% for female subjects and below 40% for male subjects as defined by the World Health Organization. All patients undergoing PCI with DES or BMS alone from March 2003 to June 2007 were included. The primary end point was all-cause mortality. Anemia was further characterized using mean corpuscular volume as microcytic, normocytic, or macrocytic., Results: A total 11,181 patients underwent PCI over a 4.5-year interval; of these, 2,172 met our inclusion criteria. There were a total of 429 deaths. The majority of patients had normocytic anemia (n = 1,931). Of the 3 anemia subtypes, macrocytic anemia (DES 26%, BMS 44%) had the highest mortality followed by normocytic (DES 17%, BMS 25%) and microcytic (DES 13%, BMS 18%) anemia, respectively. All-cause mortality was significantly lower with DES in unadjusted and multivariable adjusted Cox proportional models (adjusted hazard ratio: 0.66, 95% confidence interval: 0.54 to 0.82; p < 0.001)., Conclusions: In an adjusted analysis, the use of DES as compared with the use of BMS was associated with decreased mortality in patients with anemia. Additionally, among anemia subtypes, macrocytic anemia had the highest mortality.