Chapter 32: Anemia

General Considerations

A. Adults

Anemia is defined as an abnormally low circulating red blood cell (RBC) mass, reflected by low serum hemoglobin (Hb). However, the normal range of Hb varies among different populations. For menstruating women, anemia is present if the Hb level is ≤11.6–12.3 g/dL. In men and postmenopausal women, anemia is present if the Hb level is ≤13.0-14.0 g/dL. Other factors, such as age, race, altitude, and exposure to tobacco smoke, can also alter Hb levels.

Anemia is usually classified by cell size (Table 32-1). Microcytic anemias, mean corpuscular volume (MCV) < 80 fL, are usually due to iron deficiency, chronic inflammation, or thalassemia. Macrocytic anemias, MCV > 100 fL, are classified as megaloblastic or nonmegaloblastic. Megaloblasts are seen with vitamin B₁₂ deficiency and folic acid deficiency. Nonmegaloblastic causes of macrocytosis include alcoholism, hypothyroidism, and chronic liver disease. Causes of normocytic anemia (MCV between 80 and 100 fL) are classified as either hemolytic or nonhemolytic.

B. Children

Normal Hb levels vary with age. At birth, mean Hb is ~16.5 g/dL. This level increases to 18.5 g/dL during the first week of life, followed by a drop to 11.5 g/dL by 1–2 months of age. This physiologic anemia of infancy is mediated by changes in erythropoietin levels. By 1–2 years of age, the Hb level begins to rise, to 14 g/dL in adolescent girls and 15 g/dL in adolescent boys. Thus, laboratory values in children should always be compared with age-appropriate norms.

Many inherited causes of anemia are discovered in infancy and childhood. It is therefore important to obtain a careful family history in an anemic child, especially if the episodes of anemia are intermittent. Sickle cell anemia, thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, and spherocytosis are examples of inherited forms of anemia.

Other elements of the history are also important when evaluating a child for anemia. Because infants with anemia can exhibit poor feeding, irritability, and tachycardia rather than classic adult symptoms and signs, these atypical features should be explored with the family. Nutrition should be evaluated carefully, with attention to dietary sources of vitamin B₁₂, folic acid, and iron. Potential sources of lead poisoning must also be considered. Finally, adolescents often require additional support and explanation. For instance, adolescent girls may not know what constitutes a normal menstrual period, so the specific number of tampons and pads used should be obtained.

IRON-DEFICIENCY ANEMIA

General Considerations

Iron deficiency is the most common cause of anemia. Approximately 2% of women and 1% of men develop anemia due to the deficiency.

The average adult has 2–4 g of stored iron. About 65% of this reserve is located in the RBCs, with the remainder in the bone marrow, liver, spleen, and other body tissues. Iron deficiency occurs when there is a net imbalance resulting from either excessive loss or poor intake.

Toddlers aged 1–3 years are vulnerable to iron-deficiency anemia. National surveys report rates as high as 15% in this age group.

Pathogenesis

Extracorporeal blood loss is the most common cause of iron-deficiency anemia. When RBCs are destroyed within the body, the reticuloendothelial system usually adequately recycles iron into the next generation of RBCs. Poor iron uptake, due to either poor nutrition or inadequate absorption, is a less common cause of iron-deficiency anemia.

Women develop iron deficiency more readily than men because of increased potential for iron loss. On average, women lose an additional 1 mg of iron each day in menstruation. Pregnancy, lactation, and delivery additionally cost a woman an average of 1000 mg of iron each.

In infancy, risk factors for iron deficiency are primarily dietary and include exclusive breastfeeding beyond 6 months without iron supplementation, prolonged bottle-feeding, and excessive cow’s milk consumption. However, other risk factors for iron deficiency in childhood include Hispanic ethnicity, poverty, and being overweight.

Prevention

The US Preventive Services Task Force (USPSTF) recommends primary prevention of iron-deficiency anemia by encouraging parents to breastfeed their infants and to include iron-enriched foods in the diet of infants and young children.

Although there is insufficient evidence to recommend for or against the routine use of iron supplements for healthy infants or pregnant women, the USPSTF does currently recommend screening for iron-deficiency anemia—using Hb or hematocrit—for both asymptomatic pregnant women and high-risk infants (B recommendation).

Clinical Findings

A. Symptoms and Signs

Iron deficiency can be asymptomatic, especially in the early stages. However, patients can present with varying degrees of any of the common symptoms associated with anemia, such as weakness, fatigue, dizziness, headaches, exercise intolerance, or palpitations. Possible signs on physical examination include tachycardia, tachypnea, and pallor, especially of the palpebral conjunctivae.

One symptom associated with iron deficiency in particular is pica—the craving for ice, clay, or other unusual substances that may or may not contain iron. Rare symptoms include koilonychia (“spoon nails”), blue sclerae, and atrophic glossitis. In childhood, iron-deficiency anemia has been associated with cognitive and motor delays.

B. Laboratory Findings

Hemoglobin levels can be normal in early iron deficiency. Mild deficiency yields Hb levels of 9–11 g/dL, whereas in severe deficiency levels can fall as low as 5 g/dL.

Serum iron levels below 60 μg/dL indicate iron deficiency. As iron stores are depleted, serum ferritin falls below 30 ng/dL. TIBC therefore rises above 400 μg/dL. Percent iron saturation, which is inversely proportional to TIBC, falls below ~15%.

Although serum ferritin levels are the most accurate measure of iron deficiency, it should be noted that ferritin is an acute-phase reactant that can be elevated during acute illnesses, chronic inflammatory states, or cancer.

The gold standard of iron deficiency is bone marrow examination, which shows absent iron reserves in affected patients.

Treatment

Iron can be increased in the diet. Foods particularly rich in iron include meats (especially liver) and fish. Whole grains, green leafy vegetables, nuts, seeds, and dried fruit also contain iron. Toddlers’ multivitamins commonly contain iron. Cooking with iron pots and pans also increases iron intake.

Oral iron therapy is available in the form of iron salts. One 300-mg tablet of iron sulfate, for example, delivers 60 mg of elemental iron. One 300-mg tablet of iron gluconate delivers 34 mg of elemental iron and may be better tolerated by some patients. Up to 180 mg of elemental iron can be given each day, depending on the degree of deficiency. Absorption of oral iron is dependent on many environmental factors. An acidic environment increases absorption; thus iron tablets are often given with ascorbic acid. For this same reason, antacids should be avoided within several hours of iron ingestion. Other substances that impair the absorption of iron include calcium, soy protein, tannins (found in tea), and phytate (found in bran). Side effects of oral iron therapy include gastrointestinal distress and constipation. For this reason, some physicians routinely prescribe an as-necessary stool softener along with each iron prescription.

Iron can be given intramuscularly or intravenously to patients who cannot tolerate oral iron because of gastrointestinal upset. This route may also be convenient for patients who have concurrent gastrointestinal malabsorption or ongoing blood loss, such as those with severe inflammatory bowel disease. Phlebitis, muscle breakdown, anaphylaxis, and fever are possible side effects of parenteral iron.

Specialist consensus is that efficacy of treatment should be tracked with a CBC and differential every 3 months for a year.

ANEMIA OF CHRONIC DISEASE

General Considerations

Many chronic diseases—such as cancer, collagen vascular disease, chronic infections, diabetes mellitus, and coronary artery disease—can be associated with anemia (Table 32-2).

Pathogenesis

In spite of shortened RBC survival, bone marrow RBC production is low. This is thought to be due to (1) trapping of iron stores in the reticuloendothelial system, (2) a mild decrease in erythropoietin production, and (3) impaired response of the bone marrow to erythropoietin.

Clinical Findings

A. Symptoms and Signs

The anemia of chronic disease (ACD) is often mild and therefore general anemic symptoms, such as fatigue, dizziness, and palpitations, can be mild or nonexistent. Signs such as pallor of the palpebral conjunctivae are only sometimes present. The condition must therefore be suspected and investigated in patients known to have underlying conditions such as collagen vascular diseases, cancers, or chronic infections. The condition is often diagnosed incidentally on laboratory reports.

B. Laboratory Findings

Hemoglobin levels are generally mildly decreased (10–11 g/dL), but levels can occasionally be <8 g/dL. RBCs are often hypochromic. MCV can be either normal (80–100 fL) or low (<80 fL). Because RBC production is poor, the absolute reticulocyte count is often low (<25,000/μL). Acute-phase reactants such as erythrocyte sedimentation rate (ESR), platelets, and fibrinogen can be elevated.

Because ACD is associated with decreased production of transferrin, serum iron level and TIBC are often both low. Calculated percent saturation, however, remains normal. This is to be distinguished from iron-deficiency anemia, in which TIBC is often high, resulting in low-percent saturation. Serum ferritin level is high or normal in ACD but low in iron- deficiency anemia.

Treatment

Treatment of ACD should be aimed at the underlying condition. Symptomatic patients or heart patients often require packed transfusions of RBCs, especially if the HBG count is <10 mg/dL. Erythropoietin is also used to correct anemia associated with certain chronic diseases, especially cancer.

THALASSEMIA

General Considerations

A normal adult Hb molecule, also known as HbA, consists of two α Hb chains and two β Hb chains. The thalassemias are the diverse group of genetic diseases resulting from abnormal Hb, classified as α-thalassemias or β-thalassemias, based on the abnormal gene.

Other Hb chains exist, such as γ and δ chains. Fetal Hb consists of two α chains and two γ chains (α₂γ₂), and HbA₂ consists of two α chains and two δ chains (α₂δ₂). Although ordinarily these lesser types of Hb constitute ≤5% of the total amount of Hb, the thalassemias are characterized by increased proportions of non-A Hb because of defective α or β chains.

Thalassemia traits are more common in those of Mediterranean, African, and South Asian ancestry. This is due at least in part to the fact that these parts of the world are inhabited by Plasmodium species, and heterozygous thalassemic traits confer survival advantage to those afflicted with malaria.

Pathogenesis

Because there are four α Hb genes per individual (two on each copy of chromosome 16), there are four major types of α-thalassemia. If only one α Hb gene is damaged, the result is called α-thalassemia minima, an essentially asymptomatic condition. Damage to two different α Hb genes results in α-thalassemia minor, which has only mild clinical significance. Three damaged α Hb genes can lead to a relative abundance of α Hb, causing an abundance of Hb β₄, also known as HbH. This disorder, also called hemoglobin H disease, is characterized by severe clinical manifestations of chronic hemolysis, hospitalizations, and decreased lifespan. Absence of normal α Hb chains causes Hb Barts disease and is fatal in utero.

The two β Hb genes are found on chromosome 11. If one is damaged, β-thalassemia minor results, with few clinical effects. Infants with two damaged copies of β Hb will be phenotypically normal at birth because of the predominance of fetal Hb (α₂γ₂). Affected infants become severely symptomatic in the first year of life: 80% of patients die in the first 5 years of life as a result of severe anemia, high-output congestive heart failure, or infection.

Clinical Findings

A. Symptoms and Signs

α-thalassemia minima is almost always asymptomatic. α-thalassemia minor can be accompanied by occasional mild symptoms of anemia, including headaches, fatigue, and dizziness. Patients with HbH disease, however, often exhibit severe clinical manifestations of chronic hemolytic anemia, including hepatosplenomegaly and cholelithiasis. These patients often require chronic transfusions, usually beginning in late childhood and adolescence. The clinical appearance of β-thalassemia minor often mimics that of mild or moderate iron deficiency, and often laboratory findings are necessary to distinguish the two. β-thalassemia major, however, results in a severe phenotype. Widespread hemolysis in these patients causes pallor, irritability, jaundice, and hepatosplenomegaly.

B. Laboratory Findings

As with iron deficiency, Hb levels and MCV are often low with the thalassemias. In contrast to iron deficiency, however, thalassemias are usually characterized by an elevated RBC count. Furthermore, the decrease in MCV is often more exaggerated in the thalassemias; levels as low as 50–60 fL are not unusual. The red cell distribution width (RDW) can also be used to distinguish the two conditions. With iron deficiency, the RDW is elevated due to a variety of cell sizes, whereas the RDW is usually normal in thalassemic patients because RBCs are uniformly small.

Hemoglobin electrophoresis should be conducted on any patient with suspected thalassemia. Although some patients with α-thalassemia minima or media can have normal electrophoresis patterns, abnormalities are often seen in other thalassemic patients. In β-thalassemia minor, for example, relative proportions of fetal Hb (α₂γ₂) and HbA₂ are increased

Treatment

Patients with α-thalassemia minor, α-thalassemia minima, and β-thalassemia minor are generally asymptomatic and should be treated only if necessary. These patients may require blood transfusions under certain conditions, such as after vaginal delivery or surgery.

Patients with β-thalassemia major and HbH disease, however, require the care of a hematologist. These patients may require frequent transfusions, splenectomy, or both. Iron overload is a frequent complication in these patients, those both with and without transfusion therapy. Chelation therapy is often required to avoid end-organ damage in the heart, endocrine organs, and liver. Patients with a personal or family history of thalassemia should be offered genetic counseling when planning a family.

VITAMIN B₁₂ DEFICIENCY

General Considerations

Vitamin B₁₂ (cobalamin) is involved in two important enzymatic reactions: the conversion of methylmalonylcoenzyme A (CoA) to succinyl-CoA and the methylation of homocysteine to methionine. This latter reaction is required for synthesis of thymidine, a component of DNA.

Because vitamin B₁₂ is present in all animal products, only people with unusual diets (vegans, fad dieters) receive inadequate intake. These individuals should receive vitamin B₁₂ supplementation. Some special populations, such as pregnant women and those who have had bariatric surgery, may require increased levels of vitamin B₁₂.

Pathogenesis

When vitamin B₁₂ deficiency is not due to inadequate dietary intake, it usually reflects a defect in the B₁₂ absorption and transport chain. Vitamin B₁₂ is transported from the stomach to the jejunum by the intrinsic factor (IF), a protein produced in gastric parietal cells. Pernicious anemia occurs when autoantibodies against parietal cells are produced, resulting in a lack of intrinsic factor and inadequate uptake of vitamin B₁₂.

Clinical Findings

A. Symptoms and Signs

Many clinical features are common to all megaloblastic anemias: anemia, pallor, weight loss, fatigue, glossitis, lightheadedness, jaundice, and abdominal symptoms. Neurologic symptoms are specific to vitamin B₁₂ deficiency, however, beginning with paresthesias in the hands and feet. Disturbances in vision, taste, smell, proprioception, and vibratory sense can also occur. Untreated, vitamin B₁₂ deficiency can lead to posterior spinal column demyelination, resulting in spastic ataxia and dementia mimicking that of Alzheimer disease. These changes are often irreversible. Vitamin B₁₂ deficiency can also lead to psychotic depression and paranoid schizophrenia.

B. Laboratory Findings

The MCV is usually >100 fL, and vitamin B₁₂ levels are usually <100 pg/mL. The higher the MCV, the more likely the diagnosis. Lactate dehydrogenase and indirect bilirubin can be modestly elevated because of increased RBC destruction. The reticulocyte count can be depressed. Because DNA synthesis affects all cell lines, pancytopenia can occur. Peripheral blood smear can show markedly abnormal RBCs along with hypersegmented neutrophils, which are pathognomonic for megaloblastic anemia.

The presence of anti–intrinsic factor (IF) antibodies confirms the diagnosis of pernicious anemia. There is evidence suggesting that early or asymptomatic vitamin B₁₂ deficiency can be diagnosed by elevated levels of methylmalonic acid (as sensitive as but more specific than serum homocysteine). Increased levels of methylmalonic acid confirm B₁₂ deficiency.

The Schilling test, although rarely used today, has historically been used to confirm the diagnosis of pernicious anemia. It involves following the percentage absorption of radiolabeled vitamin B₁₂, with and without the administration of IF.

Treatment

Historically, treatment required monthly parenteral treatment of vitamin B₁₂ in doses of 100–1000 μg, usually administered daily or every other day for the first few weeks, followed by maintenance doses every 1–3 months. Once vitamin B₁₂ levels have been reestablished, oral therapy (1 mg/d) would be substituted. Recent evidence shows that oral therapy alone, 1–2 mg daily for 90–120 days is equivalent to IM treatment. Treatment often also consists of concurrent administration of folate, 1–5 mg each day.

FOLIC ACID DEFICIENCY

General Considerations

In contrast to vitamin B₁₂ reserves, which can last 3–5 years, folate reserves last only 4–5 months. The human body requires ~75–100 μg/d of folic acid, which is present in leafy green vegetables, fruits, nuts, beans, wheat germ, and liver. Like vitamin B₁₂, folate is involved in the synthesis of thymidine.

Pathogenesis

Folic acid deficiency can occur as a result of decreased intake, especially in alcoholics and patients with atypical diets. Malabsorption can also affect intake of folate. Because small intestine microvilli convert the ingested complex folic acid molecule into an absorbable one, diseases of the small intestine, such as gluten enteropathy and Crohn disease, can cause deficiency. Drugs such as anticonvulsants and oral contraceptives also predispose to folate malabsorption. Other medications (eg, antineoplastic agents, trimethoprim, and certain antimalarial drugs) inhibit the enzyme necessary for the replenishment of intracellular folate and can affect folate levels.

Folate deficiency can also result if increased requirements are not met. Pregnancy, for instance, increases folate requirements 5–10-fold by the third trimester. Patients with hemolytic anemia and exfoliative skin diseases also have increased requirements and should receive supplementation. Because folate is dialyzable, patients on dialysis can suffer from folate deficiency if they do not receive supplementation.

Folate deficiency is common among alcoholics for several reasons. First, although some folic acid is present in beer, alcoholics tend to consume less of other foods rich in folic acid, such as leafy green vegetables. Alcohol can also adversely affect intracellular processing of folate. Finally, alcohol may suppress bone marrow function.

Clinical Findings

A. Symptoms and Signs

Patients with mild folate deficiency often present with anemia on a routine blood screening. Those with more severe disease can present with pallor, weight loss, fatigue, glossitis, lightheadedness, jaundice, or abdominal symptoms, as in vitamin B₁₂ deficiency. In contrast to vitamin B₁₂ deficiency, however, neurologic symptoms are absent.

B. Laboratory Findings

Many laboratory findings are similar to those of vitamin B₁₂ deficiency: Hb levels can be variably depressed, pancytopenia can occur, and hypersegmented neutrophils can be seen on the peripheral blood smear. Also as with vitamin B₁₂ deficiency, examination of the bone marrow can show erythroid hyperplasia and marked asynchrony in maturation between cytoplasmic components and nuclear material.

With folate deficiency, however, serum and RBC folate levels are low, whereas vitamin B₁₂ levels are normal. RBC folate—which is low at <150 pg/L—is considered to be a more precise indicator of chronic folate deficiency than serum folate. In cases where diagnosis remains in doubt, an elevated homocysteine level, despite a normal methylmalonic acid level, suggests folate deficiency.

Treatment

Foods rich in folic acid should be consumed, which include leafy green vegetables, fruits, nuts, beans, wheat germ, and liver. Supplementation with oral folic acid—ranging from 1 to 5 mg daily—is used to treat deficiency. Total correction often occurs within 6–8 weeks. Patients with increased folate requirements, such as pregnant women, should receive supplementation. Some authorities recommend treating all patients with macrocytic anemia, regardless of cause, with empirical addition of folic acid.

HEMOLYTIC ANEMIA

Hereditary Spherocytosis

General Considerations & Pathogenesis

Hereditary spherocytosis (HS) is the most common inherited defect of the RBC membrane. Patients with this condition inherit one of a series of mutations of the structural proteins of the RBC membrane,. The resulting decreased membrane elasticity causes loss of the normal biconcave shape of the RBC. These deformed, spherical RBCs are then detained and phagocytosed in the narrow fenestrations of the splenic cords. Less common related defects also exist, including hereditary elliptocytosis and hereditary stomatocytosis.

Clinical Findings

A. Symptoms and Signs

Hereditary spherocytosis can be classified as mild, moderate, or severe. Individuals with mild disease rarely manifest symptoms and signs. Increased erythropoietin levels compensate for early destruction of RBCs. Individuals with moderate disease represent 60–75% of HS patients and can develop intermittent episodes of jaundice, dark urine, abdominal pain, and splenomegaly in infancy or early childhood. Individuals with severe disease have more marked jaundice and splenomegaly.

If bilirubin levels are chronically elevated, bilirubin gallstones can form, leading to right upper quadrant abdominal pain and tenderness, nausea, and a positive Murphy sign.

B. Laboratory Findings

Patients with moderate and severe disease often have low Hb, reticulocyte counts between 5% and 20%, and elevated serum bilirubin level.

The mean corpuscular Hb concentration (MCHC) is a useful test in diagnosing HS. It is generally elevated to 36 g/dL in patients with HS, reflecting decreased membrane surface area and increased Hb concentration in the RBC.

The peripheral blood smear of a patient with HS shows characteristic spherocytes—small RBCs that have lost their central pallor. Special tests can also be used to evaluate patients for HS. The osmotic fragility test involves suspending a patient’s RBCs in increasingly dilute salt solutions and observing for cell lysis. RBCs from patients with HS will be more sensitive to hypotonic solutions because of membrane instability. The newer acidified glycerol lysis test is also used.

Treatment

Patients with moderate disease may need blood transfusions; however, for patients with severe disease, regular transfusions are essentially unavoidable. Folic acid supplementation is useful for patients with this and other hemolytic diseases.

The definitive treatment is splenectomy, which leads to significantly increased RBC lifespan. For patients who have had a splenectomy, immunization against Pneumococcus and Meningococcus is recommended for secondary prevention of sepsis.

Glucose-6-Phosphate Dehydrogenase Deficiency

General Considerations

The World Health Organization (WHO) classifies glucose-6-phosphate dehydrogenase (G6PD) deficiency into five variants, from class I (the most severe enzyme deficiency) to class V (no clinical significance). The deficiency is most common in people of African and Mediterranean heritage. Although it is seen primarily in men, as are most X-linked disorders, women who carry the defective gene can also manifest symptoms, due to inactivation of their normal X chromosomes.

Overall, G6PD deficiency is the most common enzymatic disorder of RBCs in humans and affects 200–400 million people. Less common enzymatic deficiencies also exist. Pyruvate kinase deficiency, for example, has a similar clinical presentation.

The most common variants are G6PD A and G6PD Mediterranean. G6PD A is a variant in which patients have 10–60% of the normal level of G6PD and therefore experience intermittent hemolysis, generally associated with infections or drugs. G6PD Mediterranean also generally manifests with intermittent hemolysis, but the enzyme deficiency is usually more severe (eg, ~10% of normal enzymatic activity).

Pathogenesis

Glucose-6-phosphate dehydrogenase is a cytoplasmic enzyme that prevents oxidative damage to RBCs by reducing nicotinamide adenine dinucleotide phosphate (NADP) to NADPH. Individuals who are deficient in this enzyme are more susceptible to damage from oxidative substances such as superoxide anion (O₂⁻) and hydrogen peroxide. In addition to being normal byproducts of cell metabolism, these substances are produced by certain drugs, household chemicals, and foods.

Clinical Findings

Persons affected with G6PD deficiency are often asymptomatic. However, a spectrum of clinical manifestations can occur, from infrequent mild episodic hemolysis to severe chronic hemolysis.

A. Symptoms and Signs

The most common clinical manifestations are jaundice, dark urine, pallor, abdominal pain, and back pain. These symptoms usually occur hours to days after an oxidative insult, which can be caused by a number of different agents. Chemicals that can cause such an insult include primaquine, sulfa drugs, dapsone, nitrofurantoin, and naphthalene (found in mothballs). Antimalarials, aspirin, and acetaminophen can precipitate hemolysis in certain individuals as well. Attacks can also be associated with infections (such as pneumonia, viral hepatitis, and Salmonella) and diabetic ketoacidosis. Finally, foods such as fava beans have been implicated. These beans are common in the Mediterranean and are harvested in late spring.

Infants with G6PD deficiency can also present with jaundice. Again a spectrum of disease exists, from mild transient jaundice to severe jaundice, kernicterus, and death. Those with class I G6PD deficiency can have lifelong, life-threatening chronic hemolysis.

B. Laboratory Findings

Hemoglobin levels mirror the severity of disease.

During periods of active hemolysis, other laboratory measures can be abnormal. The absolute reticulocyte count is elevated above 2–3%, and sometimes above 10–15%. Haptoglobin levels are often depressed below 50 mg/dL, as this plasma protein binds Hb released from fragmented RBCs.

The peripheral blood smear in G6PD deficiency shows characteristic Heinz bodies, which represent masses of denatured, damaged Hb. “Bite cells,” which appear as RBCs with a small semicircular defect, can also be seen. The definitive test for G6PD deficiency is an enzymatic assay that measures in vitro production of NADPH.

Treatment

Individuals with mild disease require no treatment except for avoidance, whenever possible, of oxidative triggers. Individuals with more severe disease may require inpatient treatment of acute exacerbations with transfusion, intravenous fluid support, and monitoring of renal function. Although vitamin E and splenectomy have been advocated as possible treatments in more severe cases, neither has provided consistent benefit.

Sickle Cell Anemia

General Considerations

Sickle cell anemia (SCA) is a common genetic disorder. Traits that lead to SCA are common in those with African and South Asian heritage. The gene frequency for SCA in African Americans is approximately 4%.

A spectrum of other sickle cell syndromes exists. HbC results from a different mutation in the β Hb chain. Patients with HbSC disease have one of each mutation and generally experience a milder phenotype than those with homozygous sickle cell anemia (HbSS). Patients with the HbSA genotype have one sickle cell gene and one regular gene. They tend to have mild, if any, clinical manifestations of disease. Other permutations of abnormal Hb genes can cause similar syndromes. Patients with one sickle cell gene and one β-thalassemia gene, for example, can have significant clinical manifestations of hemoglobinopathy.

Pathogenesis

Patients with SCA are homozygous for a mutation in the β Hb chain. The resulting HbS, which consists of two normal α Hb chains and two abnormal β Hb chains, is poorly soluble when deoxygenated. The polymerization of HbS into elongated fibers within the RBC leads to the characteristic “sickle” shape. These abnormal RBCs occlude capillary beds and lead to the many clinical manifestations of SCA.

Prevention

Newborn screening for HbSS, HbSA, and HbSC is highly recommended and required by law throughout the United States. Several prophylactic measures can reduce the likelihood of pain crises and other manifestations of disease in patients with SCA (ie, secondary prevention). First, adequate hydration and oxygenation reduce the risk of Hb polymerization and subsequent vasoocclusive crises. Folic acid should be supplemented, 1 mg orally every day. Some physicians recommend hydroxyurea, which seems to reduce the likelihood of RBC sickling by stimulating production of fetal Hb. Infectious complications can be reduced by immunization against Streptococcus pneumoniae, Haemophilus influenzae type B, hepatitis B, and influenza. Daily oral penicillin prophylaxis should be given until age 5 years. Use of penicillin prophylaxis, along with intensive medical care, has reduced the mortality of SCA from 25% to 3% during the first 5 years of life.

Clinical Findings

A. Symptoms and Signs

Patients with homozygous SCA manifest disease early. Approximately 30% of patients are discovered by 1 year of age and >90% by 6 years of age. Acute pain episodes are the most common presentations; they can occur in the extremities, abdomen, back, or chest. Although generally no inciting factor is found, stresses such as cold, infection, and dehydration can precipitate attacks. Fever, joint swelling, vomiting, and tachypnea can accompany pain episodes.

Most patients experience autoinfarction of the spleen by early childhood due to occlusion of splenic capillary beds. For this and other reasons, patients with SCA are significantly vulnerable to infection, especially from encapsulated pathogens such as S. pneumoniae and H. influenzae. Pneumonia, meningitis, osteomyelitis, and bacteremia are causes of significant morbidity and mortality in these patients.

Pulmonary complications are the most common causes of death in patients with SCA. RBCs in the pulmonary system are particularly vulnerable to sickling because of its low PO₂ and relatively low blood pressure. Acute chest syndrome refers to the clinical triad of chest pain, pulmonary infiltrate on x-ray, and fever, which can be due to pulmonary infarction, pneumonia, or both.

Sickled RBCs can occlude vasculature and cause infarction of nearly any tissue in the body. Therefore, other serious manifestations of SCA include stroke, myocardial infarction, bone infarction, retinopathy, leg ulcers, and priapism. Depression, low self-esteem, and social withdrawal are common, especially when adequate coping mechanisms are not in place.

B. Laboratory Findings

Laboratory findings often reflect the chronic hemolysis that accompanies SCA. Classically the patient has a reticulocyte count increased to 3–15%, Hb mildly or moderately decreased to 7–11 g/dL, elevated direct bilirubin and lactate dehydrogenase, and a depressed haptoglobin level.

The peripheral blood smear shows sickling of half of the RBCs. Howell-Jolly bodies and target cells are also present on the smear, indicating hyposplenism. The white blood cell count can be elevated at 12,000–15,000/mm³, even in the absence of infection.

Treatment

Despite the preventive measures discussed earlier, most patients with SCA require frequent hospitalization for acute painful vasoocclusive crises or infectious complications. During acute exacerbations, patients often require hydration and oxygenation, analgesia with nonnarcotic or narcotic medications, antibiotics if appropriate, and blood transfusions.

Autoimmune Hemolytic Anemia

General Considerations

Autoimmune hemolytic anemia (AIHA) results when a patient produces antibodies directed against the body’s RBCs AIHA can be classified by the temperature at which the antibodies are most reactive. “Warm” autoantibodies bind most strongly near 37°C (98.6°F), whereas “cold” autoantibodies bind RBCs near 0–4°C (32–39.2°F). Occasionally, a mixture of both types of autoantibodies is present.

Pathogenesis

Although the production of autoantibodies is idiopathic in nearly 50% of cases, at other times an inciting factor can be found. Lymphoproliferative disorders such as chronic lymphoblastic leukemia and autoimmune disorders such as rheumatoid arthritis, for example, can induce production of either warm or cold autoantibodies. Infections such as Mycoplasma and syphilis have been implicated, primarily in cold AIHA. Transfusion reactions are mediated by a similar process.

Medications can induce a warm antibody autoimmune reaction. Some drugs, such as methyldopa, alter RBC antigens so that they become targets of the host immune system. Other drugs bind with RBC antigens to form immunogenic complexes. This “hapten” reaction can occur with penicillin as well as a variety of other drugs.

Prevention

Any patient who receives a splenectomy should also receive secondary prevention in the form of immunizations against Pneumococcus, Haemophilus, and Meningococcus.

Clinical Findings

A. Symptoms and Signs

Overall, a wide spectrum of possible manifestations exists. A typical patient with AIHA presents with pallor, fatigue, or headaches due to loss of circulating RBCs. Jaundice may also be present, due to elevation of indirect bilirubin resulting from the release and breakdown of RBC heme. A patient may also have splenomegaly due to increased sequestration of damaged RBCs within the splenic cords of Billroth. In some cases, hemoglobinuria can lead to renal failure. The rate of disease progression depends on the underlying cause of hemolysis. Although clinical manifestations progress slowly in some patients, in others severe symptoms can develop in a matter of hours.

B. Laboratory Findings

A positive direct Coombs test helps diagnose AIHA.

Other laboratory findings reflect the general hemolytic process. Levels of bilirubin and lactate dehydrogenase are increased, haptoglobin levels tend to decrease, and the corrected reticulocyte count is increased. Other appropriate laboratory investigations specific to underlying causes—such as collagen vascular diseases, cancer, and infections—may be warranted.

Treatment

Although further hemolysis can result, blood transfusion should be given when the Hb level is significantly low (5–7 g/dL). Corticosteroids are often considered the treatment of choice, especially when autoantibodies are warm. Those who need long-term treatment and cannot take steroids can use other immunomodulating agents such as azathioprine, cyclosporine, and rituximab. Intravenous immunoglobulin is advocated for the acute treatment of adults with AIHA, but it is not as effective in children. Exchange transfusion, which not only delivers new RBCs but also removes destructive autoantibodies and complement, can also be useful. Splenectomy should be considered in refractory cases; as previously noted, any patient who receives a splenectomy should also receive immunizations against Pneumococcus, Haemophilus, and Meningococcus. Finally, underlying disorders should be treated as appropriate.

Extrinsic Nonimmune Hemolytic Anemia

There are many causes of extrinsic hemolysis not related to immunity (Table 32-3). The first group of conditions results from mechanical damage to RBCs. Any process that enlarges the spleen, for instance, can lead to an acquired hemolytic process because the spleen is the major organ recycling RBCs. Mechanical damage can also occur as RBCs rush past a prosthetic valve or other internal machinery. Disseminated intravascular coagulation and thrombotic thrombocytopenic purpura can result in hemolysis of RBCs that flow through areas of intravascular coagulation. Mechanical destruction of RBCs can also be due to exposure to heat, burns, or even repeated trauma such as that encountered in the feet while marching long distances.

Infectious diseases such as malaria, babesiosis, and leishmaniasis can also cause an acquired hemolysis. This is due to both to direct parasitic action and increased activity of macrophages within the spleen.

Finally, drugs and toxins can lead to hemolysis. Medications such as primaquine, dapsone, nitrites, and even topical anesthesia can induce oxidative stress, damaging RBCs. This can occur even in patients without G6PD deficiency. Toxins such as lead, copper, and arsine gas, as well as venom from snakes, insects, and spiders, can also cause hemolysis.

Symptoms and signs, laboratory findings, and treatments will be based on the specific diagnosis. Rather than a specific disorder, extrinsic nonimmune hemolytic anemia is a general categorization of heterogeneous disease processes.

NONHEMOLYTIC ANEMIA

Aplastic Anemia

General Considerations

Aplastic anemia is characterized by the suppression of all bone marrow lines—erythroid, granulocytic, and megakaryocytic—leading to pancytopenia. Most commonly the disorder is idiopathic. However, drugs, toxins, radiation, infections (eg, hepatitis, parvovirus), and pregnancy can all induce aplastic anemia. Although it is uncommon—affecting only two to four persons per million per year—it is often an important consideration for differential diagnoses for undiagnosed anemias.

Pathogenesis

The etiology is unclear. Although some causative agents have been shown to be directly toxic to the bone marrow, others seem to induce an autoimmune process. The specific etiology plays a role in prognosis; drug-induced aplastic anemia carries a more favorable prognosis than idiopathic aplastic anemia. The more severe the pancytopenia, the worse is the prognosis.

Clinical Findings

A. Symptoms and Signs

Anemia leads to pallor, fatigue, and weakness. Neutropenia increases susceptibility to bacterial infections. Thrombocytopenia can present as mucosal bleeding, easy bruising, or petechiae. Splenomegaly is common in advanced disease.

B. Laboratory Findings

Pancytopenia is the hallmark of aplastic anemia. The associated anemia can be severe and is generally normocytic. The reticulocyte count is often low. The white blood cell count can be lower than 1500/mm³, and the platelet count is generally <150,000/mL. Bone marrow aspirate, which reveals marrow hypocellularity, is essential to the diagnosis of aplastic anemia and important in distinguishing it from other causes of pancytopenia.

Treatment

Fever or other signs of infection should be aggressively investigated. Often, empiric broad-spectrum antibiotics should be used. Other means of decreasing risk of infection include the use of stool softeners and antiseptic soaps. Menstrual blood loss can be suppressed with oral contraceptive pills. Although replacement of blood products is often necessary, it should be used as little as possible, to avoid sensitizing potential candidates for bone marrow transplantation. Hematopoietic growth factors (erythropoietin and granulocyte colony-stimulating factor) are seldom used, due to transient or nil effect.

In a patient aged <50 years with a human leukocyte antigen (HLA)-matched sibling, immediate bone marrow transplantation is the treatment of choice. The toxicity associated with treatment increases with age, along with the risk of graft-versus-host disease. If successful, transplantation is curative. The 5-year survival rate is approximately 70%.

In those lacking matched siblings or those aged >50 years, treatment consists of immunosuppression with antithymocyte globulin, augmented with high-dose cyclosporine. Most patients relapse, but remission rates with additional antithymocyte globulin treatments are encouraging. Survival at 5 years is ~75%.

Anemia of Chronic Renal Insufficiency

General Considerations

Although anemia of chronic renal insufficiency (CRI) commonly occurs in patients with a creatinine clearance of 30 mL/min per ≤1.73 m², it can appear in patients with serum creatinine as low as 2 mg/dL.

Clinical Findings

A. Symptoms and Signs

Patients may exhibit bleeding or bruising due to thrombocytopenia and platelet dysfunction. Pallor and fatigue are also common. Early symptoms of uremia include nausea, vomiting, weight loss, malaise, and headache. As the blood urea nitrogen (BUN) level rises, paresthesias, decreased urine output, and waning level of consciousness can be seen. Other signs and symptoms depend on the etiology of the patient’s renal insufficiency.

B. Laboratory Findings

Blood urea nitrogen and serum creatinine are generally both elevated, above 30 and 3.0 mg/dL, respectively. The anemia tends to be normocytic and normochromic, but in some cases it can be microcytic. Hyperphosphatemia, hypocalcemia, and hyperkalemia can occur, as can metabolic acidosis. Reticulocyte count tends to be normal or decreased. Bone marrow is inappropriately normal for the degree of anemia.

Treatment

Treatment involves erythropoietin replacement. Erythropoietin or darbepoetin is indicated when the Hb level is ≤10 g/dL. Darbepoetin has a longer half-life and more predictable bioavailability. Prior to initiation of therapy, the patient should be screened and treated for deficiency of iron, folate, and vitamin B₁₂ as well as for occult blood loss.

Erythropoietin is given at 80–120 U/kg per week. The most common side effect of erythropoietin therapy is hypertension. The target Hb level is 11–12 g/dL.

Anemia Associated with Marrow Infiltration

General Considerations

The bone marrow can tolerate fairly extensive infiltration. When marrow infiltration causes anemia or pancytopenia, however, it is referred to as myelophthisic anemia. The most common cause of myelophthisic is metastatic carcinoma of the lung, breast, or prostate. Other causes include hematologic malignancies (leukemia, lymphoma), infections (tuberculosis, fungi), and metabolic diseases (Gaucher disease, Niemann-Pick disease).

Clinical Findings

A. Symptoms and Signs

Anemia is most commonly manifested by pallor or fatigue. Thrombocytopenia can cause petechiae, bleeding, or bruising. Neutropenia can lead to frequent or atypical infections. Fractures, bony pain, bony tenderness, hepatomegaly, and splenomegaly may occur. Other presenting signs and symptoms are usually related to the underlying cause of marrow infiltration.

B. Laboratory Findings

The anemia tends to be normocytic and mild to moderate. White blood cells and platelets may also be decreased. Because of the hypocellular marrow, aspirate often yields few cells (“dry tap”).

Treatment

Treatment targets the underlying disease. Successful treatment of the malignancy, through radiation, chemotherapy, or bone marrow transplantation, can resolve the anemia. Erythropoietin or blood transfusion may be used to augment the RBC count. Platelet transfusions may be needed. The prognosis in patients with marrow metastases is generally poor.