case study of patient with anaemia

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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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Disclaimer: These citations have been automatically generated based on the information we have and it may not be 100% accurate. Please consult the latest official manual style if you have any questions regarding the format accuracy.

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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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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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Sickle cell anemia

Best practices for patient-centered care.

Riley, Kiernan BSN, RN; Evans, Michael M. PhD, MSEd, RN, ACNS, CMSRN, CNE; Kowalchik, Kaléi BSN, RN; Adams, Lucy; Lucey, Megan

At Pennsylvania State University College of Nursing, Kiernan Riley is a BSN-to-PhD Student, University Park Campus; Michael M. Evans is the Assistant Dean of Undergraduate Nursing Education, Commonwealth Campuses, and an Associate Teaching Professor of Nursing, University Park; Kaléi Kowalchik is a BSN-to-PhD Student; Lucy Adams is a Junior Honors Nursing Student, Scranton Campus; and Megan Lucey is a Sophomore Honors Nursing Student, Scranton Campus.

The authors and planners have disclosed no potential conflicts of interest, financial or otherwise.

For more than 88 additional continuing-education articles related toacute care topics, go to NursingCenter.com/CE .

Earn CE credit online: Go to www.nursingcenter.com/CE/nmie and receive a certificate within minutes.

What are the treatment recommendations for this disorder that predominantly affects Black Americans? Follow along with a case study to learn how to minimize barriers and optimize outcomes.

Sickle cell anemia (SCA) is an inherited blood disorder that causes the hemoglobin molecules in red blood cells (RBCs) to be defective. This causes the blood cells to have shorter lifespans and block blood vessels, resulting in anemia, fatigue, inadequate blood supply, and painful vaso-occlusive crises. Affecting approximately 100,000 individuals in the US, SCA has an estimated annual medical care cost of $1.1 billion. In the US, SCA predominately affects Black Americans, with an estimated 1 out of 365 births diagnosed with the disease, according to the CDC.

People of color often face implicit bias from healthcare providers and may be viewed with a more negative attitude than other patients. In addition, people with SCA may be viewed as “drug-seeking” because opioids are the treatment for the symptom of severe pain. The intensified stigma from the rising opioid crisis can result in pain not being managed properly and decreased quality of care for patients with SCA.

To address the complex issues surrounding treatment of SCA, a hypothetical case study is presented, which describes the events of a patient with SCA admitted to a medical-surgical unit following a vaso-occlusive crisis. A literature review was conducted using the scholarly databases CINAHL and PubMed to find the best practices for management of SCA in adults, including more education for healthcare professionals, utilization of alternative treatments, enhanced medical management, and better care coordination.

Mr. E, a 22-year-old Black male, presents to the ED with severe pain in his hands and abdomen. Mr. E has a history of anemia, gastroesophageal reflux disease, SCA, hypertension, and depression. He's currently a student at a local university where he studies psychology and plays soccer. His current daily medications include lisinopril, 20 mg; esomeprazole, 20 mg; and escitalopram, 20 mg.

Mr. E.'s vital signs are temperature, 100.4°F (38°C); pulse, 110 beats/minute; respirations, 18 breaths/minute; BP, 162/94 mm Hg; and oxygen saturation, 96% on room air. He complains of sharp, stabbing pain of 8/10 in his abdomen and hands and has 1+ edema in his hands. Mr. E's skin is pale but warm to touch. He's awake, alert, and oriented x 4 and denies any other complaints.

After evaluating Mr. E, both the ED physician and nurse believe that he's experiencing a vaso-occlusive crisis as a result of SCA. They feel that this could be related to dehydration caused by recent warm temperatures and playing soccer. After receiving orders from the ED physician, labs are drawn for a complete blood cell (CBC) count and a complete metabolic panel. In addition, a 20-gauge I.V. is inserted in Mr. E's left antecubital fossa and normal saline solution is started at 125 mL/h. Morphine 2 mg I.V. is given for pain by the ED nurse and Mr. E is admitted to the medical-surgical floor for further treatment.

Upon arrival to the medical-surgical unit, the nurse helps Mr. E get comfortable in bed and provides him with a urinal because an accurate measurement of intake and output is needed. His vital signs remain unchanged, except for a slight temperature decrease to 100.2°F (37.8°C). Labs reveal a white blood cell count of 12.3 mcL, a hemoglobin level of 10.2 g/dL, a hematocrit level of 36%, and a blood urea nitrogen level of 28 mmol/L, indicating a possible infection, anemia, and dehydration.

The hospitalist evaluates Mr. E and recommends that he continues his home medications and the I.V. normal saline solution at 125 mL/h. The hospitalist adds oral amoxicillin 500 mg every 8 hours due to Mr. E's fever, oral acetaminophen 650 mg every 6 hours as needed for a temperature greater than 100.4°F (38°C), oral folate 400 mcg daily, oral tramadol 50 mg twice a day, and a regular diet. The nurse provides Mr. E. with emotional support and he calls his parents to let them know what happened.

Pathophysiology

Predominately occurring in people of African, Arab, or Mediterranean heritage, SCA is a congenital hereditary disorder that affects the hemoglobin molecules in RBCs. In adults, the most common symptoms of SCA are vaso-occlusive crises, anemia, and hemolysis resulting in painful extremities. Other symptoms include fatigue, dactylitis (finger or toe inflammation), and jaundice. Patients with SCA have blood cells that contain an abnormal form of hemoglobin known as hemoglobin S in which both the normal beta-globin subunits of hemoglobin are replaced with hemoglobin S. This hemoglobin is defective, forming long rods that distort the RBC into a stiff sickle shape instead of its typical disc shape.

Due to their shape, sickled blood cells can't easily pass through blood vessels and get stuck, creating blockages (see Picturing SCA ). Obstructed blood vessels lead to inadequate blood and oxygen supplies, which cause severe pain and injury to the affected areas, commonly referred to as a vaso-occlusive crisis. This crisis can last from several hours to days and may be caused by dehydration.

Sickle-shaped blood cells are fragile and susceptible to rupturing, which releases hemoglobin into the bloodstream, causing hemolysis and hemolytic jaundice. These cells live for approximately 16 days, compared with healthy blood cells that live for an average of 120 days. A shortage of RBCs due to their sickle shape and short lifespan results in chronic anemia, which leads to fatigue.

Patients with SCA have an average hospital length of stay of 5.1 days, with an average cost per patient of over $7,500. In 2016, there were approximately 134,000 inpatient hospitalizations related to SCA. Approximately 90% of those hospitalizations were Black patients experiencing a pain crisis.

Barriers to care

Care of patients with SCA can be complicated, especially in the context of an acute vaso-occlusive crisis. Barriers to appropriate care exist, often stemming from social and system challenges. Some of the most commonly noted barriers include bias, stigma, healthcare provider availability and training, and inconvenient care.

As identified by Brennan-Cook and colleagues, being a person of color accessing the healthcare system can come with the impact of implicit bias of healthcare providers, which is generally viewed as a more negative attitude toward people of color than White patients. Compounding the possibility of implicit bias is the associated stigma of patients with SCA being “drug seekers.” Darbari identified the intensification of this stigma following the rise of the opioid crisis. Because opioids are the standard treatment for SCA and one of the only interventions to reduce pain in this population, patients experiencing vaso-occlusive crises may have more difficulty obtaining opioids.

Beyond implicit bias and stigmatization, the healthcare system also creates barriers to appropriate care. Jacob and colleagues identified a lack of appropriately trained physicians to care for patients with SCA. Although many healthcare providers are aware of general protocols for SCA, research shows a current gap between implementation and utilization. Lack of clear universal guidelines and quick turnover rates create a barrier for seamless care of patients experiencing a vaso-occlusive crisis.

Patients may also experience extended wait times, which may cause a patient in crisis to use the ED for symptom control. However, the ED also presents distinct barriers, including overcrowding and undertraining of those providing care. Use of the ED also disrupts continuity of care and creates a disjointed trajectory of care for patients with SCA. It's within the nursing scope of practice to evaluate and advocate for our patients to overcome these barriers and enhance the use of best practices.

Best practices

According to the Expert Panel Report released by the National Heart, Lung, and Blood Institute, rapid analgesic administration of opioids, either I.V. or subcutaneous, is imperative and should begin within 30 minutes of the triage assessment in the ED to promote safe and effective relief of vaso-occulusive crisis. Doses should be increased by 25% until pain is controlled. Meperidine should be avoided in the treatment of vaso-occulusive pain. Nonpharmacologic treatments such as heat and distraction should also be implemented to help control pain. Labs should be drawn stat and include a CBC, reticulocyte count, liver function tests, lactate dehydrogenase bilirubin, and electrolytes. In addition, patients with a pulse oximetry reading of less than 95% should be placed on supplemental oxygen and the use of incentive spirometry should be encouraged. Finally, I.V. fluids should be implemented at the maintenance rate based on the patient's weight to promote adequate hydration.

Due to the complex symptoms, stigmas, and financial burdens surrounding SCA, it can be difficult for patients to receive high-quality care throughout their disease process. Although there isn't a single best practice, the following practices can be implemented for patients living with SCA to better treat and manage their symptoms. With more education for healthcare providers on the pain and symptoms of SCA, exploration of both pharmacologic and nonpharmacologic interventions, and better screening and placement processes, treatment for patients living with SCA can become less fragmented, more person-centered, and deliver better outcomes.

Provision of nursing education on SCA

Regardless of the care setting, nurses are the main providers of direct care and play a critical role in pain management, patient education, and prevention of further symptoms or crises. Individuals with SCA have reported being stigmatized when seeking care for pain. These negative attitudes can be due to preconceived notions about pain and have the potential to act as a barrier between the nurse and patient. Pain assessment and treatment can be difficult because of the patient's subjective description of pain.

Studies show that negative attitudes regarding SCA pain extend past the ED and ICU and into medical-surgical nursing, so overall stigmatization needs to be minimized. Because nurses are the ones providing direct patient care, further education is crucial for nurses to better understand SCA pain so they can effectively educate patients. Research suggests that the potential for stigmatization because of inaccurate perceptions can be minimized by providing nurses with significant education about the pathophysiology and disease complications of SCA.

Use of complementary and alternative medicine therapies to treat SCA pain

Because of the current opioid epidemic, patients with SCA have reported decreased opioid dosing and increased stigmatization regarding opioid use. Although patients experiencing vaso-occlusive crises who are in severe pain should be treated with opioids as a first-line therapy, there's an increased need for complementary and alternative medicine (CAM) therapies during a time where opioids may not be readily prescribed to help manage pain.

A common CAM therapy used by adults with SCA is massage, which has been shown to be moderately effective for pain reduction. Another CAM therapy that has been shown to be moderately effective during pain crises is relaxation techniques to slow breathing and distract from the pain. In addition to other types of CAM, acupuncture can be used to stimulate the nervous system to relieve pain, nausea, neuropathy, anxiety, and depression. Acupuncture involves the use of heat, needles, and pressure to certain points in the skin to cause physical responses in nerve cells. Acupuncture has been shown to help individuals with SCA, cancer, headaches, and back pain.

Implementation of a screening and care referral process for patients with SCA

Individuals with SCA tend to be at risk for complications, both physiologic and psychosocial, after being treated in a hospital, which can lead to difficulties with disease management. Care coordination refers to a long-term process of improving outcomes and organizing patient care activities for patients who need chronic care. For patients with SCA, the coordination team may consist of nurses, clinicians, and hematologists, and their care may occur in different environments.

Developing a specific screening process for individuals who come into the ED and are admitted to the hospital can help improve care and create more individualized treatment for patients with SCA. The screening process should assess the patient's care needs, most severe symptoms, pain management strategies, prescriptions, primary care and insurance information, and other common demographic information to help with individualized care planning and care transition management after leaving the ED.

The use of opioids, I.V. fluids, and heat

Opioids continue to be the backbone of acute and chronic pain management for individuals with SCA. Morphine remains one of the most frequently used opioids for patients with SCA to manage vaso-occlusive crises. Morphine acts by increasing blood flow to areas that may have decreased blood flow. Despite the possible negative long-term effects of opioid use, morphine may be the most effective way to treat SCA pain. If the patient has an allergy to morphine, fentanyl can be used.

I.V. fluids are often used during treatment of patients with SCA. Patients who enter the hospital setting with vaso-occlusive pain episodes tend to be dehydrated. Although there's been some controversy over which type of I.V. fluid is optimal, studies have shown that the use of I.V. fluids can improve the hydration of deformed RBCs in patients with SCA.

Heat can be used to control pain stemming from vaso-occlusive crises. Pain is unique to every patient, but the use of heat may relax him or her and help lessen the pain. And heat is a method of pain management that can be used at home, increasing convenience for the patient.

Case study update

After completing his admission assessment and finding that Mr. E states a pain level of a 9/10, the nurse places a call to the hospitalist to request an alternate pain medication because Mr. E is experiencing a vaso-occlusive crisis that will require treatment with around-the-clock opioids. After conferring with the hospitalist, morphine 2 mg I.V. every 2 hours around the clock is prescribed and the tramadol is discontinued.

For the next 24 hours, Mr. E rests and is treated with I.V. fluids, moist heat applied to his hands for 20 minutes every 4 hours, and morphine. By the second day, he's feeling much better, is afebrile, and only taking oral acetaminophen 650 mg every 6 hours as needed for pain.

Mr. E is discharged from the hospital on the third day with instructions about the importance of hydration, especially when playing sports and in the heat, along with a consult for a hematologist to better manage his SCA and consider the use of hydroxyurea therapy to minimize future vaso-occlusive crises. He's told to continue taking oral acetaminophen 650 mg every 6 hours as needed for pain, oral folate 400 mcg daily, and his previously prescribed home medications. In addition, the nurse advises Mr. E about the importance of meeting with a geneticist to discuss family planning in the future.

Patient-centered care

Care of patients with SCA experiencing vaso-occlusive crises has room for improvement related to patient outcomes and needs. Extreme pain compounded with potential bias and stigma creates a less-than-optimal healthcare experience for those in crisis. Nurses are in a unique position to help patients experiencing a sickle cell emergency by following best-practice recommendations and working to overcome barriers to care.

did you know?

When a child inherits two sickle cell genes, one from each parent, he or she is born with SCA. If the child has one sickle cell gene, he or she will be a carrier of SCA but won't have the disease. Children with SCA will start to develop symptoms before their first year of life and are at risk for long-term complications, including anemia, vaso-occlusive crisis, splenic sequestration, stroke, infections, and priapism. Early diagnosis and proper maintenance of SCA in children are critical to prevent further complications and ensure that children have the greatest quality of life.

Nursing considerations

• Spend time educating the patient and family about preventive and maintenance care to avoid an exacerbation of SCA, including seeing his or her healthcare provider at regular intervals and staying hydrated. Also, educate the patient about pain management and pain medications to ensure that he or she has the needed knowledge for proper self-care.
• Be mindful of the many psychological effects that SCA may have on the patient and coordinate his or her care accordingly. You may need to self-reflect about your attitudes toward pain management to ensure that you're creating a safe and open environment for the patient to receive care.
• Encourage supportive measures, such as heat, fluids, elevating affected joints, and opioids, to help manage and control the patient's symptoms.

CDC: www.cdc.gov/ncbddd/sicklecell/facts.html

Mayo Clinic: www.mayoclinic.org/diseases-conditions/sickle-cell-anemia/symptoms-causes/syc-20355876

MedlinePlus: https://medlineplus.gov/sicklecelldisease.html

National Heart, Lung, and Blood Institute: www.nhlbi.nih.gov/health-topics/sickle-cell-disease

US National Library of Medicine: https://ghr.nlm.nih.gov/condition/sickle-cell-disease

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Multimodal prehabilitation for patients with crohn’s disease scheduled for major surgery: a narrative review.

1. Introduction

2. nutritional optimization, 2.1. nutritional assessment and monitoring, 2.2. nutritional intervention, 2.2.1. enteral nutrition (en), 2.2.2. parenteral nutrition (pn), 2.2.3. energy and nutritional requirements, 3. functional capacity and muscle strength optimization, 3.1. assessment and monitoring, 3.2. exercise intervention, 3.2.1. aerobic exercise training, 3.2.2. resistance exercise training, 3.2.3. inspiratory muscle training (imt), 4. psychological distress optimization, 4.1. assessment and monitoring, 4.2. types of intervention, 5. medical optimization, 6. duration of the trimodal prehabilitation program, 7. conclusions, author contributions, acknowledgments, conflicts of interest.

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Share and Cite

Fiorindi, C.; Giudici, F.; Testa, G.D.; Foti, L.; Romanazzo, S.; Tognozzi, C.; Mansueto, G.; Scaringi, S.; Cuffaro, F.; Nannoni, A.; et al. Multimodal Prehabilitation for Patients with Crohn’s Disease Scheduled for Major Surgery: A Narrative Review. Nutrients 2024 , 16 , 1783. https://doi.org/10.3390/nu16111783

Fiorindi C, Giudici F, Testa GD, Foti L, Romanazzo S, Tognozzi C, Mansueto G, Scaringi S, Cuffaro F, Nannoni A, et al. Multimodal Prehabilitation for Patients with Crohn’s Disease Scheduled for Major Surgery: A Narrative Review. Nutrients . 2024; 16(11):1783. https://doi.org/10.3390/nu16111783

Fiorindi, Camilla, Francesco Giudici, Giuseppe Dario Testa, Lorenzo Foti, Sara Romanazzo, Cristina Tognozzi, Giovanni Mansueto, Stefano Scaringi, Francesca Cuffaro, Anita Nannoni, and et al. 2024. "Multimodal Prehabilitation for Patients with Crohn’s Disease Scheduled for Major Surgery: A Narrative Review" Nutrients 16, no. 11: 1783. https://doi.org/10.3390/nu16111783

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Gene expression of iron transporters, markers of vascularization and structural integrity in placenta of mothers with and without anemia

Affiliations.

• 1 University College of Medical Sciences & GTB Hospital, University of Delhi, Delhi, India.
• 2 Department of Biochemistry, University College of Medical Sciences & GTB Hospital, University of Delhi, Delhi, 110095, India. [email protected].
• 3 Department of Biochemistry, University College of Medical Sciences & GTB Hospital, University of Delhi, Delhi, 110095, India.
• 4 Department of Pathology, University College of Medical Sciences and GTB Hospital, University of Delhi, Delhi, India.
• 5 Department of Obstetrics and Gynaecology, University College of Medical Sciences & GTB Hospital, University of Delhi, Delhi, India.
• PMID: 38734792
• DOI: 10.1007/s11033-024-09609-z

Objective: To compare the mRNA expression of placental iron transporters (TfR-1 and FPN), markers of placental vascularization (VEGF and sFLT1) and marker of structural integrity (LMN-A) in term women with and without iron deficiency anemia.

Materials and methods: A total of 30 pregnant women were enrolled; 15 cases of iron deficiency anemia (Hb 7-10.9 gm/dL) and 15 gestational age matched healthy controls (Hb ≥ 11 gm/dL). Peripheral venous blood was collected for assessment of hemoglobin levels and serum iron profile. Placental tissue was used for assessing the mRNA expression of TfR-1, FPN, VEGF, sFLT-1 and LMN-A via real time PCR.

Results: Placental expression of TfR-1, VEGF and LMN-A was increased in pregnant women with anemia compared to healthy pregnant controls. Placental expression of sFLT-1 was decreased in pregnant women with anemia compared to healthy pregnant controls. There was no change in the placental expression of FPN.

Conclusion: The increased expression of TfR-1, VEGF and LMN-A in cases of iron deficiency anemia are most likely to be compensatory in nature to help maintain adequate fetal iron delivery.

What does this study adds to the clinical work: Compensatory changes in the placenta aimed at buffering transport of iron to the fetus are seen in pregnant women with anemia compared to healthy pregnant controls.

Keywords: Anemia in pregnancy; Angiogenesis-antiangiogenesis; Iron transport; LMN-A; Placental hemodynamics.

© 2024. The Author(s), under exclusive licence to Springer Nature B.V.

PubMed Disclaimer

• Cao C, Fleming MD (2016) The placenta: the forgotten essential organ of iron transport. Nutr Rev 74(7):421–431 - DOI - PubMed - PMC
• Sangkhae V, Nemeth E (2019) Placental iron transport: the mechanism and regulatory circuits. Free Radic Biol Med 133:254–261 - DOI - PubMed
• Fisher AL, Nemeth E (2017) Iron homeostasis during pregnancy. Am J Clin Nutr 106(Suppl 6):1567S–1574S. https://doi.org/10.3945/ajcn.117.155812 - DOI - PubMed - PMC
• Benson CS, Shah A, Frise MC, Frise CJ (2021) Iron deficiency anaemia in pregnancy: a contemporary review. Obstet Med 14(2):67–76. https://doi.org/10.1177/1753495X20932426 - DOI - PubMed
• WHO (2001) Iron deficiency anemia: assessment, prevention and control. WHO/NHD/01.3, Geneva. World Health Organization, Switzerland
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Addressing disparities in abnormal menstrual bleeding and anemia

A $5.6 million grant helps launch research to improve screening and treatment for a gynecologic disorder disproportionately impacting Black and Hispanic populations

For nearly one in five women, periods are so heavy that they interfere with daily life.

When left untreated, this abnormal uterine bleeding can cause anemia, leading to fatigue, weakness and disruptive symptoms.

And the condition affects some more than others, with data showing that Black and Hispanic populations experience heavy menstrual bleeding at a disproportionately higher rate than white individuals.

Now, a $5.6 million federal grant is helping Michigan Medicine researchers launch studies to improve screening and interventions for the condition, particularly among disproportionately impacted groups.

“Our goal is to improve awareness of abnormal uterine bleeding and its treatment options among community members and primary care providers, and to use interventions that may reduce related anemia in Black and Hispanic women,” said Erica E. Marsh, M.D. , professor of obstetrics and gynecology at the University of Michigan Medical School and chief of the division of reproductive endocrinology and infertility at U-M Health Von Voigtlander Women's Hospital.

Marsh will lead the research with co-investigators Samantha Schon, M.D. , a Michigan Medicine reproductive endocrinologist and infertility specialist, and Flint community member Sarah Bailey.

The colleagues explain more about abnormal uterine bleeding and their research:

Many people may not know whether their periods are normal  Abnormal menstrual bleeding is one of the most common gynecologic disorders affecting pre-menopausal women and is estimated to impact between 10-30% of women each year.

But many women just think they have heavy periods, Marsh says, making it important to know the difference between normal and abnormal.

“When a person experiences excessive bleeding that interferes with quality of life or bleeding in between the 21-35 day menstrual cycle, they should speak to their physician,” Marsh said.

“Part of the problem is that many women may have experienced this their entire life and may not realize its abnormal.”

The average woman loses about two to three tablespoons of blood during a period, she says. Symptoms of heavy menstrual bleeding include:

• Needing to change your pad/tampon every one to two hours
• Passing blood clots larger than the size of quarters
• Bleeding that lasts more than eight days 
• Feeling faint/dizzy

Underlying conditions may contribute to heavy bleeding Some health issues may cause abnormal bleeding. Obesity, thyroid issues, fibroids, polyps, hormone problems and conditions like polycystic ovary syndrome , for example, can interfere with regular ovulation.

Abnormal periods can also signal severe stress or disordered eating, which can lead to women losing their periods.

“We use menstruation as a vital sign of health. Someone’s period tells me a lot about a potential underlying medical disorder and whether there’s a need to investigate certain symptoms further,” Schon said.

“When someone’s menstrual cycle is abnormal, we take steps to further investigate potential underlying causes.”

Heavy menstrual bleeding and resulting anemia can cause serious symptoms Heavy menstrual bleeding can cause spotting, pain, headaches, and especially fatigue and weakness.

Associated anemia can also lead to shortness of breath, decreased cognitive performance and an increased risk for morbidity and mortality. Iron deficiency, Schon notes, is present in 75% of all anemia cases.

“This is a health issue that can significantly impact a person's physical health, emotional well-being, and overall quality of life for them and their family,” Bailey said.

Treatment options vary significantly based on each case  People who experience abnormal bleeding may be diagnosed with a pelvic exam, ultrasound, pap test, and sometimes a biopsy.

Treatment options will depend on a person’s age, overall health and personal preferences, Schon says.

For people who are not trying to conceive, birth control pills or an intrauterine device can stop ovulation and/or result in lighter periods.

For others, nonsteroidal anti-inflammatory drugs or hormone treatments may relieve symptoms. In some cases, healthcare providers will recommend people increase iron rich foods in their diet or iron supplements to counter anemia as a result of the heavy loss of blood.

In the more severe cases, surgical options may be considered, including a hysterectomy to remove the uterus for those not interested in future childbearing.

New research will focus on underserved communities  Researchers hope to enroll at least 200 participants, half Black and half Latina, from Wayne, Genesee and Washtenaw counties.

“We have previously shown that a significant percentage of Black women who reported heavy menstrual bleeding are both iron deficient and anemic,” Marsh said.

“In that same population, we also showed that there is a significant gap in women’s knowledge and understanding of abnormal uterine bleeding, with almost half of African American women believing that there was nothing they could do about their heavy menstrual bleeding.”

Participants will be surveyed on medical history, quality of life, perceived severity and susceptibility of abnormal uterine bleeding, race-based treatment beliefs and reproductive knowledge.

They will also be asked about perceived medical mistrust, unfairness, discrimination and religiosity.

“Our interviews will focus on the meaning and significance of menstruation, abnormal bleeding treatment experiences, perceptions of knowledge, trust, and perceptions of differential care,” Marsh said.

Project focused on improving education, screening and interventions Researchers plans to use insights from interviews to guide and test various community based interventions.

This will include a training toolkit and roadmap for community leaders to facilitate discussions about abnormal menstrual bleeding and anemia in their homes, schools, faith-based organizations, and community centers.

Primary care providers will also be interviewed about their experiences treating patients with abnormal uterine bleeding or anemia and challenges with referrals to other specialists, perceptions of patients’ experiences and barriers to care and treatment satisfaction.

“Experts across the country agree that there’s a large, unmet need for a multi-pronged strategy to both raise awareness of the high prevalence and societal impact of abnormal uterine bleeding and iron-deficient anemia and to improve access to screening and treatment,” Marsh said.

“We will work closely with community partners to work on ways to improve educational and systemic interventions that can greatly improve health and wellbeing among people affected by this condition.”

Funding for the project stems from the National Institutes of Health to fund the Michigan Community Engaged Alliance , or Michigan CEAL, which is a community based research initiative that was created to improve awareness and reduce COVID-19 inequities among underserved communities in the state. The effort has evolved to fund ongoing community engagement projects for other conditions. A portion of the funding will be used to support community based interventions to improve cardiovascular health as well, led by Barbara Israel, M.P.H. and Jennifer Garner, Ph.D., R.D. of the U-M School of Public Health.

Case report

• Open access
• Published: 23 March 2023

Vitamin E-induced coagulopathy in a young patient: a case report

• Ritika Abrol 1 ,
• Reshma Kaushik   ORCID: orcid.org/0000-0001-7826-2092 1 ,
• Deepak Goel 2 ,
• Sonu Sama 3 ,
• Rajeev Mohan Kaushik 1 &
• Mansi Kala 4  

Journal of Medical Case Reports volume  17 , Article number:  107 ( 2023 ) Cite this article

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High-dose vitamin E intake is known to inhibit vitamin K-derived coagulation factor synthesis, which can cause serious bleeding events such as gastrointestinal bleeding and intracranial hemorrhage. We report a case of coagulopathy induced by marginally increased levels of vitamin E.

Case presentation

A 31-year-old Indian man presented with oral bleeding, black tarry stools, and bruising over his back. He had been taking non-steroidal anti-inflammatory drugs for low backache and vitamin E for hair loss. He had mild anemia with normal platelet count, thrombin time, and prolonged bleeding time, activated partial thromboplastin time, and prothrombin time. Serum fibrinogen was slightly raised. Mixing studies with pooled normal plasma, aged plasma, and adsorbed plasma were suggestive of deficiency of multiple coagulation factors due to acquired vitamin K deficiency. Serum phylloquinone was normal, while prothrombin induced by vitamin K absence-II level was increased. Serum alpha-tocopherol was slightly raised. Upper gastrointestinal endoscopy showed multiple gastroduodenal erosions. A final diagnosis of vitamin E toxicity-related coagulopathy was made. The patient responded well to pantoprazole, vitamin K supplementation, multiple fresh frozen plasma transfusions, and other supportive treatments besides the discontinuation of vitamin E supplementation. The coagulation parameters normalized, and the patient was discharged with complete resolution of symptoms and remained asymptomatic during the follow-up for 6 months.

Conclusions

Vitamin E-related inhibition of vitamin K-dependent factors with coagulopathy may occur even at marginally increased levels of serum vitamin E. This risk becomes significant in patients receiving other drugs that may increase the risk of bleeding.

Peer Review reports

Introduction

Vitamin E toxicity is rarely observed due to its ready excretion in bile and urine [ 1 ]. However, it has been noted to occur in cases of lipid or hepatobiliary disorders where its absorption or excretion may be altered. High-dose vitamin E supplementation is known to inhibit vitamin K-related enzyme activation relevant for coagulation factor syntheses, such as factors II, VII, IX, and X, as well as protein C and S. Deficiency of factors II, VII, IX, and X promotes bleeding [ 2 ], while deficiency of protein C and protein S leads to the loss of their natural anticoagulant effects, with consequent unrestrained thrombin generation, resulting in thromboembolism [ 3 , 4 ]. Generally, deficiency of factors II, VII, IX, and X is the dominant effect and may lead to bleeding. The mechanism of inhibition of vitamin K-related enzyme activation relevant for coagulation factor synthesis is evidenced by the elevation of levels of prothrombin induced by vitamin K absence-II (PIVKA-II), due to an increase in under-gamma-carboxylated prothrombin.

Vitamin E excess further inhibits factor IX activation by reducing vitamin K-dependent carboxylation of glutamate and inhibits platelet aggregation [ 5 ]. Thus vitamin E toxicity can present as coagulopathies alongside general complaints such as malaise, nausea, myalgia, and fatigue [ 6 ].

Though it is generally understood that vitamin E toxicity may occur if consumed at levels greater than 1000 mg/day, there is no fixed cut-off point [ 7 ]. The circulating alpha-tocopherol levels depend heavily on the lipid content of the blood. Vitamin E cannot be measured accurately by circulating alpha-tocopherol levels in patients who have very high or very low cholesterol levels. The same applies to patients with average cholesterol levels as well. This is because of the upregulation of biliary and urinary excretion once vitamin E levels increase in the body [ 5 ]. Because of these irregularities in vitamin E metabolism, the minimum dose, form, and duration of vitamin E intake required to induce a clinically significant effect on coagulation pathways are not known [ 7 ].

Vitamin E toxicity may be overlooked as the cause of coagulopathy if serum levels of vitamin E are only marginally increased. We report a case of coagulopathy induced by marginally increased levels of serum vitamin E.

A 31-year-old Indian man, a restaurateur by profession, presented to the emergency services with complaints of low backache for 1 month and oral bleeding, the passage of black tarry stools, and bruising over his back for the last seven days. He had intense nausea and fatigue for several days and began to develop bruising about 1 week ago. He experienced oral bleeding and passed black tarry stools three times, following which he decided to visit the emergency services.

The backache was non-specific in nature. The patient had been taking over-the-counter non-steroidal anti-inflammatory drugs (NSAIDs) in the form of ibuprofen 400 mg infrequently for the past 1 month for his backache, before his current symptoms of bleeding.

The patient had no complaints of bleeding tendencies in the past, such as frequent nosebleeds, prolonged bleeding from gums or injuries, gastrointestinal bleeds, bleeding into joints, easy bruising, and hematuria. There was no history of jaundice, peptic ulcer, malignancy, or bony aches and pains. He had never received any blood transfusions. There was no history of the use of anticoagulants, antiplatelet drugs, and corticosteroids. There was no history of heavy exposure to pesticides, injury, or surgery.

The patient also reported the use of vitamin E supplementation for his complaints of recent onset hair loss and dryness of the skin. He had taken vitamin E 400 mg twice daily for a period of 2 months, which was accompanied by a fairly poor diet due to work-related stressors.

He was a non-smoker. He drank alcohol sparingly and had no drug addictions. He consumed a mixed diet. He was residing in a semiurban area that had moderate air pollution levels.

He was a bachelor and had two elder brothers. His parents and brothers were healthy. There was no family history of any bleeding disorder in either parents, maternal grandparents, uncles, aunts, or siblings. There was no history of any consanguineous marriage in the family.

On admission, the patient was hemodynamically stable. He was well-built and in no distress. His pulse rate was 74 beats per minute, blood pressure was 122/78 mmHg, and oral temperature was 37 °C. He had nonspecific thinning of hair over bitemporal regions. Mild pallor and bleeding from the gums were present. Multiple punctate, perifollicular hemorrhages were present over his forearms (Fig.  1 ) along with large ecchymotic patches over his back (Fig.  2 ). Icterus, cyanosis, clubbing, lymphadenopathy, telangiectasis, signs of chronic liver disease, and pedal edema were absent. Neurological examination showed normal higher mental functions with a mini-mental state examination (MMSE) score of 28/30. The flapping tremor was absent. The cranial nerve examination was normal. No ocular movement dysfunction or nystagmus was seen. There were no fasciculations, motor deficits, or incoordination. Tendon jerks were normal and the plantars showed bilateral flexor response. Sensations were intact.

Petechiae over the arm

Ecchymosis over the back of the patient

Examination of the cardiovascular system and the respiratory system was normal. Abdominal examination showed no hepatomegaly, splenomegaly, or ascites. He was evaluated for gingival bleeding and melena.

The laboratory work-up showed low hemoglobin (11.0 g/dL) with normal mean corpuscular volume (87.2 fl), mean corpuscular hemoglobin (28.9 pg), leukocyte count (9900/mm 3 ), and platelet count (2,72,000/mm 3 ). Random blood sugar, liver and renal function tests, and thyroid profile were within normal range. The anemia was evaluated further. Peripheral blood film showed normocytic normochromic red blood cells, with normal white blood cells and platelets. Serum iron was 39 µg/dL, ferritin 22 µg/L, total iron binding capacity 305 µg/dL, and lactate dehydrogenase 277 U/L. Anemia was attributed to his bleeding. Bleeding time (BT) was prolonged (7 minutes, reference range 2–6 minutes). Also activated partial thromboplastin time (APTT) and prothrombin time (PT) were significantly prolonged (APTT 104.5 seconds, reference range 29–33 seconds; PT > 1 minute, reference range 11.4–14.8 seconds). Thrombin time (TT) was normal (18 seconds, reference range 14–20 seconds). Mixing studies were performed with pooled normal plasma, aged plasma, and adsorbed plasma. Full correction for APTT and PT occurred with pooled normal plasma. Mixing studies with aged plasma as well as adsorbed plasma did not show correction of abnormal PT of the patient’s plasma and were suggestive of deficiency of multiple factors. Factor VIII assay was 100% (reference range 50–150%). Factor IX assay was 9% (reference range 50–150%). The serum fibrinogen level was slightly raised (430 mg/dL, reference range 200–400 mg/dL). Due to the unavailability of resources, further factor assays were not performed.

A possibility of acquired vitamin K deficiency was considered in view of the deficiency of multiple coagulation factors. The patient was investigated further to elucidate the etiology. Serum phylloquinone (vitamin K1) level was normal (1.14 ng/mL, reference range 0.10–2.20 ng/mL). Serum PIVKA-II level was measured by chemiluminescent microparticle immunoassay (CMIA) and was increased (326.7 mAU/mL, upper normal limit 40 mAU/mL). Serum alpha-tocopherol, which is considered a surrogate marker for serum vitamin E level, was evaluated and found to be slightly raised (20.10 mg/L, reference range 5–18 mg/L).

Ultrasound examination of the abdomen was normal. Upper gastrointestinal endoscopy showed few gastroduodenal erosions with no active bleeding. Urinalysis did not show any abnormality. The stool was negative for occult blood.

Chest X-Ray and X-Rays of the lumbosacral spine were normal. The patient was further evaluated for ankylosing spondylitis, in view of the history of backache, to identify the association of any collagen-vascular disease with his bleeding complaint, and was found to be negative for HLA-B27.

Given the patient’s history, presenting complaints, and investigation findings, a final diagnosis of vitamin E toxicity-related coagulopathy was made. Exogenous vitamin E supplementation was stopped. The patient received intravenous fluids, pantoprazole, vitamin K, vitamin C, multiple transfusions of fresh frozen plasma (FFP), and other supportive treatments.

The patient’s complaints were alleviated with the treatment and the coagulation parameters normalized. The patient was discharged with complete resolution of symptoms and remained asymptomatic during the follow-up for 6 months.

This male patient presented with oral bleeding, melena, and bruising over his back. He was taking NSAIDs infrequently for low backache, and vitamin E for hair loss. Investigations suggested the deficiency of multiple coagulation factors due to acquired vitamin K deficiency. Upper gastrointestinal endoscopy showed gastroduodenal erosions. On the basis of normal serum phylloquinone, increased PIVKA-II levels, and slightly raised serum alpha-tocopherol, the patient was diagnosed as having vitamin E toxicity-related coagulopathy, which responded well to pantoprazole, vitamin K supplementation, fresh frozen plasma transfusions, and other supportive treatment besides the discontinuation of exogenous vitamin E administration. As such, this case documents the inhibition of vitamin K-dependent factors with coagulopathy at only marginally increased levels of serum vitamin E, while vitamin E toxicity-related coagulopathy has been reported earlier at much higher levels of serum vitamin E [ 5 , 8 ].

The extent of vitamin E excess-induced vitamin K suppression varies as per the dose consumed. Any preexisting subclinical deficiency may be unmasked by any level of vitamin E excess, thereby implying that there may be considerable interpersonal variability reflecting the inhibitory effects of vitamin E on individuals with a poor vitamin K status [ 9 ].

Though serum alpha-tocopherol level was only marginally increased and did not confirm the vitamin E-related toxicity convincingly, it is possible that the actual level of vitamin E may be higher than measured, as alpha-tocopherol may not measure the circulating vitamin E accurately.

Vitamin E may compete for the enzyme vitamin K epoxide reductase, which converts the precursors of vitamin K into the active form of vitamin K [ 3 ]. As a result, the activation of inactive vitamin K may be inhibited, thereby preventing the gamma-carboxylation, and thus activation, of vitamin K-dependent coagulation factors. The inability to activate the clotting cascade via these factors may increase the risk of bleeding.

Moreover, vitamin E excess decreases the availability of factor IX as it reduces the production of glutamate, which is required for factor IX production [ 3 ]. Platelet aggregation is also decreased in patients receiving vitamin E and may be in part due to a mechanism linked to protein kinase C inhibition [ 10 ]. The bleeding risk due to a marginally elevated level of vitamin E was also aggravated by NSAIDs in our patient.

Normal serum phylloquinone and increased PIVKA-II levels negate the possibility that this patient had vitamin K deficiency leading to gastrointestinal bleeding/skin changes. Moreover, our subject was a young adult and there was no evidence of any of the causes of vitamin K deficiency in adults, such as malnutrition, lipid malabsorption, malignancy, or renal disease [ 11 ].

Prolongation of both PT and APTT, and a normal TT in our patient were suggestive of coagulation factor deficiency in the common pathway (factors II, V, VII, and X), along with factor IX deficiency or presence of inhibitors of prothrombin, fibrinogen, factor V, or factor X. Full correction of the abnormal APTT and PT by pooled normal plasma ruled out factor inhibitors and suggested a deficiency of coagulation factors. The absence of correction of abnormal PT on mixing aged plasma with the patient’s plasma suggested factor V deficiency. The absence of correction of PT on mixing adsorbed plasma with the patient’s plasma was suggestive of factor II, VII, and X deficiency. Moreover, selected assays showed normal factor VIII and raised factor I (fibrinogen) levels, but deficient factor IX levels.

Inherited factor deficiency was not likely because of the absence of any abnormal bleeding until the current episode. Acquired factor deficiency due to liver disease was unlikely in view of normal liver function tests and a normal ultrasound scan of the liver. The absence of thrombocytopenia and a raised serum fibrinogen level excluded the possibility of disseminated intravascular coagulation causing factor deficiency. A raised fibrinogen level may be due to low serum iron concentrations, caused by blood loss, as a negative correlation was observed between total fibrinogen and serum iron concentrations in a large-scale epidemiological study [ 12 ].

Anticoagulant-induced factor deficiency was ruled out as the patient was not receiving any anticoagulants. The presence of combined factor deficiencies generally implies severe vitamin K deficiency, but it would be reasonable to assume that a secondary factor must exist, as an isolated vitamin K deficiency is rare due to its continual production by the gut microbiome in healthy individuals [ 13 ].

Vitamin E excess potentiated by ill-timed NSAID use could have led to the precipitation of this patient’s complaints [ 14 ]. Vitamin E excess could have inhibited vitamin K-related coagulation factor synthesis and prolonged the BT, while NSAIDs could cause gastroduodenal erosions, besides prolonging the BT, and thus add to the risk of gastrointestinal bleeding.

Vitamin E toxicity-induced coagulopathy has been described at high levels of serum alpha-tocopherol, but there is a case report of intracranial hemorrhage attributed to vitamin E toxicity occurring at serum alpha-tocopherol level of 23.3 mg/L [ 5 ]. Bleeding manifestations occurred in our case at an even lower level of serum alpha-tocopherol. Our case report highlights the often underscored bleeding risks with vitamin E consumption and that this coagulopathy can also occur at marginally increased levels of vitamin E.

Vitamin E has been lauded for its various dermatological and cardiovascular benefits, all of which are exceptional [ 15 ]. However, the same stellar reputation leads to indiscriminate use by prescription, as well as without prescription, by patients. Though the bleeding risk may be hemodynamically relevant in patients already receiving anticoagulants, our case report reveals that the risk of upper gastrointestinal bleeding could also be increased in patients taking both NSAIDs and vitamin E. Moreover, bleeding from gums, ecchymotic patches over the back, normal serum phylloquinone level, and deficiency of multiple coagulation factors, in the presence of increased PIVKA-II level, were highly suggestive of coagulopathy due to marginally increased vitamin E-related inhibition of vitamin K-dependent factors.

As the patient recovered readily with vitamin K supplementation and FFP transfusions, a final diagnosis of vitamin E toxicity-related coagulopathy was reaffirmed, although NSAID intake might have been an aggravating factor.

Vitamin E-related inhibition of vitamin K-dependent factors with coagulopathy may occur even at slightly raised levels of vitamin E. This risk is augmented in presence of other drugs that have the potential to cause bleeding.

Thus, patients must be discouraged from taking medications without proper medical consultation. Physicians too must be wary of the potential interactions of substances generally considered harmless.

Availability of data and materials

Not applicable.

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Acknowledgements

We are grateful to the patient for giving his consent to publish this case. We thank Dr. Sadhana Raturi and Dr. Madhurima Kaushik for their valuable suggestions during the preparation of the manuscript.

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Department of General Medicine, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Jolly Grant, Dehradun, Uttarakhand, 248016, India

Ritika Abrol, Reshma Kaushik & Rajeev Mohan Kaushik

Department of Neurology, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Jolly Grant, Dehradun, Uttarakhand, 248016, India

Deepak Goel

Department of Critical Care Medicine, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Jolly Grant, Dehradun, Uttarakhand, 248016, India

Department of Pathology, Himalayan Institute of Medical Sciences, Swami Rama Himalayan University, Jolly Grant, Dehradun, Uttarakhand, 248016, India

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Contributions

RK, SS, and RMK conceived the work. RK, SS, RA, DG, and MK contributed to the diagnosis and treatment. RA and SS prepared the initial manuscript. RK, RMK, and DG revised the manuscript critically for important intellectual content. All authors read and approved the final manuscript.

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Correspondence to Reshma Kaushik .

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Abrol, R., Kaushik, R., Goel, D. et al. Vitamin E-induced coagulopathy in a young patient: a case report. J Med Case Reports 17 , 107 (2023). https://doi.org/10.1186/s13256-023-03827-y

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• Acquired coagulation factor deficiency
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Prevalence, associated factors and clinical implications of medication literacy linked to frailty in hemodialysis patients in China: a cross-sectional study

• Linfang Zhu 1 , 2   na1 ,
• Yang Liu 1 , 2   na1 ,
• Fengxue Yang 3 ,
• Shaobin Yu 1 ,
• Ping Fu 1 &
• Huaihong Yuan 1 , 2  

BMC Nephrology volume  24 , Article number:  307 ( 2023 ) Cite this article

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Maintenance hemodialysis (MHD) patients have complex medication regimens that require a high level of skill to interpret medication information. However, there is currently a lack of research evaluating the ability to read and understand medication labels in Chinese MHD patients. In addition, the relationship between frailty and medication literacy among MHD patients remains unclear. Therefore, this study aims to assess the potential factors affecting medication literacy in MHD patients and to explore the relationship between frailty and medication literacy.

This cross-sectional study was conducted using convenience sampling in West China Hospital of Sichuan University, China. Using a general questionnaire, we collected demographic, clinical and laboratory data. Medication literacy was assessed by the Chinese Medication Literacy Scale, and frailty was assessed by the FRAIL Scale. Univariate analyses examined potential factors associated with medication literacy. An ordered logistic regression was used to analyze the relationships between medication literacy and these factors. Spearman’s correlation was used to assess the association between medication literacy and frailty.

A total of 290 MHD patients were included in the analysis. Inadequate, marginal, and adequate medication literacy was found in 56 (19.3%), 153 (52.8%), and 81 (27.9%) patients, respectively. Ordered logistic regression revealed factors associated with inadequate medication literacy: age (OR = 0.281, 95% CI = 0.139–0.565, p < 0.001 for < 65 years); education (OR = 8.612, 95% CI = 3.524–21.046, p < 0.001 for ≤ primary school education; OR = 3.405, 95% CI = 1.683–6.887, p = 0.001 for junior high school education); presence of caregiver medication assistance (OR = 2.302, 95% CI = 1.173–4.516, p = 0.015); frailty (OR = 0.440, 95% CI = 0.216–0.893, p = 0.023 for frail patients); and high β2-microglobulin (β2-MG) (OR = 1.010, 95% CI = 1.002–1.019, p = 0.012). Spearman’s analysis showed that medication literacy was negatively correlated with frailty in MHD patients (R=-0.189, p = 0.001).

Conclusions

Medication literacy levels in MHD patients needed improvement and were associated with certain patient characteristics, including age, education level, presence of caregiver support, β2-microglobulin levels, and risk of frailty. This study identified subgroups of MHD patients, such as those who were older, had lower education, had caregiver assistance, had high β2-microglobulin levels, or were frail, to have inadequate medication literacy. These findings underscore the need for routine screening and targeted interventions to improve medication literacy in this population.

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Introduction

Patients with end-stage renal disease (ESRD) who receive hemodialysis often experience many comorbid conditions, such as anemia, hypertension, secondary hyperthyroidism, and electrolyte disturbances [ 1 , 2 ]. These comorbidities were complex and required long-term oral administration of multiple drugs (consuming ≥ 5 medications or 12 doses per day) [ 3 ]. Polypharmacy is common among patients receiving hemodialysis [ 4 ]. However, medication nonadherence was also very common among ESRD patients receiving hemodialysis, with an average prevalence of 52.5% [ 5 ].

Since maintenance hemodialysis (MHD) patients had multiple comorbid illnesses and dialysis-associated complications, at least five or more medications were needed. Poor adherence meant that those patients needed to have the ability to read medication labels and instructions to control and prevent disease progression.

Medication literacy refers to an individual’s ability to obtain, understand, evaluate medication information and apply this information to make correct medication decisions and behaviors [ 6 ], which is an important factor for predicting accurate medication behavior. MHD patients have complex medication regimens that require substantial skills to interpret medication information and take medications accurately as prescribed.

A U.S. study found that MHD patients aged 65 and over had difficulty reading medication labels. Although most MHD patients were taking phosphate binders, only 16% of participants were able to correctly answer questions about the indications of phosphate binders [ 7 ]. The implications of this study were that routine assessment and screening of medication literacy abilities should be implemented for hemodialysis patients, especially the elderly. Targeted interventions were needed to improve their medication label reading skills and comprehension of medication uses. The findings underscored the urgency and importance of improving medication literacy among hemodialysis patients to ensure appropriate medication use and safety. Overall, this study showed that good medication literacy was an important guarantee for safe medication use and was vital to the health of MHD patients [ 7 ].

Accumulating studies have shown that age, gender, education, and economic status can affect people’s ability to understand and use medication information [ 8 , 9 , 10 ]. Elderly patients with multiple health conditions and frequent medication use are high-risk groups with low medication literacy [ 11 , 12 ]. It has been reported that family guidance can help improve medication management [ 13 ].

Previous studies have shown that patients at risk of malnutrition have lower medication literacy levels than those with normal nutritional status [ 14 ]. A study in China found that medication literacy was a factor affecting frailty in elderly patients with heart disease. People with low medication literacy were 2.759 times more likely to be frail than those with adequate medication literacy (OR = 2.759, P < 0.001) [ 15 ]. This may be due to the poor compliance and adherence caused by low medication literacy, which may increase the risk of malnutrition and cause frailty. However, the relationship between medication literacy and frailty in MHD patients has not been reported before.

As modern clinical medical systems record much health and medical data and MHD patients undergo regular dialysis and centralized examinations, we wanted to explore whether there was an association between patients’ laboratory examinations and medication literacy.

Therefore, the aim of this study was to assess medication literacy and its influencing factors in MHD patients. We further explored the relationship between frailty and medication literacy.

A descriptive cross-sectional study with analytical components was conducted.

Setting and participants

This cross-sectional study was conducted using convenience sampling. Data were collected from March 28, 2023, to May 31, 2023. Inclusion criteria were (1) clear consciousness, normal cognition, and no communication barriers; (2) receiving MHD treatment for at least 3 months; and (3) voluntary participation in the survey. The exclusion criteria were as follows: (1) unconsciousness, dementia, or mental illness; (2) communication barriers; and (3) current or previous engagement in medical and health-related work before retirement. The sample size was calculated using the formula N = Zα2P(1-P)/d2, where α represents the tolerance error, set at 0.05, and Zα = 1.96. The allowable error (d) was set at 3%.

A literature search [ 13 ] revealed that the prevalence of inadequate medication literacy among MHD patients in China was estimated to be 6.8%, resulting in a calculated sample size of 271. To account for invalid questionnaires, which were expected to constitute 5% of the total cases, the required sample size was adjusted to 285 cases.

Data collection and procedures

Data collection was conducted during the dialysis process at the Wenjiang Hemodialysis Center in the Department of Nephrology at West China Hospital, Sichuan University, Chengdu, China. Two researchers (Yang Liu and Linfang Zhu) completed the data collection through one-on-one face-to-face interviews. After signing the informed consent form, participants completed the questionnaire. In illiterate patients, the consent was read to them in the presence of a literate relative and they provided a fingerprint on the consent form to indicate their informed consent to participate. If a participant could not fill out the questionnaire because their dominant arm was being used for dialysis, the interviewers read out the questionnaire content and provided assistance. Specifically, the questionnaire was administered mainly through interviewer assessment. For patients who were capable of self-administering, they completed the questionnaire by themselves. For those who had difficulties in writing, the interviewers helped them complete the questionnaire. We adopted this approach to ensure the quality of the data collected. Once the survey was completed, researchers immediately verified and collected the questionnaires. At the end of the survey, laboratory test results were obtained through queries in the laboratory test system from the patient’s most recent centralized examination at the hemodialysis center.

The demographic characteristics collected in this study included gender, age, height, body weight, education level, monthly income, primary illness, whether medication was taken with the help of a caregiver, dialysis vintage, number of medications, and comorbidity. Evidence showed that BMI and biochemical indicators such as albumin, electrolytes, and total iron binding capacity were part of nutritional assessment [ 16 ]. β2-microglobulin reflected the level of middle molecule toxins in the MHD patient’s body. Effective removal of middle and large molecule toxins could improve the patient’s microinflammatory state and improve nutritional status [ 17 ]. Thus, the data collection also included laboratory findings obtained through the hospital Laboratory Information System from the latest centralized examination at the hemodialysis center. These findings included routine blood examinations such as red blood cell count (RBC), hemoglobin (HGB), albumin (ALB), ferritin (FER), β2-MG, predialysis creatinine (pre-CRE), serum calcium (s-Ca), serum inorganic phosphorus (s-IP), serum potassium (s-K), and parathyroid hormone (PTH). The main results of this study were obtained using two Chinese questionnaires: the Chinese Version of the Medication Literacy Scale and the FRAIL scale.

The level of medication literacy was assessed using the Chinese version of the Medication Literacy Scale, which included 14 items and consisted of four simulated drug use scenarios [ 18 ]. The specific questionnaire items could be referred to in previous studies by Qu et al. [ 14 , 15 ]. Scenario 1 involved injectable medication for diabetics, Scenario 2 was about medication for children, Scenario 3 was on cold medicine, and Scenario 4 covered OTC and prescription drug. The total score was 14, with each of the 14 items representing one point. A score of 1 was given for a correct response, and a score of 0 was given for an incorrect response. The scores for each item were added to calculate the total score of the questionnaire. There were three levels of medication literacy: “adequate drug literacy”, “marginal medication literacy”, “inadequate medication literacy”. A total score of 11 or higher indicated adequate drug literacy, a total score between 4 and 10 indicated marginal medication literacy, and a total score of 3 or lower indicated inadequate medication literacy. The Chinese version of the Medication Literacy Scale demonstrated good reliability and validity, with a retest reliability of 0.885 and a split-half reliability of 0.840. The correlations between medication literacy and the corresponding items ranged from 0.427 to 0.587. The scale could be used to assess medication literacy among Chinese people. The Cronbach’s α coefficient measured in this study was 0.854.

The Frail Scale was utilized to evaluate frailty [ 19 ]. This scale included five self-reported questions (see Table  1 ). Each question was scored as 1 for a “yes” response and 0 for a “no” response, with total scores ranging from 0 to 5. A score of 0 indicated nonfrailty, a score of 1 to 2 indicated prefrailty, and a score of 3 or higher indicated frailty. The scale could be used to screen for frailty in patients on hemodialysis and proved to be an easy-to-apply tool [ 20 ].

Ethical considerations

This study was approved by the biomedical ethics committee of the West China University of Sichuan University (IRB NO.2023 − 362).

Statistical analysis

SPSS version 25.0 was used for statistical analysis. Descriptive statistics were used to describe the patients’ baseline characteristics, frailty, and medication literacy. When the distribution of responses was approximately balanced across categorical variable levels, the chi-squared test or Fisher’s exact probability method was used to examine the factors influencing medication literacy. For continuous variables with normal distribution, univariate analysis was conducted using one-way ANOVA. The Kruskal‒Wallis H test was used in ordinal data or nonnormally distributed measures. Ordinal logistic regression was used to analyze the factors affecting the medication literacy scores of MHD patients. Spearman’s correlation analysis was used to analyze the correlation between medication literacy and frailty. A p value of less than 0.05 was considered statistically significant.

In this study, a total of 297 questionnaires were distributed, and 7 invalid questionnaires were excluded. Ultimately, 290 valid questionnaires were collected, yielding an effective recovery rate of 97.6%.

The demographic characteristics of the participants were shown in Table  1 . A total of 290 patients on MHD participated in the study (169 men, 121 women). Most participants were under 65 years old (80.69%).

The medication literacy among 290 MHD respondents was shown in Table  2 . The median score was 8.0 (4.0–11.0). Of these, 56 (19.3%) had inadequate medication literacy, 153 (52.8%) had marginal medication literacy, and 81 (27.9%) had adequate medication literacy. The highest accuracy of Item 12 was 239 (82.4%), and the lowest accuracy of Item 14 was 98 (33.8%).

The frailty among 290 MHD respondents was shown in Table  3 . The median score was 1.0 (0–2.0). Of these, 86 (29.7%) were nonfrail, 155 (53.4%) were prefrail, and 49 (16.9%) were frail. The highest responses to “yes” for Question 1 were 146 (50.3%), and the lowest responses to “yes” for Question 3 were 50 (17.2%).

The number of participants with different characteristics at each medication literacy level was listed in Table  4 . Sex, age, education, monthly income, caregiver medication assistance, frailty, β2-MG, and s-IP were all associated with medication literacy (P < 0.05). However, primary illness, dialysis vintage, number of medications, comorbidity, BMI, RBC, HGB, FER, ALB, pre-CRE, s-Ca, PTH, and s-K were not associated with medication literacy (P>0.05).

Ordered logistic regression revealed factors associated with inadequate medication literacy: age (OR = 0.281, 95% CI = 0.139–0.565, p < 0.001 for patients younger than 65); education (OR = 8.612, 95% CI = 3.524–21.046, p < 0.001 for patients with primary school education or lower; OR = 3.405, 95% CI = 1.683–6.887, p = 0.001 for junior high school education); presence of caregiver medication assistance (OR = 2.302, 95% CI = 1.173–4.516, p = 0.015); frailty (OR = 0.440, 95% CI = 0.216–0.893, p = 0.023 for frail patients); and high β2-microglobulin (β2-MG) (OR = 1.010, 95% CI = 1.002–1.019, p = 0.012). (Table  5 ).

This study revealed a high prevalence of inadequate and marginal medication literacy among MHD patients, with less than one-third demonstrating adequate literacy. Key factors associated with poorer medication literacy were older age, lower education level, taking medication with the assistance of a caregiver, frail status, and higher β2-MG levels. To our knowledge, this is the first observational study to assess medication literacy, focusing on evaluating Chinese hemodialysis patients’ numeracy and literacy regarding medication labels. The medication literacy status, associated factors and the relationship with frailty were discussed as follows.

Medication literacy status among MHD patients

Compared to the findings of Xiong et al. [ 13 ], this study indicated a higher prevalence of inadequate medication literacy among MHD patients, with only a small portion demonstrating adequate skills. This could be attributed to the use of different medication literacy assessment tools. Xiong et al. [ 13 ] employed a 9-item Chinese version of the medication literacy survey questionnaire, which only examined patients’ mastery of medication knowledge and did not assess patients’ active search for medication information and levels of medication skills [ 6 ]. The questionnaire could still be improved in assessing medication literacy in diseased or healthy populations [ 6 ]. In contrast, the MedLitRxSE questionnaire designed by Sauceda [ 21 ] and translated by Zheng et al. used in this study consisted of 14 items [ 18 ]. It evaluated patients’ numeracy and literacy regarding medication labels, emphasizing mixed skills.

It was found that MHD patients had the highest accuracy in answering questions about medication expiration dates. This may be because the vast majority of participants in this study were under 65 years old, enabling themselves to read and understand medication labels. In contrast, elderly MHD patients were susceptible to declining cognitive abilities. Comparatively, participants had the lowest accuracy in answering questions about when medications should be stopped, which was consistent with results from Zheng et al. [ 18 ]. Patients’ ability to properly understand medication information and make the right choices in case of the occurrence of side effects is essential for medication safety and avoiding harmful health issues. Due to their limited knowledge of medication, MHD patients were at risk of receiving improper and ineffective treatment. The numerous side effects and interactions between the multiple medications used by these patients further increased the risk of medication-related issues [ 22 ]. Our study thus emphasized the importance of improving medication literacy among MHD patients.

The associated factors of medication literacy in MHD patients

Many studies have confirmed that age is an influencing factor for medication literacy [ 7 , 8 , 23 , 24 ]. Due to the decreasing cognitive and literacy capacities in elderly patients, health self-management involving understanding new information may become increasingly challenging [ 25 ]. Furthermore, compared to younger individuals, elderly individuals have poorer learning and recollection abilities owing to deteriorating memory and physical ability. This leads to an inadequate grasp of medication-related knowledge and skills, ultimately resulting in lower medication literacy.

This study demonstrated that patients without formal education and with primary or junior education had lower medication literacy than those with higher education. Many studies have confirmed the influence of education levels on patients’medication literacy [ 8 , 26 , 27 ]. Individuals with higher education levels tend to have greater health awareness and are more proactive in learning medication use. Additionally, they have better access to medication information from sources such as the Internet and written materials.

Our regression analysis indicated that MHD patients who had caregiver assistance had lower medication literacy. This may be because patients overly rely on caregivers, leading to insufficient motivation to actively learn medication knowledge themselves. Although social support plays a key role in helping chronically ill patients self-manage their medication use [ 11 ] and MHD patients with positive support systems from healthcare providers were more successful in adhering to their medication regimen [ 28 , 29 ], over-support from caregivers can lead to dependence which is not conducive to self-management. Therefore, while providing support, caregivers need to moderately guide patients to learn medication knowledge themselves, ensuring that patients take initiative to improve their own medication literacy. Additionally, family support should also avoid over-supporting patients, and appropriately encourage self-management of medications. In summary, while supporting patients, healthcare providers and families need to guide patients to learn independently as well, thereby improving patients’medication knowledge and self-management capabilities.

Using Spearman’s correlation analysis, the present study found that the state of frailty was negatively correlated with the level of medication literacy, which was consistent with existing research in patients with coronary heart disease [ 15 ]. This may be because inadequate medication literacy could lead to suboptimal treatment compliance and efficacy, improper medication use, negative drug and appetite interactions [ 30 ], poor disease control, and ultimately worsened nutritional status [ 15 , 30 ]. Moreover, Cao et al. revealed that health literacy was associated with frailty in MHD patients [ 31 ]. Building upon this, medication literacy, as an application of health literacy in pharmacy practice, may also be related to frailty.

Logistic regression analysis also showed that prefrailty was an independent predictor of medication literacy in our study. Frailty indicated a decline in function, cognition and health. Patients with prefrailty were at risk of developing frailty, but effective interventions could prevent it. To maintain their health and relieve discomfort, prefrail patients may utilize self-medication and adhere to treatment regimens prescribed by their doctors, such as accurately following medication instructions. If they develop additional diseases, their medical prescriptions will increase, which requires greater medication literacy. This could explain why prefrailty patients have protective factors for medication literacy levels.

Hemodialysis is a common method for purifying blood. It could remove small molecule toxins in patients with uremia effectively, but the removal of middle molecule toxins such as β2-MG was less effective [ 32 ]. High levels of these toxins in their body could suppress appetite and even cause nausea and vomiting, leading to insufficient intake and an increased risk of malnutrition [ 33 ]. Previous studies have shown that patients at risk of malnutrition had lower medication literacy [ 14 ]. As a result, there was a link between patients’ β2-MG levels and their medication literacy.

The strength of our study lies in the fact that it showed a correlation between prefrailty, β2-MG and medication literacy, despite most previous studies indicating that medication literacy was a risk factor for frailty. Our study deepened the understanding of how a patient’s physical health could impact their medication literacy.

Limitations and future research

Our study has several limitations. First, approximately 80% of our participants were under 65 years old. Second, this was a single-center study with a small sample size, limiting the generalizability of our results. To address these limitations, further studies should be multicenter and have larger sample sizes. Interventional studies should also be conducted based on our results to improve patients’ medication literacy levels. In addition, future research should include follow-up evaluations of medication literacy and track the factors that influence it over time.

There is still a need for improved medication literacy among MHD patients. Age, education level, caregiver assistance, β2-MG levels, and prefrailty are associated with medication literacy. The correlation between frailty and poorer medication literacy implies that frail patients are an especially high-risk group in need of medication literacy support. The link with higher β2-MG suggests medication literacy may decline with worsening kidney function. This can guide clinical practice to provide targeted interventions and education to improve medication literacy and adherence in MHD patients. Future research can explore optimal educational strategies and training programs to boost medication literacy in this vulnerable population.

Data Availability

Data available on request from the corresponding author.

Abbreviations

End-stage renal disease

Maintenance hemodialysis

Predialysis creatinine

Parathyroid hormone

Red blood cell count

Serum calcium

Serum potassium

β2-microglobulin

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Acknowledgements

The authors would like to thank all of the healthcare providers and patients who participated in this study from Wenjiang Hemodialysis Center in the Department of Nephrology at West China Hospital, Sichuan University, Chengdu, China.

This study is supported by the 1·3·5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University (NO. 2019HXFH067) and Science-technology Support Plan Projects in Sichuan Province (NO. 2021YFS0162).

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Linfang Zhu and Yang Liu contributed equally as the first author to this work.

Authors and Affiliations

Department of Nephrology, Kidney Research Institute, West China Hospital of Sichuan University, Chengdu, 610041, China

Linfang Zhu, Yang Liu, Shaobin Yu, Ping Fu & Huaihong Yuan

West China School of Nursing, Sichuan University, Chengdu, 610041, China

Linfang Zhu, Yang Liu & Huaihong Yuan

Sichuan Nursing Vocational College, Chengdu, 610041, China

Fengxue Yang

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Conceptualization, L.Z., Y.L.; Investigation, L.Z, Y.L.; Methodology, S.Y., F.Y.; Resources, H.Y., P.F., Writing-original draft, L.Z., Y.L.; Writing-review and editing, H.Y. All authors have read and agreed to the published version of the manuscript.

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Correspondence to Huaihong Yuan .

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This study was approved by the biomedical ethics committee of the West China University of Sichuan University (IRB NO.2023 − 362) and was performed in accordance with the principles of the Declaration of Helsinki. All patients provided a written informed consent. In the case of illiterate patients, the consent was read to them in the presence of a literate relative and they provided a fingerprint on the consent form to indicate their informed consent to participate. This form of informed consent was also approved by the biomedical ethics committee of the West China University of Sichuan University.

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Zhu, L., Liu, Y., Yang, F. et al. Prevalence, associated factors and clinical implications of medication literacy linked to frailty in hemodialysis patients in China: a cross-sectional study. BMC Nephrol 24 , 307 (2023). https://doi.org/10.1186/s12882-023-03346-4

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DOI : https://doi.org/10.1186/s12882-023-03346-4

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• Myelodysplastic syndrome

Explanation

The most likely diagnosis is hemophagocytic lymphohistiocytosis (HLH). The patient fulfills at least five of the main nine diagnostic criteria of HLH including fever, splenomegaly, cytopenia, elevated ferritin, low fibrinogen, and evidence of hemophagcytosis on bone marrow, as demonstrated in the pictures that a histiocytes engulfing a nucleated red cell (Figure 1) and a neutrophil (Figure 2).

Myelofibrosis can be associated with splenomegaly, but is less likely here since no marrow fibrosis or tear drop cells reported. Myelodysplastic syndrome is a possible cause of pancytopenia, but no dysplasia was noted on peripheral smear or in the bone marrow. Acute promyelocytic leukemia can be associated with DIC and low fibrinogen on presentation, but should have a hypercellular bone marrow with predominance of promyelocytes. Patients with aplastic anemia are found to have profound hypocellular bone marrow, but no hemophagocytes should be found.

Case study submitted by Tzu-Fei Wang, MD, The Ohio State University, Columbus, OH

American Society of Hematology. (1). Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia. Retrieved from https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia .

American Society of Hematology. "Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia." Hematology.org. https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia (label-accessed June 09, 2024).

"American Society of Hematology." Case Study: 44-Year-Old Man with Fever, Abdominal Pain, and Pancytopenia, 09 Jun. 2024 , https://www.hematology.org/education/trainees/fellows/case-studies/male-fever-abdominal-pain-pancytopenia .

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• v.15(12); 2023 Dec
• PMC10788660

A Case of Pernicious Anemia Presenting With Severe Hemolysis

Kaitlyn n romero.

1 Internal Medicine, University of Florida College of Medicine – Jacksonville, Jacksonville, USA

Falguni Patel

Austin quan, pramod reddy.

Vitamin B12 deficiency is a well-known and overall common disease. While the etiology of vitamin B12 deficiency varies from post-surgical changes to inadequate dietary consumption, pernicious anemia should be considered as it is a common cause. Pernicious anemia is an autoimmune atrophic gastritis impairing the absorption of vitamin B12. Manifestations include neurological changes, macrocytic anemia, glossitis, and nail changes. Hemolytic anemia is an unusual complication of vitamin B12 deficiency and an even more unusual initial presentation. This case identifies a patient with previously undiagnosed pernicious anemia with severe vitamin B12 deficiency compounded by hemolytic anemia as the presenting symptom. Overall, this case highlights the importance of considering vitamin B12 deficiency-related hemolytic anemia and the need for further research into the causes and pathophysiology of vitamin B12-induced hemolysis due to its potential for fatal outcomes despite being easily treatable with cost-effective methods to treat.

Introduction

Pernicious anemia is an autoimmune disease characterized by vitamin B12 deficiency due to antibodies that target intrinsic factor (IF) or parietal cells, both directly involved in vitamin B12 absorption [ 1 ]. In the United States, vitamin B12 deficiency affects about 20% of individuals over 60 years old; however, the prevalence is significantly decreased in patients younger than 60 years old with only 6% affected [ 2 ]. Patients with pernicious anemia can be asymptomatic for up to 10 to 20 years prior to presentation, which can manifest as neuropsychiatric and even hematological symptoms. More commonly, patients present with macrocytic anemia in addition to fatigue, shortness of breath, and pallor [ 1 , 2 ]. Without supplementation of vitamin B12, neuropsychiatric conditions develop such as subacute combined degeneration, bilateral and symmetrical paresthesias, loss of vibratory and positional sense, and memory and mood disturbances [ 1 ]. Pancytopenia and hemolysis are rare presentations of pernicious anemia, especially in developed nations such as the United States [ 3 ]. In this case, we present a middle-aged female with severe anemia in the setting of newly discovered pernicious anemia with laboratory findings indicating hemolysis in which prompt repletion of vitamin B12 resolved said hemolysis.

Case presentation

A 39-year-old female with a past medical history of laparoscopic cholecystectomy in 2021 presented with complaints of a progressive, one-month history of generalized weakness, periorbital tingling, and lightheadedness. The patient stated symptoms had been constant but exacerbated by overexertion. Her menstrual cycle was described as regular and light with no clots. She has a single 5 cm uterine fibroid stable on ultrasound last month. The patient stated she eats red meat, dairy products, and vegetables daily, denying a vegetarian or vegan diet. Social history was negative for alcohol, tobacco, and illicit drug use. The patient denied any prescribed medications or supplements aside from a daily multivitamin. Family history was negative, including colon cancer or any gastrointestinal malignancies. Review of systems was negative overall including symptoms of active bleeding, B-type symptoms, bowel changes, syncope, skin rash, myalgias, oral ulcers, and arthralgias.

At presentation, the patient was hemodynamically stable and in no acute distress with vital signs within normal limits except for sinus tachycardia at 110 beats per minute, blood pressure of 115/69 mmHg, and BMI of 27. The physical examination was significant for mild subconjunctival pallor and capillary refill greater than three seconds. There were no skin or nail findings visualized, koilonychia, glossitis, gait abnormalities, or focal neurological deficits.

Initial laboratory workup was significant for severe macrocytic anemia (hemoglobin 5 g/dL, mean corpuscular volume 113 fl) with mild transaminitis (AST 129 IU/L) and hyperbilirubinemia (total bilirubin 1.3 mg/dL). A decreased haptoglobin level (<10mg/dL) and elevated lactic dehydrogenase result (3,450 IU/L) raised concern for hemolytic anemia (Table ​ (Table1). 1 ). Reticulocyte percentage was elevated which indicated an appropriate bone marrow response with potential for hemolysis. Peripheral blood smear showed oval macrocytes with minimal schistocytes (Figure ​ (Figure1). 1 ). Given the presentation of severe anemia with hemolysis, anemia workup continued and a vitamin B12 level resulted in very low (<150 pg/mL) with homocysteine elevated at 72.6 umol/L (normal range < 14.5 umol/L) and methylmalonic acid (MMA) elevated at 4.2 umol/mmol (normal range < 0.4 umol/mmol). Autoimmune and thyroid workups were unremarkable. Due to a lack of other etiologies from the patient’s history, pernicious anemia was suspected; therefore, intrinsic factor-blocking antibodies (IFBA) were ordered. Serum IFBA was elevated, 248 AU/mL (normal range < 1.1 AU/mL), as were anti-parietal cell antibodies, confirming the diagnosis of pernicious anemia. Gastrointestinal blood loss was ruled out via history and with an adequate iron panel.

Given severe hemolytic anemia from vitamin B12 deficiency, the patient was administered two units of packed red blood cells with correction of hemoglobin to 8.5 g/dL. The patient was started on intramuscular (IM) injections of 1000 mcg of vitamin B12 daily with a plan to continue for seven days and then transition to oral supplements. The hemoglobin the day after remained stable and even improved to 9.8 g/dL. Given positive initial hemolysis labs without the presence of schistocytes, a direct antiglobulin test (DAT) was planned to further assess hemolysis but was not collected per patient refusal. With vitamin B12 repletion, the hemoglobin improved to 11.7 g/dL and the patient reported resolution of initial symptoms.

The most common causes of vitamin B12 deficiency include gastrointestinal surgery (gastric bypass, ileal resection) and dietary insufficiency and less commonly from autoimmune pernicious anemia [ 3 ]. Less commonly, nitrous oxide can cause acute depletion of vitamin B12, where the majority of etiologies are chronic in nature [ 4 ]. Vitamin B12 deficiency can result in demyelination of the dorsal and lateral columns of the spinal cord causing subacute combined degeneration as evidenced by paresthesia, sensory deficits, ataxia, and weakness [ 3 ]. In patients with known vitamin B12 deficiency, common findings include anemia (37%), macrocytosis (54%), and hypersegmented neutrophils (32%); however, pancytopenia is a rare presentation and is only seen in 5% of patients [ 5 ]. Vitamin B12 is used in deoxyribonucleic acid (DNA) synthesis and is required for proper division of hematopoietic cells. Decreased levels of vitamin B12 lead to insufficient DNA replication in the setting of normal cytoplasmic/cell content replication preventing effective cell division resulting in macrocytosis [ 4 ]. This lack of maturation and arrest of development of hematopoietic cells may lead to intramedullary cell death resulting in lactate dehydrogenase being released and decreased haptoglobin as seen in our patient [ 6 ]. In cases where vitamin B12 or folate deficiency is suspected, it is important to rule out folate deficiency as treating vitamin B12 deficiency with folate can result in improved anemia with worsening neurologic symptoms [ 4 ]. MMA levels provide utility in diagnosis, such as in pregnancy when vitamin B12 levels are falsely low in the third trimester or elevated in patients with myelodysplastic syndrome [ 1 , 4 ]. However, limitations of MMA include end-stage renal disease, which can present with elevated MMA levels not accurately indicative of the severity of vitamin B12 deficiency [ 1 ]. As with our patient, pernicious anemia should still be considered with a lack of dietary and surgical causes in the patient’s history. 

With pernicious anemia, it is important to start treatment early. Although the anemia typically resolves in four to six weeks, neurologic symptoms can take several months to improve and in some cases be permanent [ 5 ]. Treatment of patients with pernicious anemia involves IM injections of vitamin B12 for improved bioavailability [ 7 ]. Injection of 1000 mcg of vitamin B12 is to be administered daily for one week followed by weekly injections for four total weeks, then followed by lifelong monthly supplementation with IM injections [ 8 ]. Alternatively, regular oral vitamin B12 supplementation (1000-2000 mcg) has been shown to be effective in the treatment of patients with etiologies of megaloblastic anemia [ 8 , 9 ]. A case series demonstrated variability in adequate dosing (500-2000 mcg) seen by lowering of MMA levels and vitamin B12 testing in patients with different etiologies of malabsorption, such as gastrectomy or pernicious anemia [ 8 ]. While oral supplementation in these patients may seem ineffective due to a lack of IFs, absorption is believed to be due to IF-independent mechanisms that provide adequate absorption at high enough doses [ 10 ]. Overall, the currently accepted treatment of pernicious anemia involves IM injections, with phosphate supplementation adequate for patients that can be closely monitored and followed up.

This case highlights an unusual, yet potentially fatal, aspect of pernicious anemia: hemolysis. Vitamin B12 is required for the conversion of homocysteine to tetrahydrofolate, which is important for DNA production [ 11 ]. With B12 deficiencies, accumulation of homocysteine causes oxidative stress to erythrocytes leading to hemolysis as seen in vitro studies; however, the completed pathogenesis is unknown [ 12 ]. Overall, the presentation of hemolysis in vitamin B12 deficiencies is rare, consisting of 1.5% of presentations [ 3 ]. It is important to consider other causes of hemolysis in patients, such as autoimmune and genetic disorders. In this case, the patient had a negative family history, subacute timing of symptoms occurring close to the fifth decade of life, and symptoms consistent with anemia that resolved with vitamin B12 supplementation, making other etiologies less likely as causes for hemolysis. More often than not, vitamin B12 deficiency hemolytic anemia often presents as non-immune with a negative DAT. In the case above, the DAT was unable to be collected; however, DAT should be collected in the setting of hemolysis, as in pernicious anemia which is an autoimmune process. There are minimal case reports with this presentation, such as a case report in Croatia that reported megaloblastic and autoimmune hemolytic anemia [ 13 ]. 

Conclusions

The case presents an unusual combination of megaloblastic pernicious anemia and hemolytic anemia in the setting of severe vitamin B12 deficiency. The prompt correction of hemoglobin and maintenance of hemoglobin with vitamin B12 administration strengthened our diagnosis. The importance of early recognition of hemolysis in vitamin B12 deficiency can save health costs by decreasing unnecessary workup for other etiologies of hemolytic anemia. Additionally, more research is required to delineate the type of hemolysis (immune versus non-immune), especially in the setting of autoimmune diseases like pernicious anemia. Given this, it is important to test for vitamin B12 deficiency in hemolytic anemia as it is easily corrected.

The authors have declared that no competing interests exist.

Author Contributions

Concept and design:   Kaitlyn N. Romero, Oshin Rai, Falguni Patel, Austin Quan, Pramod Reddy

Acquisition, analysis, or interpretation of data:   Kaitlyn N. Romero, Oshin Rai, Falguni Patel, Austin Quan, Pramod Reddy

Drafting of the manuscript:   Kaitlyn N. Romero, Oshin Rai, Falguni Patel, Austin Quan, Pramod Reddy

Critical review of the manuscript for important intellectual content:   Kaitlyn N. Romero, Oshin Rai, Falguni Patel, Austin Quan, Pramod Reddy

Supervision:   Pramod Reddy

Human Ethics

Consent was obtained or waived by all participants in this study