#99084: Anemia in the Elderly

Anemia is generally defined as a medical condition in which the number or function of erythrocytes or red blood cells (RBCs) is inadequate to meet tissue oxygenation needs. The body is unable to compensate for this reduction in the number of circulating erythrocytes.

According to Kidney Disease: Improving Global Outcomes, anemia is diagnosed in adults with chronic kidney disease when the hemoglobin concentration is <13.0 g/dL (<130 g/L) in men and <12.0 g/dL (<120 g/L) in women.

(https://kdigo.org/wp-content/uploads/2017/02/KDIGO_2012_CKD_GL.pdf Last Accessed: January 11, 2024)

Level of Evidence: Not Graded

The World Health Organization (WHO) defines anemia as an Hgb level less than 12 g/dL for women and less than 13 g/dL for men. An Hgb level of 10–11.9 g/dL for women and 11–12.9 g/dL for men is classified as mild anemia [13]. However, it is important to note that the use of Hgb level to define anemia has been controversial. In countries where nutritional deficiencies, infection, or congenital blood disorders are common, it may be difficult to apply a universal Hgb cut point [60]. In addition, there appear to be racial differences in normal Hgb levels and the point at which symptoms of anemia emerge. In general, the Black population has a lower median Hgb and higher prevalence of anemia than the White populations [5]. Further research is needed to determine if a different Hgb level would be appropriate to diagnose and begin treatment for anemia in the Black population [15].

In the past, elderly persons with mild anemia (i.e., Hgb >10 g/dL) have not received much attention from the medical community. Clinicians traditionally have not treated mild anemia, as it was considered a natural consequence of aging. However, it is now known that even mild anemia is associated with increased hospitalization and mortality in the elderly [11].

Chronic severe anemia in the elderly may lead to cardiac functional abnormalities. The reduction in tissue oxygen delivery and the compensatory tachycardia that invariably follows may, in time, lead to impaired ventricular systolic function [16]. In persons without heart disease, cardiac function begins to decline when Hgb levels fall below 7–10 g/dL. In the presence of heart disease, the Hgb level should be kept above 10 g/dL [16].

Anemia of inflammation, also known as anemia of chronic disease (AI/ACD), is the second most common anemia in elderly patients (after iron-deficiency anemia). It is a common feature of diseases that cause prolonged immune activation. Originally, AI/ACD was linked to chronic infections and autoimmune diseases in which laboratory markers of sustained inflammation are easily detected; more recently, the list has grown to include chronic kidney disease, cancer, cirrhosis, congestive heart failure, severe trauma, and obesity [18,66]. Its defining characteristics are a normocytic, normochromic anemia with low serum iron levels despite adequate iron stores and normal or high iron transport mechanisms, the result of blocked delivery of iron to developing RBCs and reduced intestinal absorption [17].

AI/ACD is caused by systemic inflammation that results in immune cell activation and formation of numerous cytokines [66]. Cytokines are chemical messengers of the body that mediate immune or inflammatory response and include tumor necrosis factor, interleukin-1, and the interferons. Over time, the impact of these messengers is to decrease absorption of iron, restrict iron trafficking, and interrupt the release of iron required for RBC production [6]. Additional pathogenic factors related to chronic inflammation include suppression of erythropoietin activity and shortening of RBC lifespan [66]. Independent of defined chronic disease states, the aging process itself is accompanied by an increase in proinflammatory cytokines and reactive oxygen species that may induce a state of low-grade chronic inflammation. In addition, older adults tend to have increased levels of pro-inflammatory cytokines secondary to multiple comorbid illnesses. As a result, AI/ACD is significantly more common in older patients, particularly those with chronic disorders [17].

It is important to note that anemia in elderly patients may be multifactorial—the result of a combination of chronic disease, blood loss, and/or vitamin deficiencies [17]. A varying percentage (25% to 85%) of patients with AI/ACD also suffer from true iron deficiency, which is often the result of concomitant or unrelated gastrointestinal bleeding or blood loss from therapeutic procedures (e.g., hemodialysis) [66]. A confirmed diagnosis requires that other etiologies have been excluded. In difficult cases, bone marrow aspiration/biopsy may be necessary to confirm the diagnosis. In patients with true AI/ACD, the severity of the anemia correlates to the severity of the underlying medical condition. When the underlying condition is treated, AI/ACD usually improves [17].

A prospective, multi-institutional cohort study was performed to characterize anemia in elderly nursing home residents. In healthy young adults, erythropoiesis increases in response to anemia or hypoxia; this study found that compensatory erythropoiesis diminishes with advancing age, attributable in part to unrecognized renal dysfunction [9]. Lower responses were also associated with chronic conditions like rheumatoid arthritis and cancer.

As noted, chronic anemia in the elderly may adversely affect cardiac function [16]. This is significant when establishing a treatment plan, as the presence of heart disease requires careful observation of Hgb levels. Chronic anemia can have other adverse effects on elderly patients, including extreme fatigue, impaired healing, and increased risk of hospitalization and death [1,16].

Nutrient-deficiency anemia is a significant cause of anemia, especially in the elderly. Iron, folate, and vitamin B12 deficiencies may be seen alone, but more often a combination of these deficiencies is present [6].

Bone marrow is the hematopoietic organ that produces most cellular components of the blood, including erythrocytes, leukocytes, and platelets. Disorders of hematopoiesis are common in the elderly as functioning bone marrow reserve diminishes with age. Myelodysplastic syndromes (MDS) are one such group of disorders and a cause of anemia in older patients, although it is relatively uncommon. These disorders are characterized by one or more peripheral blood cytopenias resulting from bone marrow dysfunction [32]. According to the French-American-British (FAB) classification system, MDS is further classified according to cellular morphology, etiology, and clinical presentation as [32]:

In 2008, the WHO revised its classification system for MDS, which is now based more on the results of genetic testing than previous systems [36]. The main differences include the elimination of the refractory anemia with excess blasts in transformation category, which is considered acute leukemia, and the addition of several subcategories and new categories. The WHO organizes MDS into the following classifications [32,36]:

As noted, myelodysplasia is more common in elderly patients, and more than 75% of patients with MDS are older than 60 years of age at diagnosis [32]. Patients may be asymptomatic, and the disease is often found as the result of routine blood tests. When present, signs and symptoms include fatigue, pallor, frequent infections, easy bruising, and petechiae. An estimated 30% of cases will progress to acute leukemia [32].

Anemia dominates the early course of MDS. Other key characteristics include macrocytosis, neutropenia, and thrombocytopenia. A poor prognosis is associated with advanced age, severe thrombocytopenia, and neutropenia.

Kidney function and glomerular filtration rate (GFR) naturally decreases with age, and it may be further decreased in the presence of chronic illnesses such as hypertension and diabetes, the two main causes of chronic kidney disease. Erythropoietin, a hormone-like substance elaborated by the kidney, is responsible for regulation of RBC production in the bone marrow. As kidney function declines, whether from disease or aging, there is a steady decrease in renal production of erythropoietin, and this is the primary etiology of anemia associated with chronic kidney disease. It can be difficult to distinguish the effects of normal aging on the kidneys from chronic kidney disease. Although a diminishing GFR with age is considered normal, the diagnostic criteria for chronic kidney disease are not modified according to a patient's age. Chronic kidney disease is defined as kidney damage or a GFR less than 60 mL/minute/1.73 m2 for more than three months [37]. It is further staged according to severity of GFR impairment and other symptoms (Table 2).

Although anemia is usually seen as a late manifestation of advanced renal impairment, women, diabetics, and African Americans may develop this complication at an earlier stage of kidney disease [37]. As noted, the primary etiology of anemia in chronic kidney disease is erythropoietin deficiency, but other causes should be considered as there may be a combination of factors contributing to the anemia. Other potential causes include:

Hemolytic anemias result from inherited or acquired disorders that result in premature destruction or removal of RBCs from the circulation. The normal lifespan of erythrocytes is 120 days; when hemolysis supervenes the rate of destruction or shortening of lifespan may be too severe for bone marrow production to compensate, resulting in anemia [38]. Sickle cell disease and thalassemia are examples of inherited hemolytic anemia; the acquired form is most often a manifestation of an immunologic disease, drug reaction, or infection. Some patients will have no known cause [38].

Sickle cell anemia is an inherited cause of hemolysis in which a genetic abnormality results in alteration of the Hgb structure, known as HgbS. The RBCs have an atypical response to hypoxia, and the cells develop a characteristic rigid sickle shape. The abnormal blood cells deliver less oxygen to the body tissues. Sickle-shaped Hgb can occlude the blood vessels, causing pain, organ damage, or stroke. The sickle cells usually die after 10 to 20 days, and anemia results [39].

Sickle cell disease occurs more often in persons with ancestors from sub-Saharan Africa, the Mediterranean, India, and Saudi Arabia [39,40]. In the United States, the rates are the highest for Black individuals, with 1 in 365 Black or African Americans having sickle cell disease [39,42]. If both parents carry the sickle cell trait, there is a one in four chance of having a child with sickle cell anemia, but carriers of sickle cell trait are generally asymptomatic. The lifespan of sickle cell patients is greatly reduced, so this type anemia is rarely seen in geriatric patients.

Thalassemias are another inherited hemolytic anemia. It is characterized by a genetic defect or deletion that causes an abnormal synthesis of one of the Hgb protein chains (alpha or beta) [43]. The alpha type is more common among African and South Asian persons, while the beta type is endemic to Mediterranean regions [43,44]. Thalassemia major occurs when the gene is inherited from both parents; thalassemia minor occurs if the gene is inherited from one parent. Severe thalassemias can cause a premature death, often between 20 and 30 years of age, but less severe forms have a favorable prognosis. Laboratory tests are usually necessary for diagnosis, but genetic studies can also be helpful [43].

In acquired hemolytic anemia, the body is producing normal RBCs, but the cells are being damaged. Potential causes of hemolysis include mechanical heart valves, immune disorders, infections, hypersplenism, drug or transfusion reactions, chronic liver disease, congestive heart failure, leukemia, and lymphoma.

Aplastic anemia is a life-threatening condition that occurs due to unexplained bone marrow failure. The bone marrow's stem cells are damaged as the result of an inherited condition or may be caused by an acquired condition, including an autoimmune disorder, exposure to toxic chemicals, chemotherapy or radiation exposure, infection, or in rare cases, pregnancy [45]. In some patients the cause of aplastic anemia remains unknown. Hereditary aplastic anemia is very rare; the acquired type is more prevalent. However, only 4 of every 1 million Americans will be diagnosed with any type of aplastic anemia annually [46]. As with other anemias, patients with aplastic anemia are susceptible to bleeding, fatigue, and infections. Pancytopenia is present when there are low counts of RBCs, WBCs, and platelets. The diagnosis of aplastic anemia is confirmed by bone marrow examination.

Unexplained anemia of aging (UAA) is a distinct disease entity, presenting as a normocytic anemia in older adult that cannot be attributed to nutritional deficiency, chronic inflammatory disease, or chronic kidney disease. The prevalence increases with age, and UAA is associated with decreased quality of life and increased mortality [65,69]. In most cases of UAA, the response to erythropoietin is blunted, suggesting an age-associated deficiency in ability to sense erythropoietin or to sustain rates of production required to maintain normal erythrocyte production [69]. In a study of 124 anemic elderly persons older than 65 years of age, 42 (37%) had anemia with these features, including low erythropoietin, lymphopenia, and low inflammatory markers [67]. The diagnosis of UAA rests on exclusion of known causes of anemia. UAA is thought to represent a heterogenous group with diverse causes such as impaired erythropoietin response to anemia, underlying stem cell disorder, or, in men, possibly testosterone deficiency [65,69]. The prevalence of UAA has been estimated at 25% to 44%, independent of whether the study population is community-based, hospital inpatient, or long-term facility residents [69].

The CBC is important for the diagnosis of anemia and for monitoring disease progression and treatment efficacy. When assessing the elderly anemia patient, the most important components of the CBC are [47]:

Clinicians should remember that laboratory values are not treated, patients are. Any abnormal laboratory results should be correlated with the physical condition of the patient and the patient's goals. Furthermore, different laboratories may use different reference values.

Symptoms of anemia may occur when the Hgb falls below 11 g/dL; when Hgb falls below 8 g/dL, the anemia is life-threatening. The CBC provides valuable insight into the type of anemia. If leukopenia and thrombocytopenia are present along with anemia, a myelodysplastic disorder is suspected. The MCV reveals the size of the cells, leading to the subclassification of anemias as normocytic, microcytic, or macrocytic, which is useful for indicating potential causes (Table 3).

Examination of a peripheral blood smear for morphologic abnormalities of RBCs (and for leukocytes and platelets as well) should be part of any evaluation of anemia. Anisocytosis indicates excessive numbers of RBCs with varying sizes; poikilocytosis denotes variation in shape and contour of RBCs [48]. Reticulocytes, which are young RBCs that mature in the marrow before release into the circulation, will appear in the blood in large numbers when there is accelerated RBC production, as occurs with hemolysis. A normal reticulocyte value is 0.5% to 1.5%; however, the reticulocyte count may be elevated in an anemic patient (reticulocytosis), indicating an erythropoietic response to the anemia [48]. Reticulocytosis may also raise suspicion for hemolytic anemia or increased RBC destruction. A low reticulocyte count (reticulocytopenia) usually indicates decreased RBC production and may point toward aplastic anemia, bone marrow depression, nutritional anemia, or ACI.

The iron profile is a crucial component to anemia evaluation. Before iron replacement therapy is initiated, the patient's iron level should be measured and documented. The serum iron level is an indicator of the amount of iron bound to transferrin in the blood. The iron profile will measure:

The iron profile, including the ferritin level, will give information about the iron availability, absorption, and iron stores of the body. Serum ferritin levels of 12–100 ng/mL can be present in both iron-deficiency anemia and AI/ACD [6]. Low serum ferritin levels are indicative of iron-deficiency anemia, and these patients should be evaluated for occult gastrointestinal bleeding from a malignancy or other cause.

A vitamin profile may also be necessary, as macrocytic anemia occurs with both folate and vitamin B12 deficiencies. As noted, low levels of folate have been associated with homocysteine accumulation, a risk factor for cardiovascular disease. Although lowering homocysteine levels may not improve outcomes, its presence as a risk factor should be considered. Replacing folate without replacing vitamin B12 may mask a B12 deficiency, leaving the patient at risk for neurologic complications. The vitamin profile may include measurements of:

Serum methylmalonic acid can be a useful diagnostic tool in identifying vitamin B12 deficiency when the B12 level is in the low-normal range (200–500 pg/mL), which can be particularly helpful for older adults, who experience symptoms at this level with greater frequency than younger patients. Methylmalonic acid begins to rise when the B12 levels fall below 400 pg/mL. The methylmalonic acid is normal in folate deficiency but may be elevated in renal insufficiency. Serum homocysteine and methylmalonic acid levels are high in 90% of patients with vitamin B12 deficiency [26].

Stool specimen for occult blood is another vital test for evaluation of anemia, as gastrointestinal bleeding is often a major contributing factor. Gastrointestinal bleeding may be intermittent, so evaluation of three different bowel movements is recommended. In preparation for the test, patients should stop taking iron supplements for 10 days and avoid red meat and food with red dye for three days prior to testing.

If the patient is positive for blood in the stool, gastroenterology consult is indicated. The patient will need endoscopy or colonoscopy to locate the source of the bleeding; blood in the stool may originate from hemorrhoids or other less serious problems. Alternatively, blood in the stool can be a sign of gastrointestinal malignancy.

Laboratory measurement of erythropoietin is not routine for evaluating anemia but is useful for assessing patients with unexplained polycythemia (abnormally elevated concentration of RBCs). The erythropoietin level is also reduced in chronic kidney disease and myelodysplasia. The normal range is 4.5–21.3 mU/mL. Patients with high erythropoietin levels and anemia will most likely not respond to erythropoietin-stimulating agents (ESAs). Measuring serum erythropoietin levels is of little diagnostic utility in patients with chronic kidney disease [49].

In cases of unexplained anemia, a referral to a hematologist is necessary for bone marrow aspiration and biopsy. Bone marrow aspiration/biopsy is necessary to evaluate cytopenias, leukocytosis, and thrombocytosis. If conducted, this procedure is generally performed in the outpatient setting.

For patients without a definable cause for the anemia, additional laboratory tests may be necessary for follow-up. If an identifiable and treatable etiology of the anemia is not found, a hematology consult is essential. Other laboratory tests that may be ordered in cases of anemia of unknown etiology include:

Elderly patients with anemia may have vague, non-specific symptoms; because the symptoms are non-specific, they are often overlooked or of limited help in differentiating between the types of anemia. Older patients are at greater risk for falls, cognitive decline, fatigue, and weakness because of advanced age, making the identification of anemia even more difficult [50]. Patients with mild anemia may remain asymptomatic. New-onset, easy fatigue, increased weakness, and shortness of breath are useful clues. Other signs and symptoms include tachycardia, bradycardia, dyspnea, chest pain, dizziness, headache, cold hands and feet, restless legs syndrome, and tarry stools. On occasion, patients may complain of visible changes in or discomfort of the tongue or lips, indicative of atrophic glottis and cheilitis. The severity of symptoms is dependent on the rapidity of onset, degree of anemia, physical status, and age of the patient [12]. Because anemia may be multifactorial, complete evaluation is necessary.

Pica may develop in some patients with anemia. Pica is a condition whereby the patient has an unusual craving to eat specific non-food item such as dirt, ice, starch, ashes, or clay. Pica is associated with both mineral deficiency (including iron-deficiency anemia) and mental health conditions. Pagophagia, a craving (pica) for ice, is present in about 50% of patients with iron deficiency, even in the absence of frank anemia [51]. Probing for pica is not part of the routine medical history, but it should be included whenever anemia is suspected or newly diagnosed, as it is a powerful clue to iron deficiency.

Patients with symptomatic anemia may present with multiple vague symptoms that do not point to any one diagnosis. To fully evaluate these symptoms, physical assessment and laboratory evaluation are necessary. Healthcare providers who work with the demented elderly should become adept at detecting medical conditions for patients unable to provide any history or symptomatology.

The physical assessment of the elder should focus on differentiating normal aging changes from pathology. The physical assessment of an anemic elder begins with visual evaluation of the patient's general physical and mental condition. This includes signs of malnourishment, pallor, breathing difficulties, and edema or ascites that may indicate chronic liver or kidney disease. Many observations can be made during the review of systems and medical history taking, including an assessment of cognitive function, such as the patient's ability to answer questions appropriately, delayed responses, and signs of compensating for a cognitive deficit.

Basic measurements lay the foundation for the physical assessment. The vital signs, oxygen saturation, height, and weight give valuable clues to the etiology of anemia. If the patient is underweight, with a body mass index of 18.5 or less, suspicion of nutrient-deficiency anemia is increased.

The major clinical signs in the anemic patient are secondary to hemodynamic changes and tissue hypoxia. Acute blood loss causes hypovolemia, hypotension, and if severe enough, signs and symptoms of shock. Over time, decreased blood volume will eventually cause orthostatic hypotension and tachycardia. This change in orthostasis is especially dangerous in elders, as it predisposes them to falls and injury. A bounding or rapid pulse may indicate that the cardiovascular system is compensating for low Hgb. Oxygen saturation may be decreased secondary to low Hgb, and increased respirations may be observed.

In addition to pallor of the skin, the inferior conjunctiva of the eye may appear pale. The tongue may appear smooth and swollen, with loss of papillae (glossitis). Angular stomatitis (cheilitis) causing irritation and fissuring of the corners of the lips may indicate nutritional or iron deficiency. Jaundice could indicate liver failure or hemolytic anemia.

Assessment of the cardiovascular system may reveal tachycardia, heart murmurs, increased peripheral edema, dyspnea, and orthopnea, which will be more pronounced in patients with chronic heart disease. Anemia may precipitate a myocardial infarction in patients with coronary artery disease or the worsening of angina due to the decreased oxygen carrying capacity of Hgb. In patients with peripheral arterial disease, intermittent claudication may develop or worsen. In patients with cerebrovascular disease, severe anemia may lead to transient ischemic attacks and cognitive decline.

Evaluation of the fingernails may reveal splitting and fraying associated with folate deficiency. Spooning of the nails (nails that grow upward) can indicate vitamin B12 deficiency.

Abdominal scars may be present due to gastrectomy or ileal resection, which gives information about possible malabsorption or gastrointestinal disorders. Older patients may give inaccurate medical histories, so these clues can be quite useful. There may be symptoms of anorexia, weight loss, constipation, and nausea.

Neurologic examination may reveal memory deficits, paresthesias, loss of position sense, and unsteady gait in patients with B12 deficiency anemia. Vitamin B12 deficiency should be considered for patients with even minimal neurologic symptoms. In later stages of vitamin B12 deficiency, the neurologic symptoms worsen and may become severe.

Close monitoring of pertinent laboratory values is necessary to evaluate patients' response to treatment. If a patient does not respond to the prescribed treatment, further evaluations and diagnostics may be needed to detect anemia of multiple etiologies.

As discussed, in cases of AI/ACD, the stabilization of the underlying chronic illness should improve Hgb and symptoms of anemia. This should be the first approach and should include assessment and treatment of other complicating factors, including iron deficiency, malignancies, or blood loss [18]. However, if the patient is experiencing impaired quality of life because of anemia symptoms or if the presence of anemia could complicate other age-related disorders, treatment with an ESA, such as epoetin alfa, and/or blood transfusion should be considered.

The British Society of Gastroenterology recommends the initial treatment of iron-deficiency anemia should be with one tablet per day of ferrous sulphate, fumarate, or gluconate. If not tolerated, a reduced dose of one tablet every other day, alternative oral preparations, or parenteral iron should be considered.

(https://gut.bmj.com/content/70/11/2030.long Last Accessed: January 11, 2024)

Strength of Recommendation/Level of Evidence: Strong recommendation, moderate-quality evidence

ESAs are used in the treatment of many anemias, regardless of etiology, and they have been found to be effective in improving Hgb levels in elderly patients. The overall goal of ESA treatment is to improve the Hgb level to the point that blood transfusion can be avoided [54,55]. Usually, ESAs are considered when the Hgb is less than 10 g/dL. However, more research in elderly patients is necessary to determine if this applies similarly to older adults. A randomized, double-blind, placebo-controlled study was conducted to evaluate the efficacy of epoetin alfa in the treatment of anemia in women older than 65 years of age [56]. Among this group, epoetin alfa was well tolerated, and the treatment group experienced an increase of 2 g/dL or more in their Hgb levels. Researchers found a direct correlation between Hgb levels and improvements in measures of fatigue and quality of life [56]. Review of mortality information related to Hgb levels indicates that levels greater than 13 g/dL are associated with poor outcomes, while Hgb levels of 9.5–11.5 g/dL are associated with better outcomes [57].

ESAs are associated with significant adverse effects, particularly in patients with cancer or chronic kidney disease. In all patients, ESAs are associated with an increased risk for serious cardiovascular events, thromboembolic events, stroke, and mortality when administered to target hemoglobin levels greater than 11 g/dL [55]. Due to the risk of deep vein thrombosis, all patients who require surgery should be given prophylaxis prior to the procedure. Prescribing of ESAs should be restricted to clinicians experienced in use and monitoring of the treatment. Because there is an increased risk of death, serious cardiovascular events, hypertension, thrombosis, and progression of certain cancers, patients should be closely monitored. In addition, patients must understand the risks associated with this treatment. Quality of life measures should be considered.

The recommended dosage of epoetin alfa is 100–150 U/kg subcutaneously three times per week along with supplemental oral iron [18]. If no improvement is seen in six to eight weeks, this dose may be increased to daily administration or to 300 U/Kg three times weekly. A once-weekly dose of 30,000–40,000 U subcutaneously is also available. If the patient has no response to treatment after 12 weeks, it is unlikely to be clinically useful [18].

In order for treatment with ESAs to be effective, iron supplementation to ensure adequate stores is necessary. Supplementation should maintain a transferrin saturation of 20% or greater and a serum ferritin level of 100 ng/mL or greater [18].

Treatment of MDS generally consists of supportive care, including transfusion of RBCs, which temporarily corrects the low blood counts. Platelet infusions become less effective over time and are associated with a risk of alloimmunization [32]. Frequent transfusions can cause an iron overload, which can damage the liver and other organs; iron overload may become a problem after as few as 10 transfusions. When the serum ferritin level is between 1,000 and 2,000 ng/mL, the patient may require iron chelation therapy with subcutaneous or oral deferasirox or subcutaneous deferoxamine and vitamin C [32,55].

An ESA (e.g., epoetin alpha 150–300 mcg/kg/day) may be used in patients with a low erythropoietin level and is most useful in patients who do not yet require transfusion and patients who have a serum erythropoietin level less than 200 mU/mL. Other possible treatments of MDS include growth factor, chemotherapy, and bone marrow or stem cell transplantation.

The mainstays of treatment of anemia in chronic kidney disease patients are ESAs and iron supplementation [54]. In 1989, the FDA approved the use of epoetin alfa for use in anemia of chronic kidney disease. Response to treatment with ESAs is inhibited in patients with kidney disease, and increased doses may be necessary to obtain an adequate response. The recommended initial dose is 50–100 U/kg per week or 10,000 U subcutaneously once weekly, with adjustment of the dose based on subsequent Hgb levels, response to treatment, and development of adverse side effects [62]. As discussed, for ESA treatment to be effective, concurrent iron supplementation is also necessary.

However, the severe adverse effects of epoetin alpha and other ESAs have made their use complicated [63]. Studies of have shown increased thromboembolic events, tumor progression, and cardiovascular events when Hgb levels are greater than 12 g/dL [51,53]. The FDA has issued a black box warning for epoetin alfa regarding the increased risk of death, serious cardiovascular events, and stroke in patients with chronic kidney disease with Hgb levels of 11 g/dL or greater [55]. Although no optimal dose or Hgb target has been established for patients with kidney disease to prevent these adverse events, an Hgb level that raises more than 1 g/dL in one week may indicate an increased risk and should initiate a reduction in ESA dose [55]. The lowest possible dose of ESA to prevent blood transfusion should be used.

Treatment of sickle cell anemia involves the use of hydroxyurea therapy, amelioration of pain, and other complications and supportive care. Blood transfusions are not used to treat normal anemia and pain associated with sickle cell disease, but it may be used during pregnancy or in cases of severe acute anemia or acute chest syndrome [41]. However, patients who receive multiple transfusions are at risk for alloimmunization and iron overload. Iron chelation therapy may be necessary to prevent damage to the organs due to high iron levels. Allogeneic bone marrow transplant may produce a cure in a small number of patients [41].

Treatment of thalassemia consists of blood transfusions, iron chelation therapy, folic acid supplements, and bone marrow and stem cell transplant, depending on the type of thalassemia diagnosed [43]. Some will require splenectomy.

The goal of treatment of aplastic anemia is to control symptoms and prevent complications. Initial treatment includes blood and platelet transfusions and IV antibiotics. While immunosuppressive drugs are effective in treating aplastic anemia, these medications further weaken the immune response, leaving the patient at risk of complications. ESAs and colony-stimulating factors are also used [45]. For severe cases, an allogeneic bone marrow transplant may be advised. However, it is important to note that elderly patients may be unable to tolerate the preparation for transplant and are at an increased risk for complications. If left untreated, death will usually occur rapidly.

For cases of acute blood loss, as in trauma or surgery, a blood transfusion is the standard treatment for patients willing to receive blood and blood products. In addition, blood transfusions are indicated in the treatment of a wide variety of anemias in elderly patients. For chronic anemia, which may be caused by myelosuppression, inflammation, infection, or malignancy, a blood transfusion is not recommended. In patients with chronic anemia, blood transfusion causes a temporary increase in Hgb but fails to treat underlying condition(s) [7]. Transfusion of blood products is generally reserved for patients with an Hgb level of 8 g/dL or less, due to risks of infection, volume overload, and transfusion reactions [11].

As noted, iron overload and clinical signs of hemochromatosis may occur with repeated blood transfusions. The excessive iron builds up in organs and tissues, especially the liver. Signs and symptoms of hemochromatosis may include joint paint, fatigue, generalized weakness, weight loss, and abdominal pain. Due to the potential hazards of iron overload on the body organs and tissues, iron should never be prescribed prior to laboratory assessment of iron stores of the body.

In patients with terminal disease, blood transfusions may be used to palliate the symptoms associated with anemia. Blood transfusions have been found to provide some relief from anemia symptoms (e.g., fatigue, dyspnea, weakness) and improved quality of life for patients suffering from cancer or terminal illness [8]. Again, this is a palliative care technique and will not be curative or a long-term solution. In fact, it is important to remember that a blood transfusion has the potential to prolong pain and suffering at the end of life and to give patients and/or their families false hope. A risk and benefit analysis should be performed prior to initiating transfusions for these patients.

Language and cultural barriers have the potential for far-reaching effect, given the growing percentages of racial/ethnic populations. As noted, patient understanding of the causes and available treatments is an essential component of caring for the geriatric patient with anemia, and it should be assured that all patients have a clear understanding of the concepts discussed. When there is an obvious disconnect in the communication process between the practitioner and patient due to the patient's lack of proficiency in the English language, an interpreter is required.

Clinicians should use plain language in their discussions with their patients who have low literacy or limited English proficiency. They should ask them to repeat pertinent information in their own words to confirm understanding, and reinforcement with the use of low-literacy or translated educational materials may be helpful.

Patient H is a White woman, 89 years of age, who resides in a skilled nursing facility. She is being evaluated due to an Hgb level of 8.1 g/dL. She is ambulatory with a rolling walker, generally alert, and oriented with some mild cognitive impairment. She is compliant with medical treatments and takes medications as prescribed. Her medical history is positive for congestive heart failure, chronic obstructive pulmonary disease (COPD), chronic kidney disease, and osteoarthritis. She is oxygen dependent on 2 L/minute per nasal cannula. She is bright and outgoing and verbalizes multiple vague physical complaints.

During her last hospitalization, one year ago for pneumonia, the nephrologist and pulmonologist told Patient H there was not much else that could be done for her. Despite the poor prognosis, her multiple medical conditions stabilized and she completed a rehabilitation program. She enjoys participating in activities and has developed friendships with some other residents. Over the past year, she has been treated for multiple infections, including bronchitis and multiple urinary tract infections.

Patient H's chief complaint is of feeling tired and short of breath at times. She also complains of arthritic pains in her neck and hands. Review of systems is notable for hearing loss, dentures, glasses, and dyspnea, mostly with exertion. She has occasional palpitations of the heart and orthopnea at times. Her bowel movements are regular, and she has not noticed any blood in the stool. She has 1+ chronic edema of the legs, which is about usual for her. She has not had a mammogram for five years, and she has not had a dual energy x-ray absorptiometry scan, colonoscopy, or other preventive care recently.

Patient H's record indicates an allergy to sulfa drugs and penicillin. She also has completed advance directives (a do not resuscitate order and a living will). She is taking the following medications:

Upon physical examination, Patient H appears well-nourished and groomed. She is mildly short of breath at rest but in no apparent pain or distress. She is 5 feet 6 inches tall and weighs 156 pounds. Her vital signs indicate a blood pressure of 132/84 mm Hg; pulse 72 beats/minute; temperature 97.4 degrees F; respirations 20 breaths/minute; and oxygen saturation 94% on 2 L/minute. Her oropharynx is clear, and her neck is supple. There is no lymphadenopathy. The patient is hard of hearing and wears glasses for distance and reading.

Patient H's heart rate is slightly irregular, with a soft systolic ejection murmur. Evaluation of her lungs indicates diminished breath sounds in the bases with no adventitious sounds. The abdomen is soft and non-tender, with active bowel sounds and no signs of hepatosplenomegaly. As noted, Patient H has 1+ pitting chronic edema and vascular changes to lower extremities. There are no active skin lesions. Neurologic assessment shows no focal deficit. Extremity strength is rated 4 out of 5. A mini-mental status exam is administered, and the patient scores 22/30, indicating mild cognitive impairment.

Blood is drawn and sent to the laboratory for CBC and a basic metabolic panel. The results are:

Patient H is in no apparent distress at present, but she appears to have anemia, as evidenced by the low Hgb. She has chronic kidney disease (stage 3), which may be contributing to the anemia. Further laboratory evaluation is necessary to determine the etiology of the anemia and to determine if specialty referral to gastroenterologist or hematologist is necessary. The clinician orders an iron profile, vitamin B12 and folate levels, reticulocyte count, and stool for occult blood. The results of this testing are:

Vitamin B12 is a water-soluble vitamin that is excreted in urine, so a high level is generally not significant. The folate level is sufficient, while the ferritin level is considered low-to-normal. The iron profile shows a low level of iron in the blood; this may be caused by gastrointestinal bleeding or by inadequate absorption of iron by the body. Patient H has medical conditions that can cause elevated cytokines, which would interfere with iron absorption. If her ferritin level was high, which it is not, it would suggest AI/ACD. Therefore, the patient appears to have anemia secondary to chronic kidney disease and possibly inadequate iron absorption and processing.

Prior to initiating treatment with an ESA, the patient is evaluated for a history of cancer, as these agents may cause progression/recurrence of cancer. Before writing the prescription for darbepoetin alfa, the clinician signs the ESA APPRISE Oncology Patient and Healthcare Professional Acknowledgement Form to document discussing the risks associated with darbepoetin alfa with the patient. The lowest dose that will prevent blood transfusion is prescribed.

The multidisciplinary team works with Patient H to develop a treatment plan. It is determined that treating the anemia will improve the patient's quality of life. The patient is prescribed ferrous sulfate 325 mg twice daily. Because vitamin C facilitates iron absorption, the iron can be given with a glass of orange juice or other citrus juice (not grapefruit). Iron must not be given with calcium, milk products, and certain medications as they can interfere with absorption. The patient should be monitored for the development of constipation and the need for stool softeners. In addition, darbepoetin alfa 40 mcg is prescribed, to be administered subcutaneously every week. This requires significant monitoring. Hgb and HCT should be measured on the day patient is to receive the injection, and the drug should be held if the Hgb is greater than 11.5 g/dL. If a current Hgb level is unavailable, the drug should not be given.

Blood pressure should be measured twice daily after treatment with darbepoetin alfa is initiated. Staff must also monitor for symptoms of a deep vein thrombosis and pulmonary embolus (e.g., unilateral edema, cough, and/or hemoptysis). Daily exercise is encouraged to help reduce the risk of a blood clot.

After one month, Patient H has received darbepoetin alfa weekly for four weeks. She is also taking the ferrous sulfate and a stool softener. The review of systems is unchanged from the previous evaluation. The physical examination is also unchanged aside from a 1-pound weight loss. No new complaints or problems are reported. A review of the patient's vital signs shows a blood pressure of 130/80 mm Hg; pulse 78 beats/minute; temperature 97.8 degrees F; and oxygen saturation 97 on 2 L/minute. Her Hgb levels over the last month have improved:

No side effects from darbepoetin alfa have been observed. Patient H's blood pressure remains stable, with no signs or symptoms of a blood clot.

The clinician orders the weekly monitoring of Hgb and HCT to continue with the darbepoetin alfa held if the Hgb is greater than 11.5 g/dL. If the medication is held more than once, the clinician will re-evaluate the dosage and frequency. The patient may only need the injection once or twice a month after the anemia is stabilized. The clinician also reduces the patient's vitamin B12 supplement to daily (rather than twice daily) and reduces her prednisone dose to 5 mg/day.

Discussion

Patient H's initial complaint was of shortness of breath and fatigue. These symptoms may have been related to the anemia or may have been a chronic complaint secondary to her congestive heart failure and COPD. The decreased hematocrit level is likely contributing to the patient's symptomatic heart failure. By exploring her condition further, it was determined that treating the anemia might improve the patient's quality of life and prevent the necessity for more extreme interventions (e.g., blood transfusion). Patient H was informed of the potential side effects of darbepoetin alfa and agreed to take it to prevent transfer to the hospital for blood transfusion.

The patient's condition was monitored closely, with weekly blood draws for Hgb. Her blood pressure remained stable, and no signs of complications were detected. Her shortness of breath and fatigue improved as the treatment progressed and her Hgb level rose above 10 g/dL. This allowed her to be more active.

For patients with terminal or end-stage conditions, treatment of anemia can restore or preserve their quality of life. Treating problems that could potentially cause suffering, while avoiding futile care, is the goal for patients with a life-limiting condition. Anemia affects the quality of life in elders by causing fatigue, poor endurance, and shortness of breath, and alleviating these symptoms can allow for more activity and comfort.

Patient P is a White man, 92 years of age, who resides in an assisted living facility. He uses a motorized scooter for mobility but can ambulate short distances with his rolling walker. He requires assistance with medication administration and attends community meals three times a day. His daughter visits once a week and assists with laundry and transports to medical appointments.

Patient P is brought to the primary care clinic by his daughter. She states that he is very fatigued and is not performing his usual daily tasks. He sleeps more than is usual and must be coaxed to attend the community meals. At times, he has refused to take medications that the staff attempt to administer. The patient minimizes his symptoms saying, "What do you expect? I'm 92 years old." Patient P's medical history is positive for Parkinson disease, hypertension, COPD, osteoporosis, compression fracture to the lumbosacral spine, and weight loss. He is a widower and reports no tobacco use and rarely drinking beer or wine. His chief presenting complaints are fatigue, shortness of breath, chronic back and leg pain, and poor appetite.

On review of systems, the patient is noted to be hard of hearing and wearing a hearing aid. Vision is adequate with correction. He wears dentures and denies pain or difficulty with mastication. He has difficulty swallowing large pills, and his caregivers crush his medications. He states his appetite is not good; he has lost 15 pounds over the last year. Patient P denies chest pain, but complains of shortness of breath. This occurs when he exerts himself and often when he lays down. He has a regular bowel movement every one to two days and denies nausea, vomiting, or diarrhea. He has not had dyspepsia but does state he does not seem to be able to eat as much as he used to (early satiety). He complains of nonradiating pain in his lower back. All other review of systems is non-contributory. Patient P has previously been tried on antiparkinsonian medications and osteoporosis medications that were discontinued due to unacceptable side effects. He is currently taking the following medications:

Upon physical examination, Patient P appears frail but well groomed; he is in no apparent distress. He is 5 feet 5 inches tall and weighs 134 pounds. His vital signs indicate a blood pressure of 110/64 mm Hg; pulse 82 beats/minute (regular rate and rhythm); temperature 97.8 degrees F; respirations 22 breaths/minute; and oxygen saturation 91% on room air.

As noted, the patient is hard of hearing with hearing aid and wears glasses. There is no evidence of lymphadenopathy or carotid bruit. His oropharynx is clear. His lungs are clear to auscultations, with diminished air flow in lung bases. The abdomen is soft and non-tender, not distended, with bowel sounds active in four quadrants. There is no hepatosplenomegaly. Extremities are clear of edema. Vascular changes are noted on both legs, and the toenails are thickened. The patient displays dry, flaky skin of lower extremities. Tenderness is noted over the lumbar spine with palpation. Disuse atrophy is noted to the extremities. Chronic skin lesions are also present, with actinic keratoses on the nose and forehead. Neurologic assessment reveals fine resting tremor of both hands and flat affect. Strength is equal bilaterally with strong hand grasps. Gait and balance are unsteady.

The clinician orders Patient P's medical records and diagnostics from previous care providers. She also requests a CBC with differential, a complete metabolic profile, and thyroid studies. A home health care evaluation is also recommended to determine if rehabilitation services would be appropriate. Patient P's laboratory studies indicate:

The low RBC, Hgb, and HCT indicate that the patient has a normocytic, normochromic anemia. However, blood-loss anemia is not ruled out by lack of microcytosis. If the blood loss is recent, changes to the cells may not yet be evident. The RDW-CV is normal, which may indicate a lack of erythropoietic response. Further laboratory evaluation is indicated.

The clinician requests an iron profile, ferritin level, folate level, vitamin B12 level, reticulocyte count, and stool for occult blood. The results of this testing are:

These findings indicate the patient is not deficient in vitamin B12 or folate. The serum iron is low while the ferritin level is high, suggesting adequate iron stores that are not being utilized by the body. This is a diagnostic indicator of anemia of chronic inflammation. The total iron binding capacity is low, showing that the blood's ability to bind transferrin with iron is reduced. Patient P has signs of a "mixed" anemia, the result of both ACI and gastrointestinal blood loss. Elderly patients often have more than one etiology contributing to the anemia, and all the possible causes should be thoroughly evaluated.

One of the stools for occult blood is positive, which may be representative of intermittent gastrointestinal bleeding. The clinician refers the patient to a gastroenterologist for further diagnostic evaluation. An endoscopy and colonoscopy should be performed if the patient and healthcare surrogate are willing. He is also prescribed a 5% lidocaine patch to be applied to his lower back in the morning and to be removed at bedtime.

Patient P visits a gastroenterologist, who performs an endoscopy and a colonoscopy. He is found to have several polyps in the large intestine, which are removed and biopsied during the colonoscopy. He tolerates the procedures well and has no adverse effects. The polyps are found to be benign.

One month later, Patient P returns to the clinic for follow-up. His review of systems is unchanged, although he reports improvement in his lower back pain. His vital signs are all stable. A CBC is completed to monitor the anemia, and the results are:

Patient P's RBC, Hgb, and HCT have improved slightly. The RDW-CV has also increased, indicating an improved erythropoietic response. The removal of the colon polyps, which may have been causing some intermittent bleeding contributing to the anemia, appears to have improved the patient's condition. Patient P is instructed to return in one month for additional follow-up.

Discussion

Patient P is a frail, elderly patient with multiple medical problems. From a primary care perspective, it is important to identify any new or existing medical problems that can be treated and improved. Elderly persons often present with multiple vague complaints that do not point to any one disorder. Laboratory evaluation is crucial to narrow down the diagnostic differential.

Because there is an upward trend in the CBC values, the necessity of a blood transfusion is reduced. However, if the anemia worsens, a hematology consult may be necessary. At 92 years of age, the patient is at risk for myelodysplasia, but if present, lower values of leukocytes, RBCs, and platelets would be expected.

While the use of an ESA might result in an improvement in elderly patients, there are multiple side effects and precautions associated with their use. For Patient P, they should be avoided unless truly necessary to prevent the need for transfusions.