Erythropoiesis

About 1% of the circulating erythrocyte mass is generated by the bone marrow each day. Precursors of RBCs are reticulocytes, which account for 1% of the total RBC count. The normal RBC is about 33% hemoglobin by volume. Hemoglobin (Hb), the oxygen-carrying molecule of erythrocytes, consists of two pairs of globin chains (i.e., α plus β, δ, or γ) that form a shell around four oxygen-binding heme groups. Healthy adults have about 95% HbA (α2β2) and small amounts of HbA2 (α2δ2) and HbF (α2γ2). Genes on chromosome 16 encode α globin chains; β chains are encoded on chromosome 11.⁵ Oxygen demand (hypoxia) serves as the stimulus for erythropoiesis. The kidney serves as the primary sensor for determining the level of oxygenation. If the level is low, the kidney releases erythropoietin, a hormone that stimulates the bone marrow to release RBCs. About 95% of erythropoietin is produced by cortical cells in the kidney. The other 5% is produced by the liver.^6,7

Etiology

Anemia has numerous causes (Table 22-1). A partial list includes genetic disorders that produce aberrant RBCs that result in RBC destruction (hemolysis), nutritional disorders that limit the production of RBCs, immune-mediated disorders that result in attacks on RBCs, bleeding disorders that cause loss of RBCs, chronic diseases (rheumatoid arthritis), infections, and diseases of bone marrow. Figure 22-1 shows the most common causes of anemia found in general medical practice.⁸ This chapter discusses select examples relevant to the practice of dentistry, to demonstrate the clinical problems involved in the management of patients with anemia.

TABLE 22-1 Types of Anemia

fL, Femtoliter; MCV, Mean corpuscular volume; RBC, Red blood cell.

* Also expressed in µm³ units.

FIGURE 22-1 Relative frequencies of anemia in clinical practice.

(Redrawn from Hillman RS, Finch CA, editors: Red cell manual, ed 7, Philadelphia, 1996, FA Davis.)

Iron Deficiency Anemia

Iron deficiency anemia is a microcytic anemia (Figure 22-2) that can be caused by excessive blood loss, poor iron intake, poor iron absorption, or increased demand for iron. Blood loss may occur with menstruation or be caused by bleeding from the gastrointestinal tract. Poor intake is more common in children who live in developing countries, where cereals and formula fortified with iron are not readily available. Malabsorption of iron can result from gastrectomy or intestinal disease that reduces absorption of iron from the duodenum and the jejunum. Increased demand is associated with chronic inflammation (autoimmune disease).

FIGURE 22-2 Microcytic anemia associated with iron deficiency. Peripheral blood smear shows red blood cells (RBCs) that are small and have marked hypochromic central pallor.

In women, menstruation and pregnancy contribute to the development of iron deficiency anemia. The repeated loss of blood associated with menses can lead to depletion of iron, resulting in a mild state of anemia. During pregnancy, the expectant mother experiences an increased demand for additional iron and vitamins to support the growth of her fetus, and unless sufficient amounts of these nutrients have been provided in some form, she may become anemic. Approximately 20% of pregnant women have iron deficiency anemia.¹¹ Also, 30% to 60% of persons with rheumatoid arthritis (who more commonly are women) have this type of anemia.¹²

By contrast, mild anemia in men usually indicates the presence of a serious underlying medical problem (e.g., gastrointestinal bleeding, malignancy). Under normal physiologic conditions, men lose little iron, and because iron can be stored for months, iron deficiency anemia is rare in men. Therefore, any man who is found to be anemic should be promptly referred for medical evaluation.

Folate Deficiency Anemia and Pernicious Anemia

Vitamin B₁₂ (cobalamin) and folic acid are needed for RBC formation and growth within bone marrow. Vitamin B₁₂ is a cofactor in methionine-associated enzymatic reactions required of protein synthesis and thus in the maturation of RBCs. Folate is needed for enzymatic reactions required for the synthesis of purines and pyrimidines of deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) and thus for the synthesis of proteins. A deficiency in daily intake (as in chronic alcoholism) or absorption (due to celiac disease or tropical sprue) of these vitamins can result in anemia.

Folate is found in fruits and leafy vegetables. It is not stored in the body in large amounts, so a continual dietary supply is needed. Its absorption and metabolism are interfered with by alcohol consumption and certain drugs (methotrexate, phenytoin [Dilantin]). Risk factors for folate deficiency include poor diet (seen frequently in the poor, elderly persons, and people who do not eat fresh fruits or vegetables), alcoholism, history of malabsorption disorders, and pregnancy (especially the third trimester). Folate deficiency anemia occurs in about 4 of 100,000 people.

Pernicious anemia is caused by a deficiency of intrinsic factor, a substance secreted by the stomach parietal cells that is necessary for absorption of vitamin B₁₂ (cobalamin). Because vitamin B₁₂ may be stored for several years, this form of nutritional deficiency is rare and usually does not develop until late adulthood. Most often, it occurs in 40- to 70-year-old northern Europeans of fair complexion, with one notable exception. Early onset in black American women, 21% of whom were younger than 40 years of age, has been observed.^13,14 Most patients with pernicious anemia have chronic atrophic gastritis with decreased intrinsic factor and hydrochloric acid secretion. Antibodies against parietal cells and intrinsic factor also are present in the sera of most patients.¹⁴ This finding strongly suggests that the disease involves an autoimmune process.

Long–standing pernicious anemia is associated with increased risk for development of gastric carcinoma. In addition, an association with myxedema, rheumatoid arthritis, and neuropsychiatric and neuromuscular abnormalities (due to a defect in myelin synthesis) has been reported.^13,14

Hemolytic Anemia

Hemolytic anemias are caused by immune attack, extrinsic factors (infection, splenomegaly, drugs, eclampsia), disorders of the RBC membrane (spherocytosis), enzymopathies (glucose-6-phosphate dehydrogenase [G-6-PD] deficiency), and hemoglobinopathies (sickle cell anemia, thalassemia). G-6-PD deficiency and sickle cell anemia are discussed here to illustrate the problems presented by the hemolytic anemias.^15,16

Hemolytic Anemia: Glucose-6-Phosphate Dehydrogenase Deficiency

The search during World War II for a substitute quinine led to the use of newer antimalarial drugs and the discovery of deficiency of glucose-6-phosphate dehydrogenase (G-6-PD), an enzyme that helps the RBC to turn carbohydrates into energy. This discovery occurred after several persons who were given primaquine developed hemolytic anemia because they lacked G-6-PD, an enzyme needed for the hexose monophosphate shunt pathway.¹³

Glucose enters the RBC through a carrier mechanism, independent of insulin. About 90% of glucose is metabolized by the glycolytic pathway. The remaining glucose is metabolized by the hexose monophosphate shunt pathway. The byproduct of the glycolytic pathway is adenosine triphosphate, which provides energy for the cell. The byproduct of the hexose monophosphate shunt pathway is nicotinamide adenine dinucleotide phosphate (NADPH), which is used to reduce various cellular oxidants.^15,16 Blockade of the hexose monophosphate shunt pathway in persons with G-6-PD deficiency allows accumulation of harmful oxidants within RBCs. These substances, which produce methemoglobin and denatured Hb, precipitate to form Heinz bodies, which attach to cell membranes. These alterations in cell membranes lead to hemolysis of the cell (hemolytic anemia).^15,16

G-6-PD is the most common enzymopathy of humans.¹⁵ At present, more than 350 G-6-PD variants have been identified. They are grouped into five classes designated I to V, with class I being severely deficient, on the basis of level of enzyme deficiency.¹⁵ The G-6-PD gene is located on the X chromosome; thus, disease inheritance is gender linked. G-6-PD A, the variant most commonly associated with hemolysis, is found in 11% of African Americans. G-6-PD MED, the second most common variant associated with hemolysis, occurs in ethnic groups from the Mediterranean, the Middle East, and Asia and is associated with sickle cell anemia.¹⁵

Clinical features of G-6-PD deficiency involve acute intravascular hemolysis, which may be severe. Jaundice, palpitations, dyspnea, and dizziness may result. Infection is the event that most commonly triggers hemolysis in G-6-PD A deficiency. Drugs are the most common trigger for hemolysis in G-6-PD MED deficiency. Of more than 40 drugs that can induce hemolysis, those of significance in dental practice include acetylsalicylic acid, acetophenetidin (phenacetin), dapsone, ascorbic acid, and vitamin K. Fava bean ingestion is the most common dietary cause of hemolytic anemia in persons with G-6-PD deficiency.¹⁵

Sickle Cell Anemia

Sickle cell hemoglobin (HbS) was the first Hb variant of the more than 600 inherited human Hb variants (hemoglobinopathies) to be recognized. Of these, more than 90% have single amino acid substitutions in the Hb chain. HbS is the result of substitution of a single amino acid—valine for glutamic acid—at the sixth residue of the β chain. In contrast, the thalassemias, another type of hemoglobinopathy, are caused by deletions or mutations of the α or β globin gene that result in a defect in globin synthesis (reduced or absent synthesis of one or more globin chains).¹⁷ The hemoglobinopathies are more commonly found in regions of malarial endemicity and in populations who have migrated from these regions, because the mutated gene(s) confer advantages against infection by Plasmodium falciparum (the agent of malaria). Hemoglobinopathies such as sickle cell anemia are inherited as autosomal recessive traits.^17,18

Sickle cell disorders are distinguished by the number of globin genes affected. The two most common types are sickle cell trait and sickle cell (disease) anemia. Sickle cell trait is the heterozygous state in which the affected person carries one gene for HbS. Approximately 8% to 10% of African Americans carry the trait. In western Africa, 25% to 30% of the population may be carriers. Sickle cell anemia is the homozygous state. A gene from each parent contributes to formation of the HbS molecule responsible for the disease. The RBC in sickle cell anemia becomes sickle-shaped when blood experiences lowered oxygen tension or decreased pH, or when the patient becomes dehydrated.^18,19 Approximately 50,000 African Americans (about 0.003% to 0.15%), or 1 in 600, have sickle cell anemia.^20,21

Distortion of the RBC into a sickled shape results from deoxygenation or decreased blood pH, causing partial crystallization of HbS, polymerization, and realignment of the defective Hb molecule (Figure 22-3). Cellular rigidity and membrane damage occur, and irreversible sickling is the final result. The net effects of these changes are erythrostasis, increased blood viscosity, reduced blood flow, hypoxia, increased adhesion of RBCs, vascular occlusion, and further sickling.^18,19 Sickling crises are rare in persons with the sickle cell trait.^18,19

FIGURE 22-3 Sickle cell anemia. Peripheral blood smear shows characteristic abnormal sickle-shaped red blood cells (RBCs).

In patients with sickle cell anemia, more than 80% of the Hb is HbS. Clinical signs and symptoms of sickle cell anemia are the result of chronic anemia and small blood vessel occlusion. These manifestations include jaundice, pallor, dactylitis (hand and foot warmth and tenderness), leg ulcers, organomegaly, cardiac failure, stroke, attacks of abdominal and bone pain (aseptic necrosis), and delays in growth and development (Figure 22-4). Aplastic crisis, an acute illness wherein production of RBCs stops and severe anemia occurs, may develop from infection, hypersensitivity reactions, hypoxia, systemic disease, acidosis, dehydration, or trauma. Diagnosis requires use of RBC indices and tests in which deoxygenating agents are used (Sickledex). Confirmatory tests use electrophoresis or high-performance liquid chromatography.^18,19,22

FIGURE 22-4 Sickle cell anemia may cause various complications. A, Leg ulcer secondary to a vasoocclusive attack. B, Growth deformation of the middle finger from dactylitis of the growth plate.

(From Hoffbrand AV, Pettit JE: Color atlas of clinical hematology, ed 4, London, 2010, Mosby.)

Complications of sickle cell anemia can occur at any age, but patients in the following age groups are more likely to manifest certain complications:

People with the sickle cell trait generally have no symptoms unless they encounter situations in which abnormally low concentrations of oxygen are present (e.g., in an unpressurized airplane, through the injudicious administration of general anesthesia). Patients with sickle cell trait are much more resistant to sickling stimuli, because only 20% to 45% of their Hb is HbS. Patients with sickle cell trait are not at risk for adverse events during dental treatment unless severe hypoxia, severe infection, or dehydration also is present.^19–21

Aplastic Anemia

Aplastic anemia occurs when the bone marrow is unable to produce adequate numbers of RBCs, white blood cells, and platelets. The hematopoietic stem cells are unable to proliferate, differentiate, or give rise to mature blood cells.²³ The incidence in the United States is about 2 cases per 1 million persons per year. The incidence is about two times higher in Asia. Aplastic anemia is most common in young adults (15 to 30 years of age) and in persons older than 60 years of age.^23–25

Some cases of aplastic anemia are caused by drugs, viruses, organic compounds, and radiation. A few, such as Fanconi’s anemia, are inherited. A majority of cases, however, are idiopathic (50% to 65%).^23–25 Anticonvulsants, antibacterials, antidiabetic drugs, diuretics, sulfonamides, and synthetic antithyroid drugs are the drugs most commonly associated with aplastic anemia. Benzene and insecticides also have been shown to cause aplastic anemia. The most common viral infection associated with aplastic anemia is viral hepatitis. A few cases />