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Introduction

Definition of anemia at older age, epidemiology of anemia in senior adults, clinical relevance of anemia at older age, pathogenesis and basic mechanisms of anemia at older age, diagnostic aspects, therapeutic options, concluding remarks and future perspectives, acknowledgments, anemia at older age: etiologies, clinical implications, and management.

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Reinhard Stauder , Peter Valent , Igor Theurl; Anemia at older age: etiologies, clinical implications, and management. Blood 2018; 131 (5): 505–514. doi: https://doi.org/10.1182/blood-2017-07-746446

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Anemia is quite frequently diagnosed in older individuals and is a key indicator of various reactive and clonal conditions. Many underlying diseases, like myelodysplastic syndrome (MDS), develop preferentially in elderly individuals. The prevalence of anemia at older age is increasing, and this is mainly attributable to more frequently applied diagnostics and demographic changes in our societies. The etiology of anemia at older age is complex and ranges from bone marrow failure syndromes to chronic kidney disease, and from nutritional deficiencies to inflammatory processes including inflammaging in immunosenescence. In a smaller number of cases, no clear-cut etiology is identified. These patients are referred to as unexplained anemia or idiopathic cytopenia of unknown significance. In others, somatic mutations in leukocytes are found, but diagnostic criteria for MDS or other hematologic diseases are not fulfilled, a condition termed clonal cytopenia of undetermined significance. Management of anemias at older age depends on (1) the severity of the anemia, (2) underlying condition(s), and (3) patient-related factors, including comorbidities. Even a mild anemia may substantially affect physical and cognitive capacities and quality of life. An underestimated aspect is that because of age-related changes, organ function such as erythropoietin production in the kidney may become suboptimal. Management and treatment of anemia in older patients often require a multidisciplinary approach and detailed investigations of organ function. In this article, we review current concepts around anemias at older age, with special emphasis on etiologies, clinical implications, and innovative concepts in the management of these patients.

Anemia is most frequent at older age, reaching a prevalence of ∼17% in the cohort of older persons >65 years of age. 1   Improved diagnostics and demographic changes in our societies have resulted in an increase in the incidence and prevalence of anemia in past decades. In fact, many underlying disorders, such as myelodysplastic syndrome (MDS), other blood cell disorders, cancer, chronic kidney disease (CKD), or certain gastrointestinal (GI) diseases develop more frequently at advanced age. In many patients, different etiologies may act together and thereby contribute to the development of anemias at older age. 2 , 3  

Based on the etiology, anemias can be divided into nutritional deficiency anemias, bleeding anemias, anemias developing in the context of chronic inflammation and in CKD, and clonal anemias. In a small number of cases, however, no etiology is found. These patients may initially be diagnosed as unexplained anemia (UA). 4   However, when applying recent classifications and a thorough workup including bone marrow (BM) studies, these cases are diagnosed as idiopathic cytopenia of unknown significance (ICUS) with isolated anemia (ICUS-A). 5-7   In some cytopenic patients, somatic mutations are detected in blood leukocytes, but diagnostic criteria for MDS or other BM neoplasms are not fulfilled, a condition termed clonal cytopenia of undetermined significance (CCUS). 7 , 8  

The management of anemias in older individuals is a clinical challenge, especially when the etiology remains uncertain and/or (multiple) comorbidities are present. An underestimated aspect is that because of age-related changes, organ function such as erythropoietin (EPO) production in the kidney or red cell production in the BM may be too low to prevent anemia under certain pathologic conditions. Management and treatment of anemia in older patients usually require a multidisciplinary approach as well as detailed investigations of organ function. In many cases, supplementation therapy or elimination of the underlying etiology can correct the anemia. In other cases, long-term treatment with interventional drugs, continuous therapy with EPO, or transfusions are required to control the anemia. With all these therapies, efficacy and benefit have to be balanced against safety and quality of life (QoL). 9   In this article, we review current concepts surrounding clinical relevance, pathogenesis, and management of anemia in older patients.

World Health Organization (WHO) thresholds were established in 1968 in a cohort of persons <65 years old, defining anemia as a hemoglobin (Hb) level of <130 g/L in men and <120 g/L in women. 10   However, Hb levels decline with age and are distinct in different ethnic groups. So far, the WHO definition 10   of anemia has been applied in the majority of studies at older age. Analyses of the American databases National Health and Nutrition Examination Survey (NHANES) III 11   and the Scripps-Kaiser database 12   have suggested higher reference values to define anemia for white men but have in general supported the validity of the WHO thresholds on the prevalence of anemia. 13  

A relevant approach might be to base the definition of anemia on Hb concentrations relevant to clinical outcomes in older persons. In fact, correlations between unfavorable outcome and Hb levels have been demonstrated. For example, “optimal” Hb concentrations of ≥137 g/L for men and ≥126 g/L for women have been described in connection with better survival in the Cardiovascular Health Study (CHS). 14   Similarly, the optimal Hb value to avoid hospitalization and mortality was 130 to 150 g/L for women and 140 to 170 g/L for men. 15  

In summary, the authors believe that the WHO definition should be used in general for the classification of anemia in older persons. However, Hb ranges associated with best possible outcome parameters might be discussed and considered in daily practice and in clinical studies to optimize clinical benefit.

Anemia in older persons is common and relevant, thus posing new challenges to health care systems worldwide. Large prospective registry studies have revealed an overall prevalence of anemia ranging from 10% to 24% in older individuals. 3   Senior adults admitted to the hospital are more frequently affected by anemia (40%), and the prevalence is even higher (47%) in nursing home residents. Considering the global prevalence of 17%, 1   as many as 15 million older persons may suffer from anemia in the European Union, and the same may hold true for North America. Prevalence increases with age, reaching nearly 50% in men older than 80 years in both hospital inpatients and outpatients ( Figure 1 ). 16   Moreover, the number of anemic patients is likely to increase dramatically in the coming years because of an aging population in Western societies. 2 , 16 , 17  

Increase in prevalence of late-life anemia. Increase in prevalence of anemia as defined by WHO (Hb <12 g/dL in women and <13 g/dL in men) with advanced age; cohort of 19 758 university hospital inpatients and outpatients (based on Bach et al 16   ).

Anemia has been associated with a number of clinically relevant conditions in many epidemiological studies ( Table 1 ). 2   Low Hb levels are a risk factor for cardiovascular diseases, 15   cognitive impairment, 18-20   insomnia, 21   impaired mood, 19 , 22   and restricted QoL. 23-26   Moreover, anemia is associated with reduced executive function 27   and physical performance. 23 , 28   Low Hb levels are associated with an increased risk for falls and fractures. 25 , 26   In addition, the presence of anemia is significantly associated with more frequent hospitalization 29   and longer hospital stays. 15 , 30   Whereas these studies highlight the relevance of prevalent Hb levels at diagnosis, future analyses should address and consider the clinical impact of the Hb decline and thus the dynamics of anemia development. 24 , 31  

Association between anemia in older adults and adverse clinical outcome based on large prospective studies

CRP, C-reactive protein; F, female; M, male; MCV, mean corpuscular volume; OR, odds ratio; OS, overall survival; RR, relative risk.

Importantly, accumulating evidence suggests that anemia is a marker for mortality 14 , 24 , 30 , 32   ( Table 1 ). The essential question is whether anemia per se determines unfavorable outcome or whether anemia is a surrogate marker for underlying processes such as inflammation or CKD. To investigate the complex interplay between anemia and confounding factors, epidemiological studies have been performed. 11 , 14 , 19 , 20 , 22-24 , 31   In particular, these studies analyzed a possible association between anemia and mortality, adjusted for confounding factors including markers of inflammation or CKD. 11 , 14 , 19 , 20 , 22-24 , 31   In support of the concept of the additive adverse effect of anemia and underlying disorders, the highest mortality has been found for nutritional disorders, chronic renal disease, and chronic inflammation as compared with UA ( Table 1 ). 11   However, epidemiological studies cannot figure out what causal role anemia plays in the restrictions and declines mentioned previously. Moreover, the underlying cause of anemia was not explicitly determined in many studies. Studies have often focused on inflammation and on CKD but might have missed other confounding factors ( Table 1 ).

In summary, even mild anemia is a relevant prognostic parameter. Moreover, in most cases anemia is considered to be a surrogate marker for underlying overt or subclinical diseases. Therefore, anemia in older individuals should definitely be taken seriously and worked up.

A wide range of causes and underlying diseases are known to result in anemia at older age ( Table 2 ; Figure 2 ). In a given disease, often >1 factor may contribute to the development of anemia. Based on pathophysiological concepts, underlying diseases may be divided into the following 3 groups.

Diseases frequently associated with anemia in the elderly

Typical and more common causes of anemia in the elderly are listed. Many more underlying disorders may be identified. In addition, in many elderly individuals, >1 disease is present and may substantially aggravate the anemia.

Insufficiently low EPO production in response to anemia is typically seen in patients with CKD but is sometimes also seen in elderly patients without impaired excretory renal function. This pure form of impaired EPO production is typically seen in elderly patients with mild anemia and may be an underestimated cause of anemia at older age or ICUS-A.

Copper deficiency may be associated with marked BM dysplasia and may even mimic MDS.

Possible mechanisms of anemia in older adults. A hyperinflammatory state is typical in anemia of inflammation (AI), CKD, and inflammaging. This state is characterized by increased hepcidin production in the liver, resulting in a direct negative impact on erythropoiesis and increased iron retention in the reticuloendothelial system (RES). Moreover, production of EPO is insufficient in response to anemia, and EPO response in the erythropoiesis is blunted. A further hallmark in the pathogenesis of AI is the increased phagocytosis of aging erythrocytes (eryptosis). Clonal disorders in leukocytes increase the risk of developing cardiovascular complications and anemia. This association may be caused by the promotion of inflammatory processes. Plus signs symbolize stimulation, and minus signs inhibition.

Anemias based on iron, folate, and/or vitamin B 12 deficiency

Lack of iron is by far the most frequent nutritional deficiency anemia. Similar to folate deficiency, iron depletion is often associated with malnutrition. Age-dependent alterations in function of GI tract, polypharmacy, and social isolation may lead to malnutrition and subsequent anemia. 33   However, in our clinical routine we experienced several times how important it is to consider that bleeding because of a variety of medications (eg, acetylsalicylic acid, standard or direct oral anticoagulants) or GI diseases, including cancer, is the most frequent cause of iron-deficient anemia in older patients. Thus, apart from iron replacement therapy, a careful GI diagnostic workup is mandatory to define a possible site of blood loss in these patients. 34  

Malnutrition, particularly in association with alcohol abuse, may result in folate deficiency. In addition, drugs like anticonvulsants and methotrexate are further causes. Pernicious anemia, the classic vitamin B 12 -deficient anemia, is relatively rare based on data from the literature and our clinical experience. By contrast, Helicobacter pylori infections, acid-reducing agents, or atrophic gastritis may cause hypochlorhydria, more frequently leading to a food-cobalamin malabsorption syndrome. 35  

Importantly, for these subtypes of anemia effective medication is available. For example, in vitamin B 12 deficiency anemia, neurologic symptoms are often detected and usually resolve immediately on initiation of vitamin B 12 supplementation.

Thus, early and correct diagnosis is essential. Therefore, we always include folate and vitamin B 12 measurement in our basic laboratory screening in elderly anemic patients.

Anemias developing in the context of chronic inflammation and in CKD

At least one-third of anemic patients older than 65 years show a hyperinflammatory state typical for CKD or for AI (cancer, autoimmune disease, and chronic infection). Underlying pathophysiological mechanisms in AI are manifold, are overlapping, and show differences in extent between patients.

First, reduced EPO production that is too low to counteract anemia and a blunted response of erythroid progenitors to EPO represent essential underlying mechanisms. 36  

A direct negative effect of different cytokines, like tumor necrosis factor α, interleukin-1 (IL-1), and transforming growth factor β, on proliferation and differentiation of erythroid progenitor cells has also been reported 37   and is at least partly because of a downregulation of EPO receptor expression on erythroid progenitors. In addition, these cytokines promote myelopoiesis with the overall net effect of reduced erythropoiesis. 38   Alterations in energy metabolism and body composition have also been reported to potentially regulate erythropoiesis in the elderly. 39  

Second, an essential mechanism driving the development of AI is an increased uptake and retention of iron (in the form of senescent/damaged erythrocytes) within the reticuloendothelial system leading to an iron-restricted erythropoiesis. 40  

Hepcidin, a mainly liver-derived antimicrobial acute phase protein, reduces both duodenal iron absorption and iron release from macrophages. 41   These effects can be explained by the interaction of hepcidin and the transmembrane protein ferroportin, the only so far known iron exporter in mammalians. 42   In macrophages, which have a general turnover of ∼20 to 25 mg of iron per day as a result of being recycled from senescent red blood cells (RBCs), this produces iron restriction with an accompanying increase in ferritin levels and decrease in transferrin saturation (TSAT), resulting in a relative iron-deficient erythropoiesis.

Increased hepcidin levels have been reported in cancer patients and patients suffering from autoimmune disease and CKD. 43   Remarkably, elevated hepcidin levels have also been reported in older patients, with an age-related increase. 44   As hepcidin seems to be the central player in iron metabolism, several mechanisms are involved in tightly controlling hepcidin. Hepcidin expression is upregulated by inflammatory cytokines like IL-6 and different bone morphogenic proteins (BMPs), mainly BMP6 and BMP2. 45   Moreover, endoplasmic reticulum stress 46   and reactive oxygen species (ROS), 47   as well as reduced levels of estrogen and testosterone, 48 , 49   seem to directly increase hepcidin expression. This helps in understanding why endocrine changes at menopause or andropause result not only in a constitutively increased presence of inflammatory mediators, 50   but also in increased hepcidin levels. 48 , 49  

Third, eryptosis, the phagocytosis of aging erythrocytes triggered by changes in their plasma membrane, is often discussed as a further hallmark in the development of AI. Recycling of aged and/or damaged RBCs occurs under physiological conditions mainly in the spleen. It is well known that in distinct situations including inflammation, RBC numbers and Hb levels drop much faster than can be explained by a pure reduction in RBC production and Hb synthesis. In fact, translocation of phosphatidylserine to the membrane surface is a first step in this process. 51   It enables macrophages to engulf erythrocytes and ultimately eliminate them from circulation. Lupescu et al showed that ROS production leads to a much higher frequency of phosphatidylserine-presenting erythrocytes in older than in younger patients. 52   Other reports have shown that disorders that are quite common at advanced age, including dehydration, diabetes mellitus, or chronic heart disease, might also affect RBC stability. 53  

In addition, the concept of a proinflammatory state or “inflammaging,” offers a potential model to explain the high prevalence of anemia and age-associated disorders including sarcopenia, asthenia, weight loss, and frailty. The term inflammaging was first used in 2000 by Franceschi et al 54   to describe a low-grade proinflammatory state associated with the aging process and immunosenescence. This condition is characterized by an age-associated chronic upregulation of the inflammatory immune response with increased levels of proinflammatory cytokines like IL-1, IL-6, and tumor necrosis factor. 55-57   In addition, activation of NF-κB signaling has been reported in older patients. 58   It is known and well described that a reduction in autophagy, as found in senior persons, leads to NF-κB activation, which in turn is known to be a potent inducer of NLRP3 inflammasome activation. The same holds true for ROS. 59   Thus, both pathways seem to activate the inflammasome response.

However, whether this state of chronic proinflammation reflects a primary age-related immune response or a systemic response to an unrecognized comorbid condition is not clear. More recent data suggest that age-related clonal hematopoiesis of indeterminate potential (CHIP) mutations in macrophages may lead to proinflammatory responses. 60   It would be plausible that mildly elevated IL-6 levels caused by age alone, body composition change, or smoldering inflammatory disease result in inhibition of EPO production and/or activation of hepcidin, both of which cause anemia. 55 , 56   Yet, one of the biggest limitations of this concept is the lack of methods that can be used to determine the suggested subclinical and often local inflammation in a clinical setting.

In fact, the cause of anemia for a relatively large proportion of UAs remains obscure, despite extended hematologic evaluation. 61   Namely, iron deficiency (ID), borderline CKD, and low-grade local inflammation may go unrecognized in a number of patients because of inappropriate cutoff levels or technical limits of laboratory tests.

UAs and clonal anemias

Clonal leukocytes are detectable in a considerable proportion of older individuals. Such clonal hematopoiesis is associated with increased mortality and an augmented prevalence of hematologic malignancies, such as MDS. Remarkably, numbers of somatic mutations in blood leukocytes increase with age. 8 , 60 , 62 , 63   In otherwise healthy individuals without cytopenia, this condition is termed CHIP. 8   However, as soon as mild anemia develops, the diagnosis changes to CCUS 8   or to overt MDS when criteria for MDS are fulfilled. 7   Indeed, the clinical features and the course of CCUS patients and MDS patients are quite similar. In addition, most CCUS patients may progress to overt MDS over time. However, CHIP and CCUS patients may also develop another hematologic neoplasm, such as acute myeloid leukemia. Based on the obvious clinical implications, we recommend that leukocytes be screened for the presence of somatic mutations in all patients with unexplained cytopenia. In addition, BM cells should be examined for the presence of cytogenetic abnormalities and flow cytometric abnormalities ( Table 3 ).

Classification of UA, ICUS-A, and pre-MDS conditions

“Unexplained anemia” (UA) is the term used in the literature so far. In these patients, a thorough workup including BM and molecular analyses is recommended. These investigations will enable classification of the diagnosis ICUS-A, CCUS, or MDS or will help exclude other malignant hematologic disorders. Based on Valent et al. 7  

IDUS, idiopathic dysplasia of undetermined significance; nd, not detected or not done.

The definition of anemia in cytopenia is based on WHO criteria: Hb <130 g/L in men and Hb <120 g/L in women. 10  

Cytopenic patients lacking molecular aberrations and not fulfilling the criteria of MDS or of any other underlying disease (causing cytopenia) are termed ICUS. ICUS presenting with anemia is termed ICUS-A. 7   As ICUS-A is often detected in older individuals, 6 , 64 , 65   it has been hypothesized that ICUS-A may be regarded as the classical prototype of an “anemia at older age.” 5  

As outlined previously, a clue to the etiology of ICUS-A may be the observation that endogenous EPO levels are often quite low, suggesting insufficient EPO production in response to anemia. 5   Because low EPO production is found in ICUS-A independent of the excretory kidney function, one hypothesis is that an endocrine defect in EPO production because of an aged kidney or a decrease in testosterone or estrogen synthesis in elderly individuals is causative in the development of ICUS-A. 5 , 66   In this regard, it is also noteworthy that such a decrease in EPO production may also be found in MDS patients, namely, those who respond to treatment with recombinant EPO. 67 , 68   In other words, individuals with CHIP or IDUS may convert to overt MDS as soon as they also develop ICUS-A during aging. This concept is supported by the Nordic score that predicts responsiveness to EPO therapy in those MDS patients who have an inadequately low EPO level. 67   Whether these EPO thresholds might be applied in other subgroups of anemia remains to be determined. A remaining question is whether true cases of ICUS-A with adequate EPO production really exist. An interesting point worth noting is that the age-related decrease in EPO production can contribute to the manifestation of an overt neoplasm, namely, MDS from a preexisting CHIP or IDUS. 65 , 69  

Primary laboratory evaluation in older anemic patients should include basic parameters including Hb, differential blood count, MCV, mean corpuscular hemoglobin, reticulocyte count, ferritin, reticulocyte Hb, TSAT, EPO level, CRP, fibrinogen, creatinine/glomerular filtration rate, vitamin B 12 , serum folate, copper, thyrotropin, lactate dehydrogenase, haptoglobin, alanine aminotransferase/aspartate aminotransferase, and serum electrophoresis. In quite a number of cases, this profile will help identify and classify nutritional deficiency including iron-deficient anemia, AI, and CKD. Depending on the clinical evaluation, more detailed investigations may be needed including gastro- and colonoscopy and ultrasound of the abdomen and kidney. BM aspiration and biopsy are mandatory to exclude hematologic disorders including MDS and to make an appropriate diagnosis, especially when additional blood count abnormalities or other signs of a clonal hematologic disease are found.

These diagnostic procedures including BM evaluation should, however, be discussed in light of the burden of the procedure and weighed against the possible therapeutic consequences of the suspected diagnosis as well as life expectancy and burden of anemia. The authors feel the patient should have a life expectancy of minimum 3 months in order to justify BM aspiration in an anemic elderly patient.

In those with unclear results molecular, cytogenetic, and/or flow cytometry studies may help reach the conclusion that the patient is suffering from a clonal BM disorder such as MDS. In such studies, detection of clonality of myeloid cells may cause a change in the diagnosis, for example from ICUS to CCUS or even to MDS. 7  

There are a number of other complex conditions and pitfalls that may pose diagnostic problems in elderly patients, especially those who suffer from comorbidities. For example, it may be difficult to assess the extent of iron deficiency in patients suffering from inflammatory bowel disease and pronounced inflammatory bowel disease–related inflammation. In these cases, soluble transferrin receptor (sTfR), the sTfR/log ferritin index, and serum hepcidin may assist in estimating the degree of iron deficiency. An index above a certain cutoff level indicates the presence of a true iron deficiency that may be overseen in an inflammatory state when using ferritin and TSAT levels only. 41   Specific cutoff levels have been published. A ratio of <1 suggests AI, whereas a ratio of >2 suggests absolute iron deficiency coexisting with AI. 41   Yet, it is important to understand that sTfR assays are not standardized, and therefore, a cutoff level for the sTfR/log ferritin index has to be established by each laboratory individually, depending on the sTfR assay. 70  

Other parameters like reticulocyte Hb content and percentage of hypochromic erythrocytes have proved to be informative to predict the response rate to iron therapy in CKD patients. 71 , 72  

Before establishing a treatment plan, the primary diagnosis and accompanying diseases with emphasis on treatable disorders should be properly defined. As mentioned before, often several causes contribute to anemia in the elderly. Then, optimal age-adjusted therapy is introduced, with recognition of potential side effects and impact on QoL. Even a weekly referral (transport burden) for injections may already interfere with QoL in frail patients. Whenever possible, the primary goal is to treat and thus eliminate the underlying disease and thereby the etiology of anemia.

In most patients suffering from true ID, oral iron substitution seems to be sufficient. 73   Moreover, in recent years new oral iron formulations like ferric maltol 74   and Sucrosomial Iron 75   showing higher efficacy and fewer side effects have been approved, thus further reducing the need for intravenous iron. Yet, sometimes oral application in the elderly is not effective because of reduced uptake in the GI tract, impaired compliance, and/or an inflammatory state leading to decreased iron utilization. 76 , 77  

In this situation, when oral iron does not ameliorate anemia, IV iron therapy may be a valuable alternative. Actually, a number of IV iron formulations are available including iron sucrose, ferric gluconate, and ferumoxytol. In recent years, new and safer formulations have been approved with mainly ferric carboxymaltose and iron isomaltoside being prescribed. Still, especially ferric carboxymaltose, but also to some extent iron isomaltoside, may rarely lead to severe hypophosphatemia with subsequent osteomalacia and bone fractures, 78   especially when high doses are needed in patients with severe ID and relatively normal kidney function. This is of special concern in elderly patients already presenting with metabolic bone diseases. Therefore, we are of the opinion that IV iron supplementation should be recommended when oral iron preparations are not tolerated, in patients nonadherent to oral iron substitution, in case of ongoing blood loss, or if iron uptake in the GI tract is insufficient.

Erythropoiesis-stimulating agents (ESAs) are so far registered for the treatment of anemia in CKD and in European Union countries in patients with MDS. Data on application of ESAs in other subtypes of anemia are limited. Nevertheless, 1 study suggested that EPO may be beneficial in a patient cohort of age 65 and older African American women with no obvious explanation for the existing anemia. 79   In that study, ESAs significantly increased Hb levels and also patients’ QoL. Yet, considering studies reporting a reduced EPO response in a large portion of UA patients, larger studies are definitely needed to support the idea of ESA therapy in UA patients. 80   In general, the risk for thromboembolic complications increases at higher Hb levels, so that the current recommendation is to maintain Hb levels between 9 and 11.5 g/dL.

Blood transfusions are the first and most effective option for the treatment of elderly patients with severe, symptomatic anemia.

Although no specific cutoff level is available for Hb, elderly anemic patients should always be transfused with recognition of comorbidities and an adequate oxygen supply that needs to be maintained. Transfusion numbers and frequency in the individual patient have to be based on many different factors and the overall situation in each case. In those with severe cardiovascular disorders, blood should be transfused more slowly and on a unit-by-unit basis, and Hb levels should be kept above 9 or even 10 g/dL in these patients. 81  

Thanks to a better understanding of mechanisms regulating erythropoiesis, new drugs are currently being developed such as hepcidin inhibitors ( Table 4 ). Currently, these drugs are mainly developed for anemia in CKD and cancer patients. However, they may be a future therapeutic approach for a defined group of elderly patients. Another group of agents are the hypoxia inducible factor (HIF)–prolyl hydroxylase inhibitors. Especially older patients with low endogenous EPO levels may benefit from these drugs. Yet, persons at advanced age may be more vulnerable to HIF stabilization. Finally, activin type II receptor agonists are currently being investigated in patients with MDS and CKD and might present a future option for the treatment of anemia at advanced age. As sufficient clinical data are not yet available, these drugs still await final approval.

New targeted drugs that may counteract anemia in older patients

IgG1, immunoglobulin G1; MM, multiple myeloma; PEG, polyethylene glycol.

Anemia in older persons poses a clinical challenge in daily practice as the population ages. In many cases, 1 or more etiologies are detected, and a thorough investigation immediately leads to the correct diagnosis. In these patients, management is largely dependent on the underlying etiology, and in many cases, anemia can be corrected by interventional therapy independent of age. Good examples are iron, vitamin B 12 , or folate deficiency. EPO deficiency with or without overt exocrine kidney insufficiency can be detected quite often in older persons. A large number of patients turn out to have an underlying (chronic) inflammatory disease. The concept of a subclinical proinflammatory state called inflammaging may be a good explanation for the development of anemia in senior persons. In other cases, a clonal myeloid or other neoplasm is detected. In a relevant proportion of patients, no underlying cause of anemia is found after a first examination, resulting in the provisional diagnosis of UA. However, in many cases no underlying etiology is found even after a thorough diagnostic workup that includes an examination of all organ systems including the BM and also cytogenetic and molecular studies. These patients may have a pre-MDS condition and are often diagnosed as ICUS-A or CCUS.

The definition of the underlying mechanisms of anemia at older age will form the basis for individualized treatment algorithms including iron supplementation, application of ESAs, and promising new drugs directed at regulation of hepcidin or HIF.

The manuscript was edited by Mary Heaney Margreiter, native-speaker translator/interpreter/editor. In addition, Bojana Borjan edited the references, and Karin Koinig edited the tables and designed Figure 2.

This work was supported by Verein Senioren-Krebshilfe (R.S.) and Horizon 2020 research and innovation program (grant 634789), MDS-RIGHT, within Personalising Health and Care program PHC-2014-634789 (R.S.). Additionally, this work was supported by Translational Implementation of Genetic Evidence in the Management of MDS (TRIAGE-MDS, Austrian Science Found I 1576) within the TRANSCAN–Primary and secondary prevention of cancer call (ERA Net) (R.S.) and by the Austrian Science Fund (SFB grant F4704-B20 [P.V.] and project P 28302-B30 [I.T.]).

Contribution: R.S., P.V., and I.T. were responsible for conception and design, manuscript writing, and final approval of the manuscript.

Conflict-of-interest disclosure: R.S. received research funding and honoraria from Celgene, Teva, and Novartis. P.V. received honoraria from Celgene, Teva, and Novartis. I.T. received research funding and honoraria from Gilead, Novartis, and Kymab.

Correspondence: Reinhard Stauder, Department of Internal Medicine V (Hematology and Oncology), Innsbruck Medical University, Anichstr 35, 6020 Innsbruck, Austria; e-mail: [email protected] .

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A case study of an older adult with severe anemia refusing blood transfusion

Affiliation.

• 1 The University Center for Bloodless Surgery and Medicine at University Hospital, The University of Medicine and Dentistry of New Jersey, Newark, New Jersey, USA. [email protected]
• PMID: 17214867
• DOI: 10.1111/j.1745-7599.2006.00188.x

Purpose: To discuss the diagnosis and treatment of severe anemia in an older adult who presents the challenge of declining blood transfusion in a real-world scenario where critical thinking, evidence-based care, and collaboration with other providers must come together to serve this patient's unique needs.

Data sources: Extensive review of the scientific literature on anemia and the situation in which a patient refuses blood transfusion presented in a case study format.

Conclusions: A thorough physical assessment, complete health history, and appropriate diagnostic workup should be used to distinguish the normal effects of senescence from the signs and symptoms of anemia. Common conditions that cause anemia in the elderly include chronic disease, iron deficiency, and gastrointestinal bleeding. These conditions may result in profound anemia. The challenge can be compounded when, because of religious tenets, a patient does not accept a blood transfusion. This case study challenges nurse practitioners to apply knowledge, seek guidance, and make appropriate referrals to care for a patient in order to render care within the parameters of the patient's belief system.

Implications for practice: The astute primary care provider recognizes that anemia is not an expected physiological change associated with aging but a manifestation of an underlying disease process. Fatigue, weakness, and dyspnea are all symptoms of anemia that may be overlooked and attributed to the aging process. Further, in keeping with the principles of autonomy and self-determination, it is the clinician's duty to work with all patients to restore them to a state of optimal health while respecting deeply held spiritual beliefs.

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• [Jehovah's Witnesses refusal of blood: religious, legal and ethical aspects and considerations for anesthetic management]. Pérez Ferrer A, Gredilla E, de Vicente J, García Fernández J, Reinoso Barbero F. Pérez Ferrer A, et al. Rev Esp Anestesiol Reanim. 2006 Jan;53(1):31-41. Rev Esp Anestesiol Reanim. 2006. PMID: 16475637 Review. Spanish.
• Care of the injured Jehovah's Witness patient: case report and review of the literature. Kulvatunyou N, Heard SO. Kulvatunyou N, et al. J Clin Anesth. 2004 Nov;16(7):548-53. doi: 10.1016/j.jclinane.2004.02.002. J Clin Anesth. 2004. PMID: 15590263 Review.
• Jehovah's Witnesses and blood transfusion revisited: a review of the benefits and risks. Orji EO, Sotiloye D, Fawole AO, Huyinbo KI. Orji EO, et al. Niger J Med. 2001 Apr-Jun;10(2):55-8. Niger J Med. 2001. PMID: 11705058 Review.

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Case Study: 32 Year-Old Female with Anemia and Confusion

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A board-style question with an explanation and a link to a relevant article is a recurring feature of  TraineE-News . The goal of the case study is to clarify specific and timely teaching points in the field of hematology. The following case study focuses on a 32-year-old woman, with no significant past medical history, who presents to the emergency department with several days of worsening confusion. The complete blood count shows a hemoglobin concentration of 9.8 g/dL and platelet count of 34 x 109/L. Creatinine is 3.1 mg/dL and the LDH is 448 IU/L. Review of the peripheral blood smear shows numerous schistocytes. ADAMTS13 level is measured and found to be 68 percent without evidence of a detectable inhibitor. The patient is diagnosed with atypical hemolytic-uremic syndrome and eculizumab is started.  

Which of the following vaccinations should be administered as soon as possible after initiating eculizumab?

• Seasonal influenza
• Varicella zoster virus
• Hepatitis B
• Meningococcus

Explanation

Meningococcal (Neisseria meningitides) infections have occurred in patients receiving eculizumab, and patients receiving eculizumab should be vaccinated. The patient has evidence of a thrombotic microangiopathy with anemia, schistocytosis, and elevated LDH. When combined with thrombocytopenia and renal failure along with an ADAMTS13 level > 10 percent, the clinical picture suggests atypical hemolytic-uremic syndrome. While similar to thrombotic thrombocytopenic purpura (TTP), it is not due to a deficiency of ADAMTS13, but rather mutations in the genes for C3, Factors H, B, and I, as well as membrane cofactor protein. The monoclonal antibody eculizumab inhibits the terminal portion of the complement cascade and is approved by the FDA to treat atypical HUS as well as paroxysmal nocturnal hemoglobinuria (PNH). The drug carries an FDA black-box warning about the risk of meningococcal disease and the product insert includes a recommendation to vaccinate patients against meningococcus as well as provide education and counseling. Ideally, the vaccine should be administered at least two weeks prior to initiation of eculizumab in order to allow sufficient immune response. For patients requiring immediate initiation of treatment with eculizumab, vaccination against meningococcus should be done as soon as possible. Should a patient develop evidence of meningoccocus, eculizumab therapy should be stopped.

• Case study submitted by Nathan Connell, MD, Brown University, Providence, RI, Trainee Council Member.

American Society of Hematology. (1). Case Study: 32 Year-Old Female with Anemia and Confusion. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/female-anemia-confusion .

American Society of Hematology. "Case Study: 32 Year-Old Female with Anemia and Confusion." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/female-anemia-confusion (label-accessed June 18, 2024).

"American Society of Hematology." Case Study: 32 Year-Old Female with Anemia and Confusion, 18 Jun. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/female-anemia-confusion .

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Patient Case Presentation

Patient  Overview

M.J. is a 25-year-old, African American female presenting to her PCP with complaints of fatigue, weakness, and shortness of breath with minimal activity. Her friends and family have told her she appears pale, and combined with her recent symptoms she has decided to get checked out. She also states that she has noticed her hair and fingernails becoming extremely thin and brittle, causing even more concern. The patient first started noticing these symptoms a few months ago and they have been getting progressively worse. Upon initial assessment, her mucosal membranes and conjunctivae are pale. She denies pain at this time, but describes an intermittent dry, soreness of her tongue.

Vital Signs:

Temperature – 37 C (98.8 F)

HR – 95

BP – 110/70 (83)

Lab Values:

Hgb- 7 g/dL

Serum Iron – 40 mcg/dL

Transferrin Saturation – 15%

Medical History

• Diagnosed with peptic ulcer disease at age 21 – controlled with PPI pharmacotherapy
• IUD placement 3 months ago – reports an increase in menstrual bleeding since placement

Surgical History

• No past surgical history reported

Family History

• Diagnosis of iron deficiency anemia at 24 years old during pregnancy with patient – on daily supplement
• Otherwise healthy
• Diagnosis of hypertension – controlled with diet and exercise
• No siblings

Social History

• Vegetarian – patient states she has been having weird cravings for ice cubes lately
• Living alone in an apartment close to work in a lower-income community
• Works full time at a clothing department store

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Chapter 6-1:  Approach to the Patient with Anemia - Case 1

Jeremy Smith

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Chief complaint, constructing a differential diagnosis.

• RANKING THE DIFFERENTIAL DIAGNOSIS
• MAKING A DIAGNOSIS
• CASE RESOLUTION
• FOLLOW-UP OF MRS. A
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Mrs. A is a 48-year-old white woman who has had fatigue for 2 months due to anemia.

Figure 6-1.

Diagnostic approach: anemia.

Anemia can occur in isolation, or as a consequence of a process causing pancytopenia, the reduction of all 3 cell lines (white blood cells [WBCs], platelets, and red blood cells [RBCs]). This chapter focuses on the approach to isolated anemia, although a brief list of causes of pancytopenia appears in Figure 6-1 . The first step in determining the cause of anemia is to identify the general mechanism of the anemia and organize the mechanisms using a pathophysiologic framework:

Acute blood loss: this is generally clinically obvious.

Underproduction of RBCs by the bone marrow; chronic blood loss is included in this category because it leads to iron deficiency, which ultimately results in underproduction.

Increased destruction of RBCs, called hemolysis.

Signs of acute blood loss

Hypotension

Tachycardia

Large ecchymoses

Symptoms of acute blood loss

Hematemesis

Rectal bleeding

Vaginal bleeding

After excluding acute blood loss, the next pivotal step is to distinguish underproduction from hemolysis by checking the reticulocyte count:

Low or normal reticulocyte counts are seen in underproduction anemias.

High reticulocyte counts occur when the bone marrow is responding normally to blood loss; hemolysis; or replacement of iron, vitamin B 12 , or folate.

Reticulocyte measures include:

The reticulocyte count: the percentage of circulating RBCs that are reticulocytes (normally 0.5–1.5%).

The absolute reticulocyte count; the number of reticulocytes actually circulating, normally 25,000–75,000/mcL (multiply the percentage of reticulocytes by the total number of RBCs).

The reticulocyte production index (RPI)

Corrects the reticulocyte count for the degree of anemia and for the prolonged peripheral maturation of reticulocytes that occurs in anemia.

Normally, the first 3–3.5 days of reticulocyte maturation occurs in the bone marrow and the last 24 hours in the peripheral blood.

When the bone marrow is stimulated, reticulocytes are released prematurely, leading to longer maturation times in the periphery, and larger numbers of reticulocytes are present at any given time.

For an HCT of 25%, the peripheral blood maturation time is 2 days, and for an HCT of 15%, it is 2.5 days; the value of 2 is generally used in the RPI calculation.

The normal RPI is about 1.0.

However, in patients with anemia, RPI < 2.0 indicates underproduction; RPI > 2.0 indicates hemolysis or an adequate bone marrow response to acute blood loss or replacement of iron or vitamins.

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Severe anemia: a case report

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Ioannis Vrettos

Emergency Medicine: Open Access

Annesha Das

International Journal of Statistics in Medical Research

Lifescience Global Canada

Purpose: To investigate the frequency and types of severe unknown anemia in patients referred to the Baqiyatallah Hospital (Tehran) for six months. Methods: In this descriptive cross-sectional study, the patients with severe unknown anemia referred to the Baqiyatallah Hospital (Tehran, Iran) were selected over six months. Following consideration of inclusion and exclusion criteria, 230 patients with severe anemia (hemoglobin (Hb) > 8gr/dl) were included. Complete medical history was obtained from the patients and additional biochemical blood analyses were applied to determine the frequency and type of anemia. SPSS (v.19) software was used to analyze the findings and the significance level was defined as a p-value <0.05. Results: In chronic disease anemia (47.5%), gastrointestinal bleeding-associated anemia (29%), bleeding malignancies anemia (21.5%), and aplastic anemia (2%). There were significant differences (p<0.05) in the frequency of different types of normocytic anemia. The highest frequency was detected in folate deficiency anemia (46%), hypothyroidism anemia (34%), and B12 deficiency anemia (20%), respectively. The hemolytic anemia represented a significant difference (p<0.05) in comparison with sickle cell anemia (95%). Also, sickle cell anemia showed a significant difference (p<0.05) between thalacemia-associated anemia (95%) and malignancy-related anemia (95%) Conclusion: Respectively, the highest frequency of anemia in patients was found in chronic diseases and gastrointestinal bleeding. It is suggested that more attention should be paid to the type of anemia of patients referred to the urgency of hospitals.

Digestive Diseases

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Background: Anemia is present in almost 5% of adults worldwide and accompanies clinical findings in many diseases. Diseases of the gastrointestinal (GI) tract and liver are a common cause of anemia, so patients with anemia are often referred to a gastroenterologist. Summary: Anemia could be caused by various factors such as chronic bleeding, malabsorption, or chronic inflammation. In clinical practice, iron deficiency anemia and the combined forms of anemia due to different pathophysiological mechanisms are most common. Esophagogastroduodenoscopy, colonoscopy, and the small intestine examinations in specific situations play a crucial role in diagnosing anemia. In anemic, GI asymptomatic patients, there are recommendations for bidirectional endoscopy. Although GI malignancies are the most common cause of chronic bleeding, all conditions leading to blood loss, malabsorption, and chronic inflammation should be considered. From a gastroenterologist’s perspective, the clinical spectrum o...

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Background: Anemia profoundly impairs bodily health, prolongs hospital stay, heightens healthcare costs and reduces overall quality of life. Very severe ane mia (particularly acute cases) portends a critical state, may progress to irreversible vital organ damage, thereby increasing mortalities. Thus, it is worthwhile to evaluate the occurrence of very severe anemia cases, its clinical/laboratory features, prevalent causes/associations and survival patterns in Benin City, Nigeria.

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What Is Anemia?

Related Conditions

Living with anemia.

Anemia is a condition that occurs when your blood has a reduced number of red blood cells or hemoglobin , the protein that helps your red blood cells transport oxygen from your lungs to the rest of your body. When you have anemia, your blood has less oxygen than normal. This can cause symptoms like fatigue and weakness, shortness of breath, dizziness , headaches , and an irregular heartbeat.

Anemia can develop in anyone regardless of age, race, or ethnicity. However, some people are more at risk for developing the condition, including people who have cancer, an autoimmune disorder , or heavy periods .

Treatment for mild to moderate anemia usually involves supplements or medications that help your blood develop more red blood cells. In more severe cases, a blood transfusion or surgery may be necessary.

There are many types of anemia. Some types are more common and easier to treat than others, but they can all lead to complications if left untreated.

Iron Deficiency Anemia

When you don't have enough iron, you are at risk of developing iron deficiency anemia . This common type of anemia usually occurs when you don't consume adequate iron in your diet. It impacts 30% of women and children. Low iron levels can also develop due to blood loss or medical conditions that make it difficult for your body to absorb iron.

While this type of anemia rarely causes death, it can lead to significant complications. Symptoms and possible complications include:

• Restless legs syndrome , a condition that causes your legs to move uncontrollably
• Heart problems
• Pregnancy complications like early labor (before 36 weeks) and low infant birth weight

Iron deficiency anemia can cause other medical conditions to worsen or cause treatments to be ineffective.

Pernicious Anemia

Pernicious anemia is an autoimmune disorder, meaning your body mistakenly attacks healthy cells. This type of anemia is relatively rare. It affects less than 2% of people over age 60 worldwide.

People with pernicious anemia have low levels of vitamin B12. Your body needs vitamin B12 to make healthy red blood cells and keep your nervous system working properly. Pernicious anemia causes larger-than-normal red blood cells that do not divide effectively. These blood cells have difficulty moving out of bone marrow (where they're made) and so cannot carry oxygen throughout your body.

If left untreated, pernicious anemia can cause serious complications. You might experience bleeding and infections, as well as irreversible brain or nerve damage. Infants of people who have a vitamin B12 deficiency are more likely to experience developmental delays and birth defects, particularly in the brain and spinal cord.

Aplastic Anemia

Aplastic anemia is a rare but serious blood condition. It occurs when your bone marrow cannot make enough new blood cells for your body to function properly. This type of anemia, which impacts about two out of every one million people in the United States, usually results from damage to stem cells inside your bone marrow. This causes your bone marrow to make fewer red blood cells, white blood cells, and platelets. Aplastic anemia often occurs because your immune system attacks and destroys the stem cells.

Untreated aplastic anemia can lead to serious complications like an irregular heartbeat and heart failure. It also increases your risk of developing bleeding issues, leukemia (a type of cancer that begins in the blood cells), and other serious blood conditions.

Aplastic anemia is a life-threatening condition with very high death rates. About 70% of people die within one year if the disease is left untreated. The five-year survival rate is about 80% for people under age 20.

Hemolytic Anemia

With hemolytic anemia, your red blood cells are destroyed faster than they can be replaced. There are multiple types of hemolytic anemia. It can be acquired or inherited, and the cause is not always known. This type of anemia is rare and impacts approximately 1-3 per 100,000 people every year. It can occur at any age.

People with mild hemolytic anemia may not need treatment, but those with more serious cases could be at risk for serious complications if the condition is left untreated. Possible complications include an irregular heartbeat, a larger-than-normal heart, and heart failure.

Anemia Symptoms

Anemia symptoms can vary depending on the severity of the condition and how quickly it develops. People with mild anemia may not experience any symptoms at all. Symptoms typically worsen as the condition progresses.

Initial symptoms of anemia include abnormally pale skin and feeling weak or fatigued. As anemia progresses, you may experience symptoms like:

• Increased thirst
• Rapid pulse
• Fast breathing
• Mouth symptoms like tongue swelling, dry mouth, and ulcers (small sores)
• Koilonychia (brittle, spoon-shaped nails )

Symptoms of more severe anemia include:

• Lower leg cramps
• Shortness of breath
• Brain damage

It's common to experience heart-related symptoms with anemia—primarily because your heart must work harder to deliver oxygen-rich blood to your body. These symptoms can include everything from arrhythmias (abnormal heart rhythms) and heart murmurs to an enlarged heart and heart failure.

SDI Productions / Getty Images

What Causes Anemia?

There are three main causes of anemia:

• Lack of red blood cell production: Nutritional deficiencies or inadequate nutrient absorption can lower your body's ability to produce red blood cells.
• High rates of red blood cell destruction: Chronic conditions can affect your body’s ability to make enough red blood cells or even lead to red blood cell destruction.
• Blood loss: Blood loss through menstruation or internal bleeding (for example, in the stomach or colon) can also lead to anemia.

Risk Factors

A variety of different conditions and genetic factors can increase your risk of developing anemia. Risk factors include:

• A diet low in iron, vitamin B12, or folic acid
• Frequent blood donation
• Heavy periods
• Colon polyps
• Colon cancer
• Autoimmune disorders
• Inherited conditions
• Blood conditions like sickle cell disease (SCD), a condition in which abnormal hemoglobin causes red blood cells to become rigid and crescent-shaped
• Metabolic conditions like glucose-6-phosphate dehydrogenase deficiency, a genetic condition that causes red blood cells to break down
• Frequent exposure to toxins like pesticides
• Radiation and chemotherapy treatments
• Viral infections like Epstein-Barr virus (EBV), a common and highly contagious herpes virus that spreads through bodily fluids like saliva

Diagnosis of anemia usually begins with a physical exam to look for a pale tongue and brittle nails. Your healthcare provider will ask about your medical history, diet, and whether other family members have ever been diagnosed with anemia.

They will also order blood tests and consider other testing options.

Blood tests might include:

• Complete blood count (CBC): A blood test that provides information on a variety of markers including your red blood cells, white blood cells, and platelets. It's one of the most common ways to check for anemia.
• Mean corpuscular hemoglobin concentration (MCHC): A blood test that measures the amount of hemoglobin a red blood cell has relative to the cell's volume.
• Mean corpuscular hemoglobin (MCH): A blood test that measures the average amount of hemoglobin within your red blood cells.
• Hematocrit levels: A blood test that measures the percentage of red blood cells in your blood.
• Mean corpuscular volume (MCV): A blood test that measures the average size of your red blood cells.

Other possible tests and diagnostic tools include:

• Bone marrow tests: Two bone marrow tests—aspiration and biopsy—can detect anemia, and they're often performed together. Aspiration is a procedure to collect a small amount of fluid from your bone marrow. Your healthcare provider will then perform a biopsy, which involves removing a small amount of bone marrow tissue. The goal of a bone marrow test is to determine if your bone marrow is healthy and if it makes normal amounts of blood cells.
• Urine tests: Urine tests help determine if your kidneys are working properly. They may also detect bleeding in your urinary tract.
• Genetic tests: Genetic tests detect the presence of genes that affect how your body makes red blood cells.
• Other diagnostic tests: A colonoscopy can detect bleeding in your colon. Your healthcare provider may also consider an endoscopy to look for bleeding in the esophagus, stomach, and small intestine. For an endoscopy, a doctor or surgeon inserts a flexible tube with a camera, called an endoscope, into your body.

Anemia Treatments

Treatments for anemia depend on the cause and severity of your condition. Some forms of anemia can be treated with dietary changes and supplements. More severe anemia might require blood transfusions, blood or bone marrow transplants, or surgery.

The primary goal of treatment is to increase your red blood cell count or hemoglobin and improve oxygen levels in your blood, as well as relieve your symptoms and improve your quality of life. Other treatment goals include treating the underlying condition causing your anemia as well as preventing complications such as heart or nerve damage.

Including more iron-rich foods in the diet is one of the main treatment strategies for early or mild iron deficiency anemia. Iron is naturally present in a variety of animal and  plant-based foods . Heme iron is the type of iron found in animal foods like meat, poultry, seafood, and eggs. Non-heme iron is found in plant foods. Your body absorbs about 25% of dietary heme iron and about 17% of dietary non-heme iron.

Heme iron also enhances the absorption of non-heme iron. Therefore, people who don’t eat animal sources of iron often need to eat more sources of plant-based iron or take an iron supplement to meet their daily needs. Daily iron recommendations are about 1.8 times higher for  vegetarians and vegans .

Foods rich in iron include:

• White beans
• Dark leafy greens

You can combine these with foods high in vitamin C like broccoli, oranges, and strawberries. Vitamin C helps your body absorb iron.

Supplements

The most common approach to treating iron deficiency anemia is through oral supplementation (a pill taken by mouth) of iron. The dose depends on factors like your age and iron deficit, as well as your ability to tolerate potential side effects. For more severe cases, iron therapy (iron given through an intravenous line, or IV, into your vein) is used. One benefit of this approach is that it only takes one or two sessions to replenish the iron in your body.

For people with pernicious anemia, healthcare providers may use B12 supplements or shots to restore vitamin B12 levels. Nose gels and sprays can be valuable options for people who have difficulty swallowing pills.

Dietary supplements are minimally regulated by the FDA and may or may not be suitable for you. The effects of supplements vary from person to person and depend on many variables, including type, dosage, frequency of use, and interactions with current medications. Please speak with your healthcare provider or pharmacist before starting any supplements. 

Medications

Medications that treat the underlying condition causing anemia can also treat the anemia itself. If your current medication is causing anemia, your healthcare provider may make adjustments or change your medication to reduce your symptoms.

If you have aplastic anemia or hemolytic anemia, you may be prescribed medications to suppress your immune system, known as immunosuppressants. For aplastic anemia, they also may prescribe medications that stimulate your bone marrow to make red blood cells, such as erythropoietin therapy (injections of a hormone called erythropoietin, which helps with red blood cell production).

Blood Transfusions

If you have severe iron deficiency anemia, your healthcare provider may recommend a blood transfusion to quickly increase your iron and red blood cell levels. This procedure usually takes one to four hours and includes monitoring before and after the procedure. Blood transfusions also help treat aplastic anemia.

Blood and Bone Marrow Transplants

For people with severe aplastic anemia, a healthcare provider may recommend replacing damaged stem cells in your bone marrow with healthy cells. During this procedure, high doses of chemotherapy (medications used to treat cancer)—and possibly radiation—destroy ineffective stem cells before donor stem cells are put into your body. This type of transplant works best in people who have donors with closely matching cell types. It's typically used for children and young adults.

Surgery is sometimes required for internal bleeding that causes anemia. People with hemolytic anemia might also have surgery to remove the spleen because the spleen removes abnormal cells from the blood. This approach is rarely used.

Some types of anemia can be prevented, particularly those caused by vitamin or mineral deficiencies. Other types of anemia are long-lasting conditions that require ongoing management and treatment.

Including iron-rich foods in your diet can also help prevent iron deficiency anemia, especially if you combine them with foods high in vitamin C.

You can also try to avoid potential triggers that can increase your risk of anemia. For example, some types of anemia are triggered by things like particular foods or cold temperatures. If you have hemolytic anemia, washing your hands often and maintaining distance from people who might be sick can reduce your risk of infection.

If you have heavy periods, talk to an OB-GYN about how to address this condition before anemia develops.

There are a number of conditions related to anemia, many of which involve the heart. For example, anemia commonly occurs with acute coronary syndromes (ACS), a group of conditions caused by sudden or severely limited blood flow to the heart.

Other common related conditions include:

• Heart failure: Anemia frequently occurs with heart failure. Research suggests this is due to the complex relationship between iron deficiency, kidney disease, and cytokine production. Cytokines are proteins that help fight infections.
• Hypertension : Anemia is common among people with hypertension (high blood pressure). People with anemia also tend to have higher blood pressure readings.
• Chronic pulmonary obstructive disease (COPD): Anemia is common in people with COPD, a chronic lung disease that damages the lungs and makes breathing difficult. Up to 33% of people with COPD have anemia.
• Hypothyroidism : People with thyroid diseases like hypothyroidism (underactive thyroid gland) often have anemia. The reasons for this connection remain unclear.
• Chronic kidney disease (CKD): Certain factors can increase the likelihood that you have anemia with chronic kidney disease. For instance, one 2020 meta-analysis of 28 studies found that female patients with kidney disease were 36% more likely to develop anemia.
• Rheumatoid arthritis : Anemia is common in people with rheumatoid arthritis (RA), an autoimmune disease that causes joint inflammation. Estimates of how many people have both conditions vary widely, but falls within 30-60%.

Anemia can often be treated and managed with supplements, lifestyle interventions, and medications. Treating it early can also improve energy levels, allow you to be more active, and improve your overall quality of life—especially if you have mild or moderate anemia.

However, some types of anemia can be severe, long-lasting, and even fatal. If left untreated, some types of anemia can cause multi-organ failure and eventually lead to death.

Talk to your healthcare provider if you think you may have anemia. People who receive prompt and appropriate treatment can often live long and healthy lives.

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Shiferaw WS, Akalu TY, Aynalem YA. Risk factors for anemia in patients with chronic renal failure: A systematic review and meta-analysis .  Ethiop J Health Sci . 2020;30(5):829-842. doi:10.4314/ejhs.v30i5.23

Wilson A, Yu HT, Goodnough LT, Nissenson AR. Prevalence and outcomes of anemia in rheumatoid arthritis: A systematic review of the literature . Am J Med. 2004 Apr 5;116 Suppl 7A:50S-57S. doi:10.1016/j.amjmed.2003.12.012

Badireddy M, Baradhi KM. Chronic anemia . In: StatPearls . StatPearls Publishing; 2023.

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5 Surprising Things That Can Contribute to an Iron Deficiency

Photo Illustration by Joules Garcia for Verywell Health; Getty Images

Key Takeaways

• Without enough iron, the body can’t produce enough hemoglobin, the protein that carries oxygen from the lungs to all parts of the body.
• This can lead to symptoms like fatigue, weakness, shortness of breath, dizziness, and pale skin. 
• Experts say that low iron levels can be caused by more obvious causes, like excessive blood loss and not eating enough iron-rich foods, or sneakier causes, like certain foods and medications blocking iron absorption.

Iron deficiencies are quite common, affecting nearly 10 million adults in the United States, including 5 million with iron deficiency anemia. Despite this prevalence, many people don’t know they have low iron levels and may experience certain symptoms for years without knowing the cause.

Part of the reason why? Even if you take an iron supplement or eat plenty of iron-rich foods, lots of things block the absorption of iron.

Here’s what you need to know about factors that could be causing low iron levels and what you can do about it, according to experts.

What Causes Low Iron Levels?

Most of the iron in your body is found in a red blood cell protein called hemoglobin. As a result, chronic blood loss is a major cause of iron deficiency, whether from heavy monthly periods, surgery, blood thinner use, or a health condition like peptic ulcer disease, Margaret Ragni, MD, MPH , a professor of medicine and clinical and translational research at the University of Pittsburgh and Medical Director of the Hemophilia Center of Western PA in Pittsburg, told Verywell in an email. 

Of course, not consuming enough iron-rich foods can also lead to an iron deficiency. This is common in vegan or vegetarian diets that may lack sufficient iron found in animal products.

But some causes of iron deficiency, like those below, are less obvious.

Chronic Disease

Certain medical conditions, such as celiac disease or Crohn’s disease, can impact the body’s ability to absorb iron from food, Abayomi Ogunwale, MD, MBBS, MPH , Assistant Professor of Family Medicine at McGovern Medical School at UTHealth Houston, told Verywell in an email. Other chronic diseases, such as kidney disease or cancer, can also interfere with the body’s ability to use and store iron properly.

Drinking Certain Beverages

Drinking coffee, tea, and milk can also affect iron absorption—especially if you consume these beverages close to when you take an iron supplement.

“Coffee and tea both have high levels of compounds called oxalates and flavonoids called tannins. Tannins and oxalates bind to iron to form non-nutritious compounds, thereby limiting absorption and utilization of iron,” Ogyunwale said. “Milk contains casein and calcium, which directly reduce iron absorption.”

If you take an iron supplement, Ogyunwale said it’s best to do so on an empty stomach so that nothing hinders its absorption.

“Iron is best taken early in the morning on an empty stomach with water or fruit juice (preferably one rich in vitamin C like orange juice, which aids its absorption), one to two hours before meals, dairy, teas, coffee, and calcium-containing supplements,” he said.

Taking Certain Medications

The use of certain medications may negatively impact your iron levels.

“NSAIDs affect iron levels, but indirectly. They can cause irritation of the mucosal lining of the upper digestive tract, causing minor or major bleeds, which predispose you to iron deficiency,” Ogyunwale said. He added that some antibiotics can also cause hemolysis, or blood cell breakdown, which also contributes to low iron levels.

Other medications and vitamins may inhibit the absorption of iron if you’re taking an iron supplement.

“Proton pump inhibitors for acid reflux, heartburn, and stomach ulcers such as esomeprazole, omeprazole, pantoprazole, and dexlansoprazole suppress iron absorption, so it is best to separate use of these medications from an iron supplement by at least two hours,” Ogyunwale said. “The same goes for calcium phosphate. If you take a zinc supplement, it’s best absorbed when taken about one hour before iron.”

Strenuous exercise like running and long walking, especially on hard road surfaces, can contribute to a red blood cell breakdown called march hemoglobinuria, Ragni said.  This iron-depleting phenomenon is also referred to as footstrike hemolysis, and is thought to occur as capillaries in the foot repeatedly pound on the ground.

Life Stages

Certain life stages or conditions can increase the body’s need for iron, including pregnancy, breastfeeding, and rapid growth in children and adolescents, Ragni said.

How Do You Know If You Have Low Iron Levels?

Ragni said the main way to find out if you have low iron levels is through a blood test.

There are several types of iron tests, each with different normal value ranges. However, these ranges may vary slightly depending on the source or specific laboratory and factors like age, sex, and individual health conditions:

• A serum iron test measures the circulating amount of iron in the blood, and low levels may indicate an iron deficiency. A normal range is 60 to 170 micrograms per deciliter (mcg/dL).
• A transferrin test measures transferrin, a protein that moves iron throughout the body. High signs of transferrin may be a sign of iron deficiency anemia. A normal range is 204 to 360 milligrams per deciliter.
• A total iron-binding capacity (TIBC) examines how well iron attaches to transferrin and other proteins in the blood. If TIBC levels are high, it may indicate low iron in the blood due to iron deficiency anemia. A normal range is 240 to 450 mcg/dL.
• A ferritin blood test measures how much iron is stored in the body. Low ferritin levels can indicate low iron stores and iron deficiency. A normal range is 30 to 400 nanograms per milliliter (ng/mL) for males and 13 to 150 ng/mL for females.

What Happens If You Have Low Iron Levels? 

When iron levels in the body become low, it can lead to a decreased blood count and low heme levels, also known as anemia, Ogunwale said. This happens because iron is essential for producing hemoglobin, the component of red blood cells responsible for carrying oxygen throughout the body. 

“Humans cannot make the oxygen-carrying proteins called hemoglobin without iron,” said Ogunwale. “This can manifest in different ways and severity depending on various individual clinical factors.”

Symptoms of low iron levels and subsequent anemia may include:

• Brittle nails
• Cracks at the corner of the mouth
• Generalized weakness
• Shortness of breath
• Impaired cognition
• Restless legs
• Palpitations
• Increased heart rate
• Pica: a craving for non-nutritional substances like ice, clay, soil, or paper

If the anemia persists over a long period, it can lead to more severe outcomes such as organ failure, heart failure, and kidney failure, said Ogunwale.

What Can You Do If You Have Low Iron Levels? 

If you have low iron levels, the first thing you should do is identify why the iron deficiency has happened to prevent it from happening again.

“This means a visit to the doctor’s office for history taking, physical exams, and laboratory tests,” Ogunwale said.

You could also discuss with your provider about additional ways to boost your iron levels through lifestyle and dietary changes, Ogunwale said. For example, you can incorporate iron-rich foods such as beef, poultry, pork, lamb, salmon, tuna, sardines, and eggs into your diet. Vegetarians can increase their iron intake by eating baked beans, lentils, whole-meal pasta, bread, nuts, seeds, kale, spinach, broccoli, or tofu. 

What This Means For You

To determine if you have low iron levels, whether from a condition, your diet, or other lifestyle risk factors, experts recommend visiting your primary care physician for a blood test.

Miller JL. Iron deficiency anemia: a common and curable disease . Cold Spring Harb Perspect Med . 2013;3(7):a011866. doi:10.1101/cshperspect.a011866

National Institutes of Health Office of Dietary Supplements. Iron: fact sheet for consumers .

Yoshida M, Suzuki H, Hamaguchi S, et al. March hemoglobinuria progressed to acute kidney injury after kendo practice: a case report . BMC Nephrol . 2022;23(1):368. doi:10.1186/s12882-022-02988-0

Fazal AA, Whittemore MS, DeGeorge KC.  Foot-strike haemolysis in an ultramarathon runner .  BMJ Case Rep . 2017;2017:bcr2017220661. doi:10.1136/bcr-2017-220661

Mount Sinai. Serum iron test . 

StatPearls. Biochemistry, transferrin .

Mount Sinai. Ferritin blood test . 

American Society of Hematology. Iron-deficiency anemia . 

By Alyssa Hui Hui is a health news writer and former TV news reporter. She was the 2020 recipient of the Midwest Broadcast Journalists Association Jack Shelley Award.

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Case Study - A severe case of anaemia

17 April 2009

Nausea, tiredness and mild jaundice can all indicate severe anaemia, with urgent care required Dr David Morris explains.

Suzanne was a 54-year-old librarian who I had not seen before in surgery. She reported feeling nauseous and tired and, curiously, she thought her skin had taken on a yellow colour.

When pressed for further symptoms she admitted to shortness of breath on exercise and possibly weight loss but denied abdominal pain, dysphagia, rectal bleeding, change in bowel habit or change in colour of stool or urine.

Suzanne thought her symptoms may have first appeared around six months previously but had become progressively more intrusive since then.

Although Suzanne's sclera looked clear her skin did appear to have a yellow tinge to it. She was not tachypnoeic at rest but was tachycardic, with a regular pulse of 108 beats per minute.

Her chest was clear, heart sounds were normal and there was no calf swelling or tenderness. Abdominal examination revealed no tenderness, masses or organomegaly.

Iron deficiency anaemia was listed in her medical history 20 years previously, but other than a few minor gynaecological procedures the remainder of the history was unremarkable.

Suzanne was a lifetime non-smoker, consumed alcohol in only small quantities, ate a well-balanced diet and did not take any regular medication.

My first thoughts were to exclude anaemia and thyroid disorder and to check for renal or hepatic dysfunction. Blood tests were arranged accordingly.

Test results Suzanne was called back in urgently on receipt of the blood tests, which showed a severe macrocytic anaemia with a haemoglobin of 5.2g/dL and a mean cell volume (MCV) of 112fL.

Her white cell count was adequate, although platelets were on the low side at 131 x 109/L. Her bilirubin level was elevated to 59 micromol/L with other LFTs normal. U&Es, TFTs and fasting glucose levels were normal with an ESR of 19mm/hr.

Possible underlying diagnoses of a macrocytic anaemia are listed in the box. Given the blood test results, the most likely causes in Suzanne's case were B12 or folate deficiency, a haemolytic anaemia or myelodysplasia.

At this point I was considering hospital admission, but the advice following a phone call to the haematologist was that hospital admission and blood transfusion were probably unnecessary and that B12 and folate levels would be assessed urgently. If the latter were normal then analysis of bone marrow would be indicated.

The absence of a significant reticulocytosis argued against haemolytic anaemia as being a primary cause of the anaemia.

B12 levels were reported as being very low with repeat analysis to be performed on a separate analyser. Ferritin and folate levels were within normal range.

Management The diagnosis was pernicious anaemia. Suzanne started a series of six IM injections of 1mg hydroxocobalamin over of two weeks and also given supplementary folic acid and ferrous sulphate to support erythropoiesis.

Within a week of commencing treatment Suzanne was feeling much better, with resolution of nausea, increased energy and reduced shortness of breath. Repeat blood testing gave a haemoglobin level of 7.5g/dL, an MCV of 107fL and normal platelet and bilirubin levels.

After a month Suzanne's haemoglobin had climbed to 11.4g/dL and MCV had normalised. She was advised to have lifelong three-monthly hydroxocobalamin injections.

Discussion Vitamin B12 is an essential factor in the synthesis of thymidine and DNA, so deficiency will lead to impaired red blood cell production. Intrinsic factor produced in the stomach binds to B12 and this complex is subsequently absorbed in the terminal ileum.

Deficiency of B12 usually arises either from poor intake (notably a vegan diet, as B12 is not found in plants) or from malabsorption, either because of lack of intrinsic factor from the stomach (pernicious anaemia of post-gastrectomy), or because of dysfunction of the small intestine (Crohn's disease or ileal resection).

If malabsorption is the problem then B12 must be given intramuscularly.

Pernicious anaemia is an autoimmune atrophic gastritis in which parietal cell and intrinsic antibodies are produced. It is associated with other autoimmune conditions and has a female preponderance.

A mild jaundice can be seen in pernicious anaemia because relatively abnormal red cells produced by the compromised marrow are haemolysed, liberating bilirubin. There may be an accompanying leukopaenia and thrombocytopaenia, which are rapidly corrected on initiation of B12 supplements.

B12 deficiency can lead to a peripheral neuropathy, typically reported as a symmetrical paraesthesia of hands and feet, ataxia, weakness, glossitis, angular stomatitis and, in the elderly, a reversible dementia.

• Dr Morris is a GP in Shrewsbury, Shropshire

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• Case report
• Open access
• Published: 15 June 2024

An incidental finding of a hemoglobin E variant in a diabetic patient with an abnormal glycated hemoglobin level: a case report

• Rashmi Karki 1   na1 ,
• Samir Lamichhane   ORCID: orcid.org/0000-0003-0748-0767 2   na1 ,
• Runa Jha 1 &
• Rekha Manandhar 1   na1  

Journal of Medical Case Reports volume  18 , Article number:  279 ( 2024 ) Cite this article

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Metrics details

Glycated hemoglobin is a well-known marker for evaluating long-term glycemic control. However, the accuracy of glycated hemoglobin measurement can be affected by the presence of hemoglobin variants, which makes the determination and interpretation of glycated hemoglobin values in terms of glycemic control not only difficult but also misleading. Here we present the first ever case of a patient with type 2 diabetes with hemoglobin E from Nepal, diagnosed incidentally because of spurious glycated hemoglobin levels.

Case presentation

A 45-year-old Hindu Mongolian female with a history of type 2 diabetes for around 9 years but not very compliant with follow-ups was referred to our facility for plasma fasting and postprandial blood glucose levels and glycated hemoglobin. Fasting and postprandial blood sugars were found to be high. A consistent very low glycated hemoglobin by two different high-performance liquid chromatography (HPLC) methods compelled us to call the patient for a detailed clinical history and for the records of investigations done in the past. The patient has been a known case of type 2 diabetes for around 9 years and presented irregularly for follow-up visits. Around 4 years ago, she presented to a healthcare facility with fatigue, severe headaches, pain in the abdomen, discomfort, and dizziness for a couple of months, where she was shown to have high blood glucose. She was referred to a tertiary-level hospital in Kathmandu, where she was prescribed metformin 500 mg once daily (OD). Due to her abnormal hemoglobin A1c reports, she was then sent to the National Public Health Laboratory for repeat investigations. Her blood and urine investigations were sent. Complete blood count findings revealed high red blood cell and white blood cell counts, a low mean corpuscular volume, and a high red cell distribution width-coefficient of variation. Other parameters, including serum electrolytes, renal function tests, liver function tests, and urine routine examinations, were within normal limits. A peripheral blood smear revealed microcytic hypochromic red cells with some target cells. Hemoglobin electrophoresis showed a very high percentage of hemoglobin E, a very low percentage of hemoglobin A2, and normal proportions of hemoglobin A and hemoglobin F. A diagnosis of homozygous hemoglobin E was made, and family screening was advised.

Conclusions

Clinicians should be aware of the limitations of glycated hemoglobin estimation by ion exchange high-performance liquid chromatography in patients with hemoglobin E and other hemoglobin variants. If the clinical impression and glycated hemoglobin test results do not match, glycated hemoglobin values should be determined with a second method based on a different principle, and glycemic status should be confirmed through alternative investigations, preferably those that are not influenced by the presence of hemoglobin variants (for example, boronate affinity chromatography, fructosamine test, glycated albumin test, the oral glucose tolerance test, continuous glucose monitoring, etc.). Consistent or even doubtful results should also raise the suspicion of a hemoglobin variant, which should be confirmed through further evaluation and investigations.

Peer Review reports

Introduction

Glycated hemoglobin (HbA1c), initially identified as “unusual” hemoglobin in patients with diabetes over half a century ago [ 1 ], has now become a well-known marker of long-term glycemic control in individuals with diabetes mellitus [ 2 ], reflecting an average blood glucose level over a period of around 3 months. Glycemic control being an important factor for the progression to long-term complications, HbA1c strongly correlates with the risk of developing chronic complications associated with diabetes as well [ 3 ]; hence, it has become not only a diagnostic tool but also a screening tool for individuals at risk of diabetes [ 4 ]. However, the accuracy of HbA1c measurement can be affected by various factors such as erythropoiesis, glycation, erythrocyte destruction, and the presence of hemoglobin (Hb) variants [ 5 ], which makes the determination and interpretation of HbA1c values in terms of glycemic control not only difficult but also misleading [ 6 ]. Here, we present a case of a variant of Hb, the HbE, diagnosed incidentally in a patient with type 2 diabetes mellitus suspected initially because of repeated abnormal HbA1c levels detected with an ion-exchange high-performance liquid chromatography (HPLC) and hence subjected to further investigations by Hb capillary electrophoresis to confirm the diagnosis. To our knowledge, this is the first ever incidentally diagnosed case of HbE in a patient with type 2 diabetes from Nepal, all because of spurious HbA1c levels.

A 45-year-old Hindu Mongolian female, with a history of type 2 diabetes for 9 years and under medication for the last 4 months, visited the National Public Health Laboratory (NPHL), Teku, to test for plasma fasting and postprandial blood glucose levels and HbA1c.

We tested HbA1c by high-performance liquid chromatography (HPLC) Biorad VARIANT II, which showed HbA1c to be only 1.1% (Fig.  1 ). The control test run for the day was within range. Fasting and postprandial blood sugars were found to be 173 mg/dL and 280 mg/dL, respectively. The patient sample was rechecked with HPLC TOSO 7234X, which showed HbA1c of 2.1%. In view of this, the patient was contacted and advised to have a complete blood count (CBC) and hemoglobin electrophoresis. We took a detailed history of the patient and requested the records of investigations done in the past.

HbA1c detection by HPLC

According to the patient, she was apparently well around 9 years ago (the patient herself was not sure about the exact date) when she started developing increased urination, increased thirst, weakness, and occasional dizziness for a couple of months. She then visited a local health care facility near her hometown, where she was examined and sent for some blood and urine investigations (she has misplaced the lab reports, or probably lost them, according to her). According to her, she was told that she has high blood sugar levels and was advised to make some lifestyle modifications, such as dietary changes and increasing physical activities. She was also prescribed medication (she has no records of the medications prescribed then) and was asked to follow up in the next 3 months. Thereafter, she was doing fine with no complaints for a couple of years, and she never followed up with any healthcare facility until around 3–4 years ago (May 2020), when she presented herself to a healthcare facility in Kathmandu city with complaints of fatigue, severe headaches, pain and discomfort in the abdomen, and occasional dizziness and a feeling of lightheadedness for a couple of months. She also complained of weakness and decreased tolerance for physical activity. Physical examination was unremarkable, and laboratory investigations revealed high blood glucose and serum triglyceride levels (fasting blood glucose: 175 mg/dL; postprandial blood glucose: 193 mg/dL; serum triglyceride: 290 mg/dL). Other investigations were within normal limits (Table  1 ).

With these reports, she was referred to a tertiary-level hospital in Kathmandu. On 1 January 2021, she visited Shree Birendra Hospital (a tertiary-level hospital in Kathmandu), where she was further evaluated. At this time, she also admitted having a history of a slight decrease in vision for the last few months and was evaluated for any eye findings. Apart from a slightly presbyopic finding, everything else was normal. Intraocular pressure was within normal limits. There were no findings suggestive of diabetic retinopathy. The fundus examination was normal. Further lab workup findings revealed the following: TLC: 11,660 cells/mcL; Differential Count (DC): Neutrophils  = 76, Lymphocytes = 17, Monocytes = 5, Eosinophils = 1, Basophils = 1; MCV: 64.4 fL; MCH: 21.9 pg; RDW-SD: 36.1 fL; RDW-CV: 17.3 fL; postprandial (PP) blood glucose (two hours after taking a meal): 294 mg/dL; and HbA1c: 2.1%. Ultrasonography (USG) of the abdomen and pelvis showed a bulky uterus. All other investigations were within normal limits (Table  1 ).

She was prescribed metformin 500 mg OD and advised to make lifestyle modifications once again. She was then referred to the National Public Health Laboratory (NPHL), the central reference laboratory in Nepal, for repeat investigations to confirm the abnormal HbA1c reports and for all other relevant investigations. On arrival at NPHL (21 January 2021), she was thoroughly interviewed for a detailed medical history. She was a nonvegetarian, and she did not smoke tobacco or consume alcohol. She had never received a blood transfusion before. Apart from the metformin prescribed earlier, she was not on any other medications. There was no family history of low hemoglobin levels or blood transfusions. There was no other significant medical history in any of her family members, as far as the patient could remember. She gave a history of iron supplementation a long time ago (around 9 years ago when she first presented to a healthcare facility) for around 3 months but not thereafter. She denies any history of any means of blood loss. She has been married for around 25 years and has two kids (elder son: 23 years old, younger daughter: 21 years old). Physical examination was unremarkable and provided the following data: height: 5 feet; weight: 68 kg; body mass index (BMI): 29.3. Laboratory investigations are as follows:

CBC findings revealed hemoglobin of 13.6 g/dL, RBC of 6.2 × 10 6 cells/mcL, total leucocyte counts of 13,700 cells/mcL ( N  = 77, L = 18, M = 4, E = 1, B = 0), platelet count of 2.8 × 10 5 cells/mcL, and packed cell volume (PCV) of 42.1%. Red cell indices included mean corpuscular volume (MCV), mean hemoglobin concentration (MCH), mean corpuscular hemoglobin concentration (MCHC), and RDW-CV%, which were found to be 67 fL, 21.7 pg, 32.3 g/dL, and 17.9%, respectively. All other investigations were within normal limits (Table  1 ).

The ultrasonography (USG) report of the abdomen and pelvis revealed a bulky uterus and was otherwise unremarkable.

Hb electrophoresis was performed in the SEBIA MINICAP FLEX PIERCING electrophoretogram, which showed 93.2% HbE, 2.4% HbA2, 2.9% HbF, and 1.5% HbA (Fig.  2 ). A peripheral blood smear revealed microcytic hypochromic red cells with some target cells. White blood cell (WBC) and platelet morphology seem to have no abnormalities.

Detection of HbE by capillary electrophoresis

On the basis od these findings, a diagnosis of homozygous HbE was made, and family screening was advised.

Discussion and conclusion

Glycated hemoglobin (HbA1c), an effective and objective retrospective marker reflecting an average blood glucose level over a period of around 3 months, has now become a well-known indicator of long-term glycemic control in individuals with diabetes mellitus. However, there are various factors that may influence and falsely alter the level of HbA1c and its measurement and hence need to be considered in patients with abnormal readings.

HbA1c levels seem to inversely correlate with the rate of erythropoiesis, and hence factors that decrease the rate of erythropoiesis (including iron, vitamin B 12 , and folate deficiency) and/or increase erythrocyte life span (for example, due to splenectomy) falsely increase the level of HbA1c. Conversely, administration of erythropoietin, iron, and vitamin B 12 and conditions associated with reticulocytosis and decreased erythrocyte lifespan (for example, splenomegaly or even pregnancy) tend to falsely decrease the level of HbA1c [ 1 , 7 ]. There has been evidence of a false increase in HbA1c in cases of alcoholism and in patients with chronic kidney disease (CKD), as well, possibly through the same mechanism (alcohol interferes with folate metabolism, and patients with CKD have decreased erythropoietin levels) [ 1 , 7 , 8 ]. Several other conditions, for example, hyperbilirubinemia, carbamylated hemoglobin, chronic opiate use, etc., are also seen to be associated with a high HbA1c level [ 1 ]. However, chronic liver disease, rheumatoid arthritis, hypertriglyceridemia, and even the use of drugs such as ribavirin and dapsone have been shown to be associated with decreased HbA1c [ 1 , 7 , 9 , 10 ]. Genetic or chemical alterations in hemoglobin undoubtedly have some associations with HbA1c, and hence certain hemoglobinopathies, including the HbE disease, the presence of HbF, and methemoglobinemia, may also alter the level of HbA1c [ 1 , 7 , 11 ]. Here we discuss the presence of HbE and the misleading value of HbA1c levels.

Hemoglobin E, a variant hemoglobin, is characterized by a mutation in the β globin gene ( HBB gene) causing substitution of glutamic acid for lysine at position 26 of the β globin chain, resulting in a heterogeneous group of disorders whose phenotypes range from asymptomatic to severe disease [ 12 , 13 ]. HbE trait and HbEE are mild disorders, while a combination of HbE with other forms of hemoglobinopathies does exist that can have a markedly different and more serious clinical course, producing a wide range of clinical syndromes of varying severity [ 13 , 14 ]. The heterozygous form of HbE is usually characterized by minimal red cell morphological abnormalities and normal red cell indices, while homozygotes for HbE can have red cells with significant morphological abnormalities, including increased numbers of target cells, and can present with mild microcytic hypochromic anemia [ 14 ].

Despite advances in the standardization of methods for glycohemoglobins, including HbA1c, an increasing number of hemoglobinopathies have been shown to interfere with the accurate measurements and determination of these glycohemoglobins. Even the most commonly used methods, that is, the HPLC methods for HbA1c determination, lacked the resolution necessary to differentiate hemoglobin variants [ 6 ]. The demonstration of additional peaks in the chromatograms and either too low or too high values of HbA1c has been shown as compared with the nondiabetic reference range in different types of hemoglobinopathies [ 15 ].

Patients homozygous for HbE, that is, those receiving mutated genes from both parents, have a very low HbA level, with around 80% of Hb being HbE itself. The mutation associated with HbE tends to alter the ionic charges on Hb and hence interferes with the measurement of HbA1c via the ion-exchange HPLC method, especially in homozygous cases [ 16 , 17 ]. Unique mutation(s) on the N-terminal of β-globin in some hemoglobinopathies such as the Hb Graz and the Hb Long Island variants also seem to cause inappropriately high and low apparent HbA1c titers via HPLC methods. However, estimations with the boronate affinity technique and the immunoassay technique seem to be unaffected. The boronate affinity method has shown values in an acceptable and clinically reasonable range for all hemoglobin variants, as evidenced by several studies [ 18 , 19 ]. In fact, affinity methods have already been suggested as an acceptable and more useful method for reflecting glycemic control because they mainly measure glycohemoglobin regardless of the glycation site and hence may be clinically more accurate [ 15 ]. Studies have shown that results from the HbA1c immunoassays were also comparable to those from HPLC assays, showing good correlation, appropriate precision, and low bias [ 20 ]. Immunoassays utilizing various antibodies raised against specific epitopes of hemoglobin, for example, the Amadori product of glucose plus the first eight amino acids on the N-terminal end of the beta chain of hemoglobin, and many more, have shown good correlation with established methods for estimating glycohemoglobin [ 21 ]. However, as the quality of an immunoassay typically depends on the specificity of the antibody to the specific epitope on HbA, specific mutations altering the common epitopes used for the assays will hinder the accuracy of the test. One such example includes the hemoglobin variant with mutations affecting or altering the epitope at the N-terminal chain. The mutation seems to affect the ability of the monoclonal antibody that is used in the assay to detect hemoglobin [ 22 ]. Some uncommonly occurring variants that span the commonly used epitope include HbE and HbD (Los Angeles), where mutations occur at β26 and β121, respectively. There are some other evidences/studies that have reported that immunoassays have been shown to produce false HbA1c results in certain Hb variants [ 23 , 24 , 25 , 26 ]. Hence, choosing a method where the antibody epitope does not span the specific area in the Hb variant is crucial. However, it is not practical or even feasible to produce several specific antibodies (according to the individual patient) at each facility, and hence understanding the effects of such hemoglobinopathies while estimating the glycohemoglobins is crucial. To be precise, the effect of various hemoglobinopathies on HbA1c measurements is highly method-dependent. So, it is always better to be correlated clinically, and whenever the HbA1c results do not fit the clinical picture, some additional peaks in HPLC chromatograms are displayed, or any such doubtful scenario has been presented, it should not be ignored, and further investigations are advisable. Glycemic status over a short period of time (1–3 weeks) can also be reflected by the fructosamine test. Some researchers have therefore recommended confirmation with the fructosamine test or the glycated albumin test as an alternative [ 14 , 24 , 27 , 28 ]. Fructosamine results depend on the glycation of serum proteins and are not influenced by hemoglobin variants [ 19 ]. However, falsely low levels may occur in patients with hypoalbuminemia, for example, in patients with nephrotic syndrome or severe liver disease [ 29 ]. The glycated albumin test, reported as a percentage of total albumin, also reflects short-term glycemic status, typically over the preceding 2–3 weeks, and is not influenced by situations that falsely alter A1C levels [ 29 , 30 ]. Moreover, the tests that rely purely on blood glucose levels, including the oral glucose tolerance test (OGTT) and even continuous glucose monitoring, could possibly be the ones that are least affected by various factors, as discussed earlier. The OGTT is advocated for screening and diagnosis, and self-monitoring of blood glucose levels is advised for management during pregnancy [ 29 ]. Continuous glucose monitoring for up to 5 days has also been shown to correlate well with HbA1c levels [ 29 ].

The mutations associated with hemoglobin E disease are primarily seen to be prevalent in the eastern half of the Indian subcontinent and throughout Southeast Asia [ 12 , 23 ]. In 1954, Chernoff and colleagues first described that it has occurred in conjunction with β thalassemia, in which case it presents with a severe form of the disease known as the compound heterozygosity for hemoglobin E/β thalassemia [ 24 ], and since then several other cases have been reported from several parts of Southeast Asia [ 25 , 26 , 27 , 31 ]. Cases have been reported from some parts of Nepal, as well, but to our knowledge, this case report is the first ever report of an incidentally diagnosed HbE variant in a patient with type 2 diabetes mellitus in Nepal.

Several studies have evidenced and reported that various hemoglobinopathies, including HbE disease, interfere with accurate measurements of glycosylated hemoglobin, including HbA1c. A study conducted on the prevalence of hemoglobin variants and their effect on HbA1c measurement among the indigenous population of north Bengal showed Hb variants to have a significant effect on HbA1c measurement [ 32 ]. A clinically silent and very rare hemoglobinopathy, hemoglobin Himeji, has been reported in a Portuguese patient with diabetes with a discrepancy between fasting plasma glucose and HbA1c [ 33 ]. Yet another case series of two female Malay patients with HbJ, an Hb variant, showed persistently high HbA1c levels despite good glycemic control [ 34 ].

Because of the local occurrence of Hb variants and the ethnic origin of a given population, every individual laboratory must establish and validate its own assay method. Also, while managing patients with diabetes, knowledge of hemoglobinopathies influencing HbA1c determination methods is essential. Moreover, in populations with a high prevalence of hemoglobinopathies, hemoglobin typing should be considered basic information prior to HbA1c measurement, as suggested by some other studies, as well [ 35 ].

Hence, to conclude, clinicians should be aware of this limitation of HbA1c estimation by ion-exchange HPLC in patients with HbE and other Hb variants, though HPLC has been an important and one of the most commonly used modalities [ 26 ], among the several others such as immunoassay techniques, boronate affinity chromatography, etc., to detect it [ 18 ]. If the clinical impression and HbA1c test results do not match, then HbA1c values should be determined with a second method based on a different principle and confirmation of the glycemic status through alternative investigations. The boronate affinity method has been shown to be clinically reasonable for all hemoglobin variants. Similarly, the fructosamine test and the glycated albumin test could also be used as alternatives, as they are also not influenced by the presence of hemoglobin variants. The OGTT and continuous glucose monitoring can obviously be other reliable alternatives, though they have their own disadvantages, such as the fact that they will not reflect glycemic control over a longer period of time, as does the HbA1c, and need repeated measurements. Moreover, an abnormal HbA1c level in a diabetic patient or any other subject during routine evaluation or screening for diabetes could raise the suspicion of an Hb variant. Therefore, physicians and especially endocrinologists should take this fact into account and immediately seek further evaluation and investigations to confirm the diagnosis of Hb variants in such patients and advise the patients to screen their family members.

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Rashmi Karki, Runa Jha & Rekha Manandhar

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RK and RM conceptualized and designed the case report. The acquisition, analysis, and interpretation of patient data were also performed by RK and RM. The collection and assembly of relevant literature and background information, as well as writing and revising the manuscript focusing on the clinical aspects of the case, were done by SL. RK assisted SL in drafting and revising the manuscript, with a focus on the literature review. RK also contributed to the intellectual content and critical revision of the manuscript. Supervision and mentorship throughout the case report development were done by RJ and RM. All authors have read and approved the final version of the manuscript to be published.

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Karki, R., Lamichhane, S., Jha, R. et al. An incidental finding of a hemoglobin E variant in a diabetic patient with an abnormal glycated hemoglobin level: a case report. J Med Case Reports 18 , 279 (2024). https://doi.org/10.1186/s13256-024-04518-y

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Response to Immunosuppressive Therapy in Aplastic Anemia—A Single Centre, Prospective Study of 158 Patients from a Tertiary Care Centre in India

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• Published: 17 June 2024

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• Mahathi Krishnan 1   na1 &
• Deepak Amalnath   ORCID: orcid.org/0000-0002-3286-0107 2   na1  

Immunosuppressive therapy (IST) with Antithymocyte globulin (ATG) and cyclosporine is the therapy of choice in aplastic anemia (AA) patients who are more than 40 years of age and younger patients who do not have matched sibling donor for stem cell transplant (SCT). The overall response rate to IST is approximately 65%. The two preparations of ATG that are available in India are Atgam (Pfizer) and Thymogam (Bharat serum, India). Most of the published studies, from India, have used ATGAM. We present the largest study on IST (with Thymogam) from India. This is a single centre prospective study conducted in a tertiary care institute in southern India, from July 2016 to June 2022. All patients of age more than 13 years with diagnosis of aplastic anemia were included. Those with inherited bone marrow failure syndromes were excluded. Severity of AA and response rate was classified based on standard criteria. Patients were followed up till discharge and then monthly for at least 6 months. A total of 158 patients ( males-85, females- 73) received IST (Thymogam plus cyclosporine).Most of the patients had non severe AA(58%) followed by severe (28%) and very severe AA(14%). At 6 months post IST, the overall response rate (ORR) was 66% (complete response- 2% and partial response -64%) while the mortality rate was 13%.The ORR was 64% at 12 months and 61% at 24 months after IST. Age, Gender and severity at presentation did not influence response rates.

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Acknowledgements

The authors would like to thank the department of Pathology for their essential role in the diagnosis and follow up of the patients.

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Mahathi Krishnan

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Krishnan, M., Amalnath, D. Response to Immunosuppressive Therapy in Aplastic Anemia—A Single Centre, Prospective Study of 158 Patients from a Tertiary Care Centre in India. Indian J Hematol Blood Transfus (2024). https://doi.org/10.1007/s12288-024-01794-y

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The role of donor type and pre‐transplant immunosuppression on outcomes of hematopoietic stem cell transplantation in children and young adults with severe aplastic anemia

• Reema Kashif , Biljana Horn , +13 authors Deepak Chellapandian
• Published in Pediatric Transplantation 20 May 2024

18 References

Alternative donor bmt with post-transplant cyclophosphamide as initial therapy for acquired severe aplastic anemia., comparison of outcomes of frontline immunosuppressive therapy and frontline haploidentical hematopoietic stem cell transplantation for children with severe aplastic anemia who lack an hla-matched sibling donor., comparable long-term outcomes between upfront haploidentical and identical sibling donor transplant in aplastic anemia: a national registry-based study, prospective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia., immunosuppressive therapy for pediatric aplastic anemia: a north american pediatric aplastic anemia consortium study, similar outcome of upfront‐unrelated and matched sibling stem cell transplantation in idiopathic paediatric aplastic anaemia. a study on behalf of the uk paediatric bmt working party, paediatric diseases working party and severe aplastic anaemia working party of ebmt, alternative-donor hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for nonmalignant disorders., similar outcomes after haploidentical transplantation with post-transplant cyclophosphamide versus hla-matched transplantation: a meta-analysis of case-control studies, a randomized controlled study in patients with newly diagnosed severe aplastic anemia receiving antithymocyte globulin (atg), cyclosporine, with or without g-csf: a study of the saa working party of the european group for blood and marrow transplantation., myelodysplastic syndrome evolving from aplastic anemia treated with immunosuppressive therapy: efficacy of hematopoietic stem cell transplantation, related papers.

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• Regan JJ, et al. Use of Updated COVID-19 Vaccines 2023-2024 Formula for Persons Aged ≥6 Months: Recommendations of the Advisory Committee on Immunization Practices—United States, September 2023. MMWR. Morbidity and Mortality Weekly Report 2023; doi:10.15585/mmwr.mm7242e1.
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• Stay up to date with COVID-19 vaccines. Centers for Disease Control and Prevention. www.cdc.gov/coronavirus/2019-ncov/vaccines/stay-up-to-date.html. Accessed April 2, 2024.
• COVID data tracker. Centers for Disease Control and Prevention. https://covid.cdc.gov/covid-data-tracker/#demographics. Accessed April 2, 2024.
• Najafabadi BT, et al. Obesity as an independent risk factor for COVID‐19 severity and mortality. Cochrane Database of Systematic Reviews. 2023; doi:10.1002/14651858.CD015201.
• People with certain medical conditions. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html. Accessed April 2, 2024.
• AskMayoExpert. COVID-19: Outpatient management (adult). Mayo Clinic; 2023.
• Emergency use authorizations for drugs and non-vaccine biological products. U.S. Food and Drug Association. https://www.fda.gov/drugs/emergency-preparedness-drugs/emergency-use-authorizations-drugs-and-non-vaccine-biological-products. Accessed April 2, 2024.
• How to protect yourself and others. Centers for Disease Control and Prevention. https://www.cdc.gov/coronavirus/2019-ncov/prevent-getting-sick/prevention.html. Accessed April 2, 2024.
• COVID-19: What people with cancer should know. National Cancer Institute. https://www.cancer.gov/about-cancer/coronavirus/coronavirus-cancer-patient-information. Accessed April 2, 2024.
• Hygiene and respiratory viruses prevention. Centers for Disease Control and Prevention. https://www.cdc.gov/respiratory-viruses/prevention/hygiene.html. Accessed April 2, 2024.
• Preventing respiratory viruses. Centers for Disease Control and Prevention. https://www.cdc.gov/respiratory-viruses/prevention/index.html. Accessed April 2, 2024.
• Maintaining a care plan. Centers for Disease Control and Prevention. https://www.cdc.gov/aging/publications/features/caregivers-month.html. Accessed April 2, 2024.
• COVID-19: What People with Cancer Should Know. National Cancer Institute. https://www.cancer.gov/about-cancer/coronavirus/coronavirus-cancer-patient-information. Accessed April 11, 2024.

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• PMC10332331

A Case of Severe Aplastic Anemia in a 35-Year-Old Male With a Good Response to Immunosuppressive Therapy

Ekaterina proskuriakova.

1 Internal Medicine, Mount Sinai Hospital, Chicago, USA

Ranjit B Jasaraj

Aleyda m san hernandez, anuradha sakhuja, mtanis khoury.

2 Hematology and Oncology, Mount Sinai Hospital, Chicago, USA

Aplastic anemia (AA) is a severe but rare hematologic condition associated with hematopoietic failure leading to decreased or total absent hematopoietic precursor cells in the bone marrow. AA presents at any age with equal distribution among gender and race. There are three known mechanisms of AA: direct injuries, immune-mediated disease, and bone marrow failure. The most common etiology of AA is considered to be idiopathic. Patients usually present with non-specific findings, such as easy fatigability, dyspnea on exertion, pallor, and mucosal bleeding. The primary treatment of AA is to remove the offending agent. In patients in whom the reversible cause was not found, patient management depends on age, disease severity, and donor availability. Here, we present a case of a 35-year-old male who presented to the emergency room with profuse bleeding after a deep dental cleaning. He was found to have pancytopenia on his laboratory panel and had an excellent response to immunosuppressive therapy.

Introduction

Aplastic anemia (AA) is a rare condition characterized by the combination of hypoplasia or aplasia of the bone marrow and pancytopenia in at least two of the three main lines of cells: red blood cells (RBCs), white blood cells (WBCs), and platelets [ 1 ]. An estimated incidence of this disease is 0.6 to 6.1/million per year with a sex ratio of about 1:1 [ 2 ]. AA is more common in Asia than in Western countries [ 3 ]. This could reflect the variability of exposure to different environmental factors, such as drugs, chemicals, viral pathogens, or genetic predisposition. Although this condition could be seen in any age group, two incidence peaks of AA are reported: in young adults (20-25 years old) and the elderly population with a peak after the age of 60 [ 4 , 5 ].

The three main mechanisms of AA are direct injuries, immune-mediated disease, and bone marrow failure (inherited or acquires) [ 1 ]. The most common etiology of AA is considered to be idiopathic, responsible for 65% of cases. Seronegative hepatitis accounts for about 10% of cases and tends to develop three months after the episode of acute hepatitis [ 6 ]. Telomerase abnormalities are found in approximately 5% of late-onset AA [ 7 ]. Among hereditary causes, Fanconi anemia is the most common, which presents in the first 10 years of life with pancytopenia, hypoplasia, and bone abnormalities [ 8 ].

The clinical manifestation of AA is usually some non-specific finding due to pancytopenia, such as fatigue, dyspnea on exertion due to anemia, mucosal bleeding like petechiae, heavy menses, gingival bleeding due to thrombocytopenia, or fever with neutropenia [ 9 ]. A bone marrow examination with a finding of aplastic or hypoplastic marrow is required to establish a diagnosis. In addition, cytogenetic studies, such as fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS), help make a diagnosis and rule out other hematologic abnormalities responsible for pancytopenia [ 9 ]. Peripheral blood-flow cytometry could be helpful in order to exclude paroxysmal nocturnal hemoglobinuria (PNH) [ 10 ].

Management of AA in patients without reversible causes depends on the age of the patient and disease severity. For young and healthy individuals under 50 years old, an allogeneic hematopoietic cell transplant (HCT) should be performed before initiation of immunosuppressive therapy (IST). Those who are older than 50 years old or younger individuals who cannot have HCT should start on full-dose IST, including eltrombopag, which is a thrombopoietin agonist, anti-thymocyte globulin (ATG) that eliminates antigen-reactive T-cells, cyclosporin A inhibiting interleukin-II (IL-2), and prednisone that leads to the destruction of immature T-lymphocytes [ 9 ]. Supportive treatment with transfusions of leukoreduced RBC for hemoglobin (Hgb) less than 7 mg/dL or platelets less than 10,000/microliters and infection treatment or prophylaxis is also indicated for patients with AA [ 1 ].

Here, we present a case of a 35-year-old male who presented to the emergency room with profuse bleeding after deep dental cleaning and was found to have pancytopenia on his laboratory panel.

Case presentation

A 35-year-old male presented to the emergency department (ED) of our hospital for persistent bleeding of his gums. He had been having episodes of minimal gum bleeding for a week that he attributed to an infection and had gone to a dentist on the day of admission for dental cleaning. He started having profuse bleeding after the dental procedure, which did not resolve with the application of pressure and was advised to go to the ED.

At the time of admission, he was in mild distress and concerned about the bleeding. The patient did not have any dizziness, headache, palpitations, or bleeding anywhere else. He denied similar episodes in the past or a family history of bleeding. The patient denied tobacco, alcohol, or illicit drug use and was not on any anticoagulants/anti-platelets. The patient migrated from Mexico 20 years ago and worked in construction. He denied any sick contact or recent travel. On examination, his vital signs were stable, but he was in mild distress. He was having profuse bleeding in his bilateral lower gums, both the buccal and lingual side, and in the buccal side of his upper gums. The rest of the examination was unremarkable.

Initial laboratory results were significant for pancytopenia (Table ​ (Table1). 1 ). The chemistry panel was significant for elevated blood urea nitrogen and mild hypokalemia (potassium = 3.4 mEq/L). The liver function test, renal function test, coagulation panel, and other electrolyte results were normal. The peripheral blood smear test showed normal WBC and platelet morphology, decreased platelet number, abnormal RBC morphology, marked hypochromasia, and slight schistocytes.

g/dL: grams per deciliter; mm 3 : cubic meter; µm 3 : cubic micrometer; pg/cell: picogram per cell

CBC: complete blood count; WBCs: white blood cells; RBCs: red blood cells; Hbg: hemoglobin; Hct: hematocrit; MCV: mean cell volume; MCH: mean cell hemoglobin; PT: prothrombin time; INR: international normalized ratio; PTT: partial thromboplastin time

Within two hours, the patient became hypotensive and developed hemorrhagic shock, and was admitted to the intensive care unit. The patient’s mouth was packed, and he received multiple transfusions of packed RBC and platelets. Further test results (Table ​ (Table2) 2 ) were negative for any infections. However, he was positive for parvovirus and cytomegalovirus IgG antibodies, which were likely from a previously cleared infection. The reticulocyte count was 0.9 after correction for hematocrit, and haptoglobin and lactate dehydrogenase (LDH) were both within normal limits, pointing toward the hypoproliferation of the bone marrow rather than hemolysis.

HIV: human immunodeficiency virus; HBVs Ag: hepatitis B surface antigen; HBVc IgM Ab: IgM antibody against hepatitis B core antigen; HBV cIgM: hepatitis B virus cytoplasmic IgM; HCV IgG Ab: IgG antibody against hepatitis C; HAV IgM: IgM antibody against hepatitis A; COVID-19: coronavirus disease 2019; CMV IgG Ab; IgG antibody against cytomegalovirus; CMV IgM Ab: IgM antibody against cytomegalovirus; parvovirus B19 IgG Ab: parvovirus B19 IgG antibody; parvovirus B19 IgM Ab: parvovirus B19 IgM antibody

The bone marrow biopsy showed a hypocellular bone marrow with 5-10% cellularity consistent with AA (Figure ​ (Figure1, 1 , Figure ​ Figure2 2 ).

PNH flow cytometry with fluorescein-labeled proaerolysin (FLAER), which is a high-sensitivity assay that assesses the glycosylphosphatidylinositol (GPI)-linked CD59 on erythrocytes, was abnormal with elevated PNH monocytes (2.001%) and polymorphonuclear neutrophil (PMNs) (0.381%). No circulating blasts and megakaryocytes were seen. The overall AA is associated with PNH.

The patient was not accepted for the Allogenic Hematopoietic Stem Cell Transplant (HSTC) Center due to the lack of insurance. The patient was started on triple immune suppression therapy: ATG, cyclosporine (CsA), and prednisone. The patient was started on equine ATG 40 mg/kg/day IV for four consecutive days in combination with CsA 10 mg/kg every 12 hours and prednisolone (0.5 mg/kg/day). In addition, he received eltrombopag 150 mg per oral (PO) once per day, an oral thrombopoietin-receptor agonist, and diphenhydramine 25 mg to prevent serum sickness from ATG. The patient continued to be on neutropenic precautions and close monitoring of all cell line levels, with goals of Hgb 7 g/dL and platelet count 10,000/mm 3 .

The patient was discharged home to continue outpatient chemotherapy. On the last follow-up at the outpatient clinic, three months after admission, recovery of all the three cell lines was noted (Table ​ (Table3 3 ).

CBC: complete blood count; WBCs; white blood cells; RBCs: red blood cells; Hbg: hemoglobin; Hct: hematocrit; MCV: mean cell volume; MCH: mean cell hemoglobin

The 35-year-old patient with no significant past medical history presented to the hospital with oropharyngeal bleeding. The severity of his thrombocytopenia expanded and the bleeding worsened upon his presentation to the hospital. His decreased WBC count and neutropenia put him at a high risk of infection. Low Hgb and below-normal reticulocytes showed that his RBC production was profoundly impaired. The bone marrow biopsy ruled out other differential diagnoses, but the cause of AA development was still questionable. In addition, the patient was found to have PNH, which could be associated with AA in 40% of patients. However, there are contradictory data in the literature about the impact of PNH clones on patients with AA undergoing immunosuppressive treatment.

AA can be associated with a broad spectrum of pathologies that could lead to the loss of progenitor cells and pancytopenia. There are three main mechanisms of its development: disrupting extrinsic factors, expression of familial genetic mutations, or damage by an autoimmune attack on hematologic cells [ 1 ]. The extrinsic mechanisms of AA are usually apparent and include exposure to therapeutic radiation, benzene, chemotherapy [ 11 ], several medications, or pesticides, such as organophosphates [ 7 ]. Nevertheless, this patient did not take any medications or have no known history of radiation or chemotherapy.

A genetic abnormality that is mainly associated with AA is Fanconi anemia, a condition attributed to DNA repair abnormalities. This syndrome is usually manifested in patients during the first or second decade with other congenital defects, such as thumb or facial abnormalities and short stature [ 12 ]. Dyskeratosis congenita is another common mechanism, a condition caused by mutations in genes responsible for the repair of telomeres. Patients can present with skin pigmentations, oral leukoplakia, and dystrophic nails [ 13 ]. Congenital abnormality was highly unlikely in this patient; he did not have any family history of such conditions, nor had a clinical manifestation.

Another common cause of AA can be seronegative hepatitis, which can develop in up to 10% of cases approximately three months before the manifestation of AA [ 14 ]. It usually occurs in the younger population. However, this patient did not have any risk factors or any history related to the development of hepatitis. Other viruses that could predispose to AA include HIV or parvovirus B19 [ 15 ]. IgG usually develops two weeks after infection and persists for life, with an increase in level post-re-exposure. Transient aplastic crisis (TAC) is characterized by the abrupt onset of anemia with absent or low-level reticulocytes and can be associated with B19 in patients with hematologic abnormalities. TAC and B19 can also lead to other cytopenias in other blood lineages [ 16 ]. TAC could be a potential explanation for the patient’s symptoms as his blood tests revealed elevated IgG levels to B19. This finding can reflect only previous infections and has no association with AA in this patient. Nevertheless, regardless of the trigger, the patient’s presentation and the severity of his AA were associated with a high chance of death without urgent management.

Management of AA depends on the severity of the condition, the age of a person, access to the treatment or availability of a matched stem-cell donor, and the presence of other comorbidities that decrease the chance of getting a cell transplant [ 17 ]. The patient’s laboratory values met the criteria for severe AA, which are defined by bone marrow hypocellularity of less than 30% and involvement of at least two out of the three criteria: absolute reticulocyte count less than <60 ×109/L, absolute neutrophil count less than 0.5×109/L, or platelet count less than 20 ×109/L. Younger age (less than 40) and the presence of a matched sibling donor favor the use of the allogeneic HSCT. Usually, older patients (>40 years) and those who do not have access to HSCT are treated with IST, which includes a combination of ATG and CsA with response rates up to 80% and survival rates the same as those after HSCT [ 18 ]. However, rates of relapse and evolution to myelodysplastic syndromes are higher with IST treatment [ 19 ]. Bacigalupo et al. showed an overall survival rate of 87% and a response rate of 77% in 100 patients treated with CsA, ATG, prednisone, and filgrastim [ 20 ]. Nevertheless, the patient did not have access to the treatment with an allogeneic stem cell transplant. He was commenced on full IST with eltrombopag, ATG, and CsA with prednisone and diphenhydramine to prevent serum sickness from ATG.

Some studies have revealed factors that predict a better response to IST, such as younger age, high absolute reticulocyte and lymphocyte count, and mutations in the PIGA, BCOR, or BCORL1 genes [ 21 ]. Mutations in the PIGA gene lead to the lack of the GPI-anchored proteins, CD59, and decay-accelerating factor (DAF or CD55) in patients with PNH. Deficiency of these GPI-anchoring proteins in WBCs and RBCs leads to the development of the so-called escape clones of PNH in AA [ 22 ].

The explanation of this immune escape mechanism is proposed to be associated with cytotoxic T cells that target normal hematopoietic stem cells (HSCs), and PNH-positive HSCs are protected from this immune attack. These T cells’ target can most likely be GPI anchors in patients with AA [ 23 , 24 ].

PNH escape clones can be found in more than 50% of patients with AA at the time of diagnosis, as in this patient. According to the AA guidelines of the British Society for Standards in Haematology, all patients with AA should be screened for PNH clones [ 17 ]. The impact of PNH clones on the treatment outcome of patients treated with IST has been discussed in the recent meta-analysis that showed a better response rate in the group diagnosed with PNH [ 25 ].

Apart from IST, patients with AA usually require supportive care that includes prophylaxis and treatment of infections, transfusions of leukoreduced packed RBC if the level of Hgb is less than 7 mg/dL, or platelets if their level drops below 10 x 109/L, or less than 50 x 109/L with active bleeding [ 1 ]. The patient presented with a platelet count of 4 x 109/L; therefore, he received multiple platelet transfusions before being discharged home.

The patient gradually improved on IST and was eventually discharged home to continue outpatient chemotherapy. On the last follow-up at the outpatient clinic, three months after admission, recovery of all the three cell lines was noted.

Conclusions

In this case report, we described a case of a healthy young man with no medical history who presented to the hospital with persistent bleeding from his gums and was found to have AA. The patient’s laboratory values met the criteria for severe AA, and he was also found to have PNH that could be associated with AA in 40% of patients. Patients with age less than 40 and the presence of a matched sibling donor favor the use of HSCT. Our patient did not have access to the bone marrow transplant. Therefore, he was commenced on full IST with ATG, prednisone, and CsA. In addition to IST, the patient was also receiving eltrombopag. The patient with severe AA responded excellently to the therapy, recovering all the three cell lines after three months of management. Therefore, young age, no significant past medical history, and concomitant diagnosis with PNH can be the main factors leading to a better response rate to IST in patients diagnosed with severe AA.

The authors have declared that no competing interests exist.

Human Ethics

Consent was obtained or waived by all participants in this study