As noted, the risk of developing anemia increases with age. An average of 6.5% of individuals have anemia at 60 to 69 years of age; this increases to 19.4% at 80 to 85 years of age [5]. The prevalence of anemia increases with age and is highest in elderly men 80 to 85 years of age [5]. The prevalence of anemia overall is in the range of 17% to 20%, with little difference between men and women (Figure 1). The prevalence increases as aging advances and does so to a greater extent and more rapid rate in men than women. Data from the National Health and Nutrition Examination Survey (NHANES) show that the prevalence of anemia in men 65 to 74 years of age is 7.6% and increases to 39.5% in men 85 years of age and older [5]. By comparison, the prevalence of anemia in women in the same age categories starts at a similar rate (7.6%) but reaches a rate (21%) only half that of men by 85 years of age. The prevalence of anemia is higher among men than women 75 to 84 years of age and those older than 85 years of age. Rates of anemia in nursing home patients are estimated to be 48% to 63%, and anemic residents of long-term care have a higher associated mortality rate [9,10].

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].

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].

An estimated 15% to 23% of anemic elders have iron deficiency [11]. Iron-deficiency anemia is characterized by depletion of iron stores and inadequate bone marrow iron deposits required for normal hematopoiesis. Gradually, circulating RBCs become microcytic and hypochromic (smaller and paler). However, the presence of normal RBCs (normocytic anemia) does not exclude iron-deficiency, as microcytosis is a late finding of severe iron deficiency. Elderly individuals may be at increased risk for decreased iron absorption due to medication side effects, chronic illness and inflammation, dietary iron deficiencies, and malabsorption.

The most common cause of iron-deficiency anemia in the elderly is occult blood loss from the gastrointestinal tract. Bleeding may be chronic or acute depending on the underlying etiology. Common causes include NSAID use, gastric ulcer, colon cancer, diverticulosis, and vascular malformation (angiodysplasia) of the bowel submucosa. In one study, gastrointestinal malignancy was present in 6% of patients with iron-deficiency anemia [19]. Other studies have reported iron-deficiency anemia as the presenting symptom in 15% of colorectal cancers [50]. Endoscopic evaluation is indicated for all patients with iron-deficiency anemia (but particularly those with family histories of gastrointestinal cancers), and colonoscopy is recommended, regardless of age, if upper endoscopy does not reveal a source of bleeding [20]. Stool should be tested for occult blood in the initial anemia work-up. It is important to also consider other potential causes of microcytic anemia during the evaluation of elderly patients with suspected iron-deficiency anemia. For example, lead poisoning, which interferes with the incorporation of iron into hemoglobin, can lead to a hypochromic, microcytic anemia despite adequate iron stores.

Pernicious anemia is the classic term for a subtle autoimmune disorder that causes chronic malabsorption of vitamin B12 in older adults [21]. It is characterized by a decrease in RBCs resulting from impaired intestinal absorption of vitamin B12, caused by autoimmunity against intrinsic factor or gastric parietal cells (which produce intrinsic factor). Intrinsic factor is necessary for the absorption of vitamin B12, and decreased production of intrinsic factor leads to reduced absorption of vitamin B12 [21].

Body stores of folate range from 500–20,000 mcg. It is necessary for humans to absorb 50–100 mcg of folate daily to replenish losses through bile and urine [31]. Food sources of folate include green vegetables, yeast, liver, beans, whole grains, and wheat bran. Many foods are also fortified with folate, including some breakfast cereals, rice, breads, and pasta [31]. Signs and symptoms of folate deficiency (e.g., weakness, fatigue, difficulty concentrating, dyspnea) develop gradually and usually become apparent after about four months.

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]:

Refractory anemia

Refractory anemia with ringed sideroblasts

Refractory anemia with excess blasts

Refractory anemia with excess blasts in transformation

Chronic myelomonocytic leukemia

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).

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].

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]:

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:

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.

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].

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].

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.