As he waited to be taken down to the gym for his physical therapy session the day after his knee replacement, Joe reached for a cup of ice water and rattled it, selecting a few ice cubes to chew on. He was frustrated by his poor endurance and couldn’t remember when he had last felt so tired — all he seemed to do was lie around on the CPM machine! The nursing staff had told him that since his surgery, he had developed a cardiac arrhythmia and needed to move slowly. They were constantly nagging him not to get out of bed by himself after that last time when his head swam, his calves cramped, and he nearly fell. Joe felt irritated that after a lifetime of being “the strong one,” he now felt as weak as a kitten, and he seemed to have trouble concentrating when his therapist was trying to teach him his exercises. Joe sighed wearily as his physical therapist approached and was surprised when she told him that the mystery was solved: After surgery, his hematocrit had dropped to 27%, his blood hemoglobin was only 8 g/dL, and he was due for a blood transfusion that afternoon.

Common symptoms of anemia include weakness, fatigue, dizziness or lightheadedness, irritability, shortness of breath, depression, chest pain, cardiac arrhythmias, a cold sensation in the extremities, poor concentration, calf cramps, and a desire to eat ice or other unusual non-food items (pica).¹ When an inadequate amount of oxygenated blood is available in the circulatory system following blood loss during major surgery, symptoms can arise quickly, with potentially dangerous or life-threatening consequences. At its worst, anemia can cause oxygen deprivation to the brain and other organs, resulting in plummeting blood pressure, shock, heart failure, organ damage, and even death. Anemia and its symptoms may also come on more slowly in response to chronic conditions, diseases, or medications, but this scenario is no less serious: With chronic anemia, the heart will pump harder in an attempt to circulate adequate amounts of oxygen throughout the body, resulting in abnormal thickening of the heart muscle (left ventricular hypertrophy), ischemic heart disease, myocardial infarction, and eventually, sudden cardiac arrest.²

In the nineteenth century, a relationship between weakness from chronic anemia and poor eyesight from vitamin A deficiency was observed and was treated with distasteful doses of cod liver oil, rich in vitamins A and D, which helped improve iron absorption.³ By the early twentieth century, people who were pale and who fatigued easily were simply told to eat more liver, a food rich in iron and vitamin B-12, to build up their strength. Although ingestion of cod liver oil and liver is rarely prescribed for anemia in modern times, the practice of supplementing the diet with certain nutrients to “thicken the blood” and restore energy and vigor was first substantiated by groundbreaking, Nobel Prize-winning research on pernicious anemia in 1934.⁴ While not all forms of anemia can be treated by dietary supplementation, the presence of anemia remains a reliable window into the inner workings of the human body that can significantly affect recovery from illness or surgery, functional independence, and life span.

Anemia Defined

Anemia is not a disease itself, but it is a commonly experienced symptom of an underlying problem that can interfere with a patient’s ability to build strength and endurance. Anemia is defined as a condition in which there is an inadequate number of healthy red blood cells (RBCs) in the body, an abnormally low amount of the iron-rich protein hemoglobin in the existing red blood cells, or both.⁵

The bright red color of hemoglobin is what gives RBCs, also known as erythrocytes, their distinctive bloody color. As RBCs circulate through the body, oxygen molecules attach to cellular hemoglobin at the lungs and are subsequently deposited in the body’s tissue cells — as hemoglobin is emptied of oxygen at the tissues, it picks up carbon dioxide and other waste gases to transport them back to the lungs to be exhaled, leaving the hemoglobin once more available to pick up fresh oxygen on inhalation. To produce and maintain the correct number of RBCs (erythropoesis) in the body at any given time, two systems must interact in a coordinated fashion: the bone marrow and the kidney. In the healthy body, RBCs are made from stem cells in the bone marrow over a period of five to seven days, from where they are released into the circulatory system for an average of 120 days before being destroyed and replaced.⁷ As the number of RBCs cyclically drops and oxygen transportation becomes less efficient, the kidneys are stimulated by the relative hypoxia to produce and release the hormone erythropoietin, which in turn stimulates the bone marrow to create more RBCs. This sensitive, ongoing feedback mechanism between the bone marrow and the kidneys is necessary to maintain adequate oxygenation of the brain, heart, and tissues. 

Rogue RBCs

When there are inadequate numbers of RBCs, or when the RBCs contain insufficient hemoglobin, anemia results. Anemia can be of acute onset, occurring with perioperative blood loss or trauma, or it may be chronic in nature, arising from vitamin and iron deficiencies, gastrointestinal bleeding, or certain chronic diseases. The three main causes of anemia are blood loss, inadequate RBC production, or increased RBC destruction (hemolysis). 

Women are twice as likely to have anemia than men, with approximately 8% of women and 4% of men in the community demonstrating hemoglobin levels below the anemia threshold; the prevalence of anemia in the patient population is unknown, but it is estimated to be much higher.⁷ Anemia is much more common in women of childbearing age due to regular blood loss secondary to the monthly menstrual cycle and also from vitamin deficiencies and fluid volume changes during pregnancy. The risk for anemia is also greater in people who are malnourished, the elderly, alcoholics, vegetarians, those who are suffering from chronic untreated illnesses, and those who have inherited certain familial diseases like sickle cell anemia. Other independent risk factors include the use of medications such as nonsteroidal anti-inflammatory medications, aspirin, and warfarin, which can increase the incidence of gastrointestinal blood loss.⁵

Pumping Iron

The most common cause of anemia throughout the world is iron deficiency anemia. In the United States, 2% of men and up to 20% of women of reproductive age are affected, resulting in fatigue, poor endurance, cognitive impairment, and reduced work and exercise capacity.⁸ Iron stores are regulated by absorption in the jejunum of the small intestine, which varies according to whether the body is in an iron-depleted or iron-overload state. Iron is absorbed from dietary intake, and it’s removed from the body via blood loss. Iron is ingested from meat as heme iron, the most readily absorbed type of iron, and from certain plant and dairy foods as non-heme iron. The absorption of iron is enhanced by stomach acid and enhancers such as ascorbic acid (vitamin C) and is inhibited by calcium, fiber, bran, cereals, coffee, tea, and wine.⁸ Iron absorption may also be impaired when a patient is using medications that raise the gastric pH, such as antacids, proton pump inhibitors, or histamine blockers.

For iron deficiency to occur, the depletion of iron stores in the body must exceed dietary iron absorption, which can occur with occult gastrointestinal bleeding, chronic hemorrhoidal bleeding, heavy menses, pregnancy, blood donation, and conditions that create poor gastrointestinal absorption, either alone or in combination with inadequate dietary iron intake or excessive intake of iron inhibitors in the diet.

The formation of new RBCs (erythropoesis) requires the presence of iron to create hemoglobin. Because the majority of the body’s iron is found in the circulating RBCs within hemoglobin, when an insufficient amount of iron is present, RBC size (mean corpuscular volume, or MCV) becomes smaller. Decreased MCV (< 80 fl), as recorded in the patient’s complete blood count (CBC), is a hallmark of microcytic anemias (small cell anemias) such as iron deficiency anemia.⁸ Other lab tests that may indicate iron deficiency anemia include analysis of the body’s serum iron level and amount of stored iron (ferritin), which is usually decreased, and the total iron-binding capacity and level of iron-carrying protein (transferrin), which is usually increased. A fecal occult blood test may be useful to rule out chronic gastrointestinal bleeding. Differential diagnosis for microcytic anemia includes sideroblastic anemia secondary to bone marrow dysfunction, thalassemia (an inherited blood disorder), anemia associated with chronic diseases, and lead poisoning. Treatment for iron deficiency anemia includes daily iron supplementation and treatment for underlying causes of blood loss.

Bigger, Not Better

The most common cause of macrocytic anemia (large cell anemia), in which the MCV is bigger than normal (> 100 fl) is vitamin B-12 deficiency, vitamin B-9 (folic acid) deficiency, or a combination of the two. It is estimated that as many as 10% to 15% of adults over the age of 60 in the U.S. are deficient in vitamin B-12.¹¹ However, only 0.5% of the general population is currently deficient in vitamin B-9, reduced from 16% of the population before 1998.¹² Beginning in 1998, in response to studies showing that folic acid deficiency was associated with neural tube birth defects, the U.S. Food and Drug Administration began adding folic acid to all enriched cereals, breads, pastas, flours, rice, corn meal, and other grain products sold in the United States, making vitamin B-9 deficiency a rare occurrence.

With macrocytic anemias, inadequate numbers of RBCs contain an insufficient amount of hemoglobin; therefore, the hematocrit and hemoglobin levels are typically low despite the large size of the RBCs. Vitamins B-9 and B-12 are necessary for DNA synthesis, so when there is not enough of these essential vitamins in the body, the RBCs are unable to produce DNA fast enough to divide at the correct time while they grow, resulting in large, immature RBCs that lack sufficient amounts of hemoglobin, creating an anemic state.¹¹ Deficiency in these two important B vitamins can be caused by either inadequate dietary intake or poor absorption by the gastrointestinal tract.

Whereas vitamin B-9 is found easily in cereals, grains, rice, and pasta, vitamin B-12 is found solely in animal proteins like beef, fish, poultry, dairy products, and eggs. Liver, as a primary storage location for vitamin B-12, is a rich source of the vitamin when ingested, as discovered by the 1934 Nobel Prize winners.⁴

Pernicious anemia, a form of macrocytic anemia that affects 2% of the population, is caused by an inherited autoimmune disorder that creates antibodies against gastric intrinsic factor that is necessary for vitamin B-12 absorption.11 Other causes of poor B-12 absorption include atrophic gastritis, bariatric surgery that resects part of the stomach and/or small intestine, celiac disease, alcoholism, insufficient dietary intake of animal proteins with a vegetarian diet, and use of antacids.

Vitamin B-12 deficiency is of particular importance to uncover due to its devastating outcome: Uncorrected B-12 deficiency can cause demyelinating peripheral neuropathy that causes paresthesias in the hands and feet and irreversible damage to the white matter of the spinal cord and brain, as well as cardiac palpitations, fatigue, weakness, cognitive impairment, and even dementia in older patients. But unmasking B-12 anemia is complex, as the deficiency may be present for years before hematologic signs of anemia manifest. Even then, it may go unnoticed because high levels of folic acid can correct the underlying macrocytic anemia, effectively masking the B-12 deficiency and allowing the nerve damage to progress unchecked.¹³ When serum levels of B-12 are borderline and/or the patient is symptomatic, confirmatory blood tests should be run, including levels for serum folate, homocysteine (Hcy), and methylmalonic acid (MMA). Antibody tests for gastric intrinsic factor may also be run when pernicious anemia is suspected. Differential diagnosis for B-12 and/or B-9 deficiency anemia includes hypothyroidism, disorders of the liver or spleen, and chronic alcoholism. Treatment includes dietary supplementation with foods rich in the vitamins, and in cases of pernicious anemia where gastrointestinal B-12 absorption is poor, lifelong injections of vitamin B-12.

Middle Ground

Anemias may also occur where the MCV is within normal range, between 80 fl to 100 fl. This condition, in which there are inadequate numbers of RBCs that lack sufficient hemoglobin, is called normocytic anemia, due the normal average size of the RBCs. The primary causes of normocytic anemia are those relating to an underlying chronic disease or a sudden blood loss event, such as during surgery. Fluid overload sustained from excessive intravenous fluids, high sodium intake, water retention, and pregnancy can result in a low hematocrit and symptoms of anemia. Normocytic anemia may also be caused by an underlying vitamin B-2 (riboflavin) or B-6 (pyroxidine) deficiency.^14,15 However, because vitamins B-2 and B-6 are readily found in fortified cereals, animal products, and milk in the U.S., deficiencies of these vitamins are rare. Conversely, patients that ingest mega-doses of vitamin B-6 in an effort to combat carpal tunnel syndrome place themselves at risk for B-6 toxicity, which can result in permanent symptoms of peripheral neuropathy.¹⁵

Some patients with an apparent normocytic anemia may really have concurrent microcytic and macrocytic anemias acting together, as can occur when there are simultaneous deficiencies in iron and vitamin B-12, which effectively normalizes the average size of the RBCs. When patient symptoms and history make clinicians suspect this may be the case, the red blood cell distribution width (RDW) must be analyzed in the CBC: When the RDW is elevated, it suggests that there is an abnormally large variation in the range of RBC sizes.

Normocytic anemia is also frequently seen in patients who have chronic renal failure, with as many as 60% of patients with chronic renal failure developing anemia.¹⁶ As the kidneys become progressively damaged, scarring begins to occur inside the kidneys, and the cells responsible for producing erythropoietin (the protein that enhances erythropoesis) die off. This typically occurs during Stage 3 kidney failure, when the glomerular filtration rate falls below 60 ml/minute.¹⁷ When kidney cells are unable to produce enough erythropoietin, the bone marrow does not receive the signal to produce enough RBCs, resulting in anemia that impairs the patient’s ability to participate in activities and quality of life.

Once damaged, the kidneys can no longer produce erythropoietin on their own, so ongoing treatment must include injections of recombinant human erythropoietin to stimulate formation of RBCs for the remainder of the patient’s life. The two forms of synthetic erythropoietin that are currently available are epoetin alfa (Procrit) and darbepoetin (Aranesp), which are given according to the patient’s hemoglobin levels on a weekly, twice monthly, or monthly basis. Patients will typically also need iron supplementation due to the increased iron utilization associated with replacement erythropoietin therapy. If iron stores are very low in the presence of chronic renal failure, the patient’s blood work may reflect the presence of a microcytic, rather than a normocytic, anemia. When the patient’s hemoglobin is found to be less than 8 g/dL, a blood transfusion may become necessary; however, transfusions are usually reserved for acute cases of blood loss following trauma or recent surgery, due to the potential for allergic reactions, fever, lung damage, and immune reactions.¹⁸ 

Anemia at a Glance

When patients exhibit signs and symptoms that include weakness, fatigue, pallor, dizziness, postural hypotension, or poor exercise tolerance, therapists must consider anemia as a possible cause. The true test for anemia is the CBC, which will help determine whether the patient has anemia, and if so, which type. The key measurements in the CBC include mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), and mean corpuscular hemoglobin concentration (MCHC). Chronic blood loss typically results in CBC trends that mirror iron deficiency anemia; in fact, patients diagnosed with iron deficiency anemia are advised to search for underlying causes of chronic blood loss (e.g., gastrointestinal bleeding, dysfunctional uterine bleeding, chronic renal failure) as the most likely etiology. When differentiating between B-12 and B-9 deficiency anemia, it is also important to compare MMA and Hcy levels to confirm which vitamin is deficient. Analyzing the number of reticulocytes (immature RBC freshly released from the bone marrow) is also useful in helping determine whether the anemia is caused by increased blood loss or accelerated destruction of RBCs: When the reticulocyte count is low, it can reflect problems in the bone marrow, which may necessitate a bone marrow biopsy to uncover the cause.⁵

Although anemia can occur at any age, the development of anemia becomes increasingly common with aging and affects approximately 11% of individuals age 65 and older and more than 20% of those older than 85.¹⁹ Overall, one-third of anemias in this cohort are attributed to nutritional causes (iron, B-9, and B-12 deficiencies), one-third to chronic disease or infection (chronic renal failure, cancer, autoimmune diseases), and one-third are ultimately unexplained. Older people who develop anemia are at increased risk for poor balance, falls, poor endurance, cognitive dysfunction, depression, congestive heart failure, functional dependence, and decreased life expectancy.²⁰ 

Anemia is generally asymptomatic when mild, but as untreated anemia progresses it can worsen existing medical conditions, impair quality of life, and may even become life-threatening. Regardless of age, it is important for therapists and patients alike to have routine blood work performed, and when the CBC report is printed, to be able to recognize trends and changes in each individual case so as to recommend appropriate intervention.