Anemia Nursing CE Course

of blood, the physiologic basis of RBC production, and the mechanisms of blood cell destruction (Longo, 2017).

Components of Blood

Blood consists of both liquid and solid components. Plasma—the liquid portion—is comprised primarily of water. It carries nutrients, proteins, and hormones throughout the body and transports waste products to the kidneys and digestive tract for removal. The solid constituents of blood are of three types: white blood cells (WBCs), RBCs, and platelets. WBCs are components of the immune system, consisting of five specific subtypes (i.e., monocytes, lymphocytes, neutrophils, basophils, and eosinophils) that work to fight infection and other illnesses. WBCs have variable lifespans: some live for only 24 hours, but the average WBC lifespan is 13 to 20 days. Mature RBCs (i.e., erythrocytes, see Figure 1) carry Hb, a protein that transports oxygen from the lungs to all body tissues. The body relies on oxygen as a critical component for all cellular functioning and processes. Hb also carries waste products—mainly carbon dioxide—from the tissues to the lungs, where they are expelled through breathing. Erythrocytes appear as biconcave discs with a uniform shape and size that lack organelles and granules. They have an average lifespan of 120 days and are pink in appearance due to their high Hb content. Hematocrit reflects the percentage, by volume, of RBCs in a given volume of blood. Platelets are essential blood cell fragments that help blood clot in response to an injury, laceration, or blunt trauma. Platelets gather at the site of an injury to seal minor cuts or breaks in blood vessels and work with proteins called clotting factors to stop bleeding. Platelets have an average lifespan of 7 to 10 days (Longo, 2017).

Figure 1

Red Blood Cells

(Qimono, 2017)

Hematopoiesis

Hematopoiesis (Figure 2) is the ongoing process of blood cell production in the human body. It occurs in the liver and spleen of a fetus, but after birth, it occurs primarily in the bone marrow. Extramedullary hematopoiesis is the formation of blood cells at sites other than the bone marrow. While extramedullary hematopoiesis is normal for a fetus, it is usually a sign of disease if it occurs after birth. Hematopoiesis is regulated through a series of steps and involves the biochemical stimulation of undifferentiated cells to undergo mitotic cell division (i.e., proliferation) and cell maturation (i.e., differentiation). Hematopoiesis continues throughout the lifespan, maintaining homeostasis in response to infection or injury. When there is an increase in the destruction of circulating cells, such as during acute bleeding, hematopoiesis accelerates to compensate for the loss. In long-term dysfunction, as in chronic illness, there is a greater increase in the rate of hematopoiesis than in acute conditions such as hemorrhage (Longo, 2017; McCance & Huether, 2019).

While several components appear in circulating blood, each serving specific roles, every cell type originates from hematopoietic stem cells. Stem cells grow, multiply, and differentiate under the control of cytokines and growth factors. During the differentiation process, stem cells follow distinctive paths to maturity and travel down committed lines of blood cells. Each line of blood cells differentiates or matures to perform a specific function. The average human body requires nearly 100 billion new blood cells per day. Hematopoietic stem cells are self-renewing to ensure that a stable population of stem cells is always readily available (McCance & Huether, 2019).

Figure 2

Hematopoiesis

(Haggstrom, 2007)

Erythropoiesis

Erythropoiesis is the process by which erythrocytes develop within the bone marrow. Erythropoiesis begins with the development of erythroid progenitor cells, which are precursors to erythrocytes. Erythropoietin (EPO) is the primary regulatory hormone for RBC production; it is produced by healthy kidneys and communicates with the bone marrow to maintain, grow, and develop erythroid progenitor cells. Under the influence of EPO, cells proliferate and differentiate into specialized pro-erythroblasts, which then pass through a series of stages to become reticulocytes. Reticulocytes are immature erythrocytes and can be measured to assess how well the bone marrow is compensating for anemia. An expected reticulocyte count is 1% of an individual's total RBC count. Approximately 1% of the body's circulating erythrocyte mass is generated every 24 hours. Therefore, reticulocytes are a good indicator of erythropoietic activity, signaling how well new RBCs are being produced. On average, reticulocytes mature into erythrocytes within 24 to 48 hours (Longo, 2017; McCance & Huether, 2019). Refer to Figure 3 for a graphic depiction of erythrocyte development.

Figure 3

The Development of an Erythrocyte 

(Immunopaedia.org, n.d.)

Since erythrocytes have an average lifespan of 120 days, normal RBC production strives for daily replacement of 0.8% to 1.0% of all circulating red cells in the body. Under ideal conditions, when the Hb concentration falls below 12 g/dL, plasma EPO levels increase in proportion to the severity of the anemia. As individuals age, the level of EPO needed to sustain normal Hb levels increases, leading to a higher prevalence of anemia among older adults. In addition to EPO, sufficient iron, vitamin B12, folate, and other vitamins and minerals must be available for the body to make enough healthy RBCs and Hb. Therefore, the critical elements of erythropoiesis consist of EPO production, iron availability, the proliferative capacity of the bone marrow, and effective maturation of erythrocytes; a defect in any of these critical components can lead to anemia (Jameson et al., 2018).

Etiology 

The physiologic basis of red cell production and destruction explains the mechanisms that can lead to anemia. Anemia has a complex array of etiologies and is not a disease but a manifestation of an underlying disorder. Anemia occurs only in the presence of clinical injury severe enough to disrupt the normal hematological hemostatic mechanisms and exceed the body's hematological reserves (Ignatavicius et al., 2018; McCance & Huether, 2019). There are numerous etiologies of anemia, but most can be grouped into the following major categories:

• blood loss (acute or chronic bleeding)
• deficient erythropoiesis (inadequate production of RBC)
• hemolysis (excessive destruction or breakdown of RBCs)
• a combination of these mechanisms (McCance & Huether, 2019)

Blood Loss

Blood loss occurs when the body loses too many RBCs and can be acute or chronic. With acute blood loss, anemia does not develop for at least several hours, as the body's compensatory mechanisms kick in to offset the loss. To compensate for reduced blood volume during hemorrhage, the interstitial fluid in cells diffuses into the intravascular space. This expands plasma volume to maintain adequate blood volume, increasing venous return, preload, and stroke volume. This increases cardiac output to maintain adequate oxygen delivery to tissues and organs. The increased fluid decreases the blood's viscosity (thickness) and causes RBC mass dilution, resulting in anemia. In cases of severe bleeding or in situations where timely and adequate intervention is lacking, the cardiac compensatory mechanisms eventually fail, leading to congestive heart failure (CHF). The resulting tissue hypoxia leads to compensatory mechanisms of the pulmonary system, inducing an increased rate and depth of respiration, tachycardia, and related clinical sequelae. When more than 30% of the blood volume is acutely lost, most individuals cannot compensate via the usual mechanisms and often have signs of hypovolemia, including postural hypotension and tachycardia. If the blood volume loss is greater than 40%, hypovolemic shock symptoms develop, including confusion, diaphoresis, hypotension, tachycardia, and dyspnea. These patients have significant deficits in vital organ perfusion, develop hypoxia, and require immediate volume replacement to avoid fatal outcomes. Potential causes of acute blood loss include trauma, injuries, surgery, and childbirth. Chronic blood loss leads to anemia over time if it occurs more rapidly than the body can restore or replace the loss or if accelerated erythropoiesis depletes the body's iron stores. Chronic blood loss can be caused by cancer, heavy menstrual cycles, or gastrointestinal ulcers. The most common reason for anemia in adults is gastrointestinal bleeding (Ignatavicius et al., 2018; Longo, 2017; McCance & Huether, 2019).

Deficient Erythropoiesis 

Deficient erythropoiesis occurs when the body makes too few RBCs. Anemia due to decreased erythropoiesis is called hypoproliferative anemia and is characterized by reticulocytopenia, a reduced number of reticulocytes on the peripheral blood smear. Causes of decreased production of erythrocytes may include altered Hb synthesis (IDA, thalassemia, anemia of chronic disease [ACD]), altered deoxyribonucleic acid (DNA) synthesis due to deficient nutrients (pernicious anemia or folate deficiency anemia), stem cell dysfunction (aplastic anemia or myeloproliferative leukemia), and bone marrow infiltration (carcinoma or lymphoma; McCance & Huether, 2019).

Hemolysis 

Hemolytic anemia occurs when RBCs are destroyed faster than they are produced. Hemolysis can occur in response to intrinsic (inherited) abnormalities of the RBCs or extrinsic (acquired) factors. Inherited causes of hemolytic anemia include defects in the RBC membranes, enzymatic pathways, or Hb synthesis, such as in thalassemia and sickle cell disease. Acquired causes of hemolytic anemia are usually immunologic, such as RBC destruction due to autoantibodies (immune-mediated hemolysis from blood transfusion reactions), allergic reactions (drug-induced hemolytic anemia), infection/inflammatory responses (bacterial infections, disseminated intravascular coagulation [DIC]), or exposure to toxic drugs or chemicals. Hemolysis can occur within the blood vessels or lymphoid tissues that filter the blood, such as the spleen and liver, resulting in splenomegaly or enlargement of the spleen. RBCs are destroyed at a more rapid rate when the spleen is enlarged. The body attempts to compensate for premature RBC destruction by increasing levels of EPO. This generally leads to increased reticulocyte production unless iron or other essential nutrients are depleted (Barcellini, 2022; McCance & Huether, 2019; National Heart, Lung, and Blood Institute [NHLBI], 2022a). Further diagnostic information may be gained in these cases by obtaining a lactate dehydrogenase (LDH), bilirubin, haptoglobin level, direct antiglobulin test (DAT), or peripheral blood smear (Means & Brodsky, 2022).

Types of Anemia

There are several types of anemia, and the distinctions between each type are essential to understand, as the presentation, symptoms, and treatment can vary widely.

Iron-Deficiency Anemia 

While IDA is the most common type of anemia worldwide, it is also the most treatable. Iron is a component of hemoglobin and is required for normal erythropoiesis and several other biologic processes within the body. Since iron is recyclable, the body maintains a balance between iron contained within hemoglobin and iron stored for future hemoglobin synthesis. It takes years of inadequate oral iron intake in adults for IDA to develop. While IDA can be caused by a diet lacking adequate iron, folate, or other essential vitamins or minerals, it can also result from poor absorption due to malabsorption disorders (e.g., H. pylori infection) or other gastrointestinal issues such as inflammatory bowel disease. The leading site of iron absorption is within the duodenum, so surgeries that bypass this part of the bowel commonly lead to a higher incidence of IDA due to decreased absorption and reduced intestinal transit time. This most frequently occurs following bariatric surgery, particularly gastric bypass, and the incidence of IDA can range from 25% to 50% within this population (DeLoughery, 2017; McCance & Huether, 2019).

Chronic blood loss (e.g., gastrointestinal bleeding related to oozing gastritis, gastric or duodenal ulcers, or gastrointestinal malignancies) often leads to IDA due to depletion of the body's iron stores (DeLoughery, 2017; McCance & Huether, 2019). Women of childbearing age are at risk of IDA due to iron losses through menstruation, with an average loss equivalent to 16 mg of iron per menstrual cycle or higher for those with menorrhagia (excessive bleeding during menstruation). Those at highest risk are African American females of childbearing age living in urban areas with low socioeconomic status. Adolescent girls are also at increased risk for IDA because of decreased iron stores from menstruation and rapid growth. Other conditions leading to IDA due to increased bleeding include uterine fibroids and endometriosis (Auerbach & Landy, 2022; Garzon et al., 2020; Lowdermilk et al., 2016).

Anemia is also common during pregnancy and delivery, with IDA being the most prevalent type of anemia among these individuals. About 50% of pregnant individuals do not have enough iron. During pregnancy, the body needs more iron to support fetal growth. Pregnant patients require almost twice as much iron as patients who are not pregnant. During an average pregnancy and birth, the body requires 1,000 to 1,200 mg of iron. Over 40% of women already have no or low (<500 mg) iron stored at the beginning of pregnancy. This increases the risk of IDA once iron demand increases as the pregnancy progresses, with 1 to 2 mg/day required in the first trimester and 4 to 5 mg/day during the second and third trimesters. Most guidelines recommend increasing iron consumption to at least 27 mg/day to cover the amount required daily and maintain iron stores. Most prenatal vitamins meet this recommended intake, so pregnant patients are advised to take prenatal vitamins with iron daily. A fetus will deplete a pregnant individual of their iron stores and are therefore usually unaffected in mild cases of IDA. When severe, IDA can increase the likelihood of preterm labor, low birth weight, intrauterine growth restriction, and intrauterine fetal demise (Auerbach & Landy, 2022; Garzon et al., 2020; Lowdermilk et al., 2016).

Premature birth is the most common cause of infant death. Both premature birth and low birth weight raise an infant's risk for health and developmental problems at birth and throughout childhood. Severe anemia can also lead to maternal mortality. According to the WHO, anemia is associated with 40% of maternal deaths worldwide. The American College of Obstetricians and Gynecologists estimates that 5% of women who give birth lose 1,000 mL of blood or more during delivery, resulting in the loss of approximately 250 mg of iron. Therefore, patients should be tested for IDA 4 to 6 weeks after childbirth (Auerbach & Landy, 2022; Garzon et al., 2020; McCance & Huether, 2019).                          

Symptoms of IDA usually present gradually, and the earliest signs are weakness, fatigue, and shortness of breath with physical activity or even mild exertion. As the condition progresses, poor circulation can lead to changes within the epithelial cells, causing the nails to become thin, brittle, and ridged. On a physical exam, koilonychia may be evident, which is the upward curvature of the nails. Patients may also exhibit pallor of the skin and conjunctivae. Some patients report dryness and soreness of the mouth with cracks at the corners. In more severe cases, the tongue may become red and painful; the degree of pain is often associated with IDA severity. A common manifestation of IDA is pica, a hunger for non-food substances such as dirt, ice, or paper. Other clinical manifestations include gastritis, irritability, neuromuscular alterations, headaches, numbness, tingling, and vasomotor symptoms (Auerbach, 2022; Braunstein, 2022; McCance & Huether, 2019). 

The recommended dietary intake of iron is 8 mg/day for adult men and 18 mg/day for premenopausal women. Food contains two kinds of iron: heme and non-heme. Heme iron is found in meat, fish, and poultry. Heme iron is most readily absorbed and utilized by the body, boosting iron levels much more effectively than non-heme iron sources. Most adults absorb up to 30% of the heme iron they consume. Non-heme (or non-meat) sources of iron are less effectively absorbed; some examples include plant-based foods such as vegetables, fruits, nuts, and iron-fortified cereals. While these are still critical components in a healthy, well-balanced diet, adults only absorb 2% to 10% of iron from non-heme food sources. Therefore, supplementation is advised for individuals who maintain vegetarian or vegan diets as it is difficult to ingest large enough quantities to meet iron requirements if only utilizing non-heme sources (DeLoughery, 2017; National Institutes of Health [NIH], 2022a).

Megaloblastic Anemias

Megaloblastic anemias are conditions in which the bone marrow produces unusually large, thick, immature RBCs called megaloblasts. Megaloblasts are structurally abnormal and are usually oval-shaped instead of round, like healthy RBCs. Megaloblastosis, defined as asynchronous nuclear maturation, involves a decreased rate of cell division relative to cytoplasmic expansion. This condition results from a defect in DNA synthesis that affects rapidly dividing cells within the bone marrow. The most common cause of megaloblastic anemia is a deficiency in the essential nutrient cobalamin (vitamin B12, which causes pernicious anemia, below) or folate (vitamin B9, which causes folate deficiency anemia, below), but it may also be related to copper deficiency, myelodysplastic syndrome, aplastic anemia, or drugs that interfere with DNA synthesis (Longo, 2017; McCance & Huether, 2019; Means & Brodsky, 2022).

Pernicious Anemia

Pernicious anemia is a vitamin B12 deficiency that develops from impaired uptake of vitamin B12 due to a lack of intrinsic factor (IF). IF is a glycoprotein produced by the gastric parietal cells (stomach lining) that helps the body absorb dietary vitamin B12 in the intestine. Vitamin B12, or cobalamin, is a water-soluble vitamin essential for proper RBC formation, neurological function, and DNA synthesis. It is found in animal products, such as meat, eggs, milk, poultry, fish, and fortified cereals. While the term pernicious anemia was initially used to refer only to vitamin B12 deficiency resulting from a lack of IF, vitamin B12 deficiency due to other causes is also often called pernicious anemia (McCance & Huether, 2019; NHLBI, 2022d).

When vitamin B12 is ingested orally, it binds to IF. Nuclear maturation and DNA synthesis in RBCs occur through a series of biochemical reactions requiring synergistic activity between vitamin B12, folic acid, and IF. When deficiencies in any of these essential nutrients exist, DNA synthesis within the RBC is impaired, leading to distinctive RBC and bone marrow changes. If left untreated, pernicious anemia can cause permanent damage to nerves and other organs and increase the risk of stomach cancer, heart failure, and death (Longo, 2017; McCance & Huether, 2019).

Vitamin B12 deficiency is most commonly caused by the loss of gastric parietal cells, malabsorption, or inadequate dietary intake. Pernicious anemia usually develops slowly over several years or even decades, as the median age at the time of diagnosis is 60 years old. Symptoms of pernicious anemia may be vague and include fatigue, weakness, mood swings, and gastrointestinal symptoms such as anorexia, nausea, abdominal pain, and weight loss. Patients often report a reduced sense of touch or describe peripheral neuropathy such as stocking-glove paresthesia, "pins and needles," or numbness and tingling in the hands, fingers, feet, or toes. These neurological manifestations are due to nerve demyelination and neuronal death. The tongue can become sore, and on physical examination, patients may have evidence of a smooth, beefy red tongue. An affected patient's skin may be light yellow due to a combination of pallor and icterus, and hepatomegaly (enlargement of the liver) may be present. They may exhibit ataxia and loss of positioning and vibrational sense on a neurological exam or report an unsteady gait, difficulty walking, or clumsiness and stiffness of the arms and legs. Dementia is another sign associated with pernicious anemia, and an increased prevalence of vitamin B12 deficiency is reported in patients with Alzheimer's disease (Braunstein, 2022; McCance & Huether, 2019).

Folate-Deficiency Anemia

Folate (folic acid) is a water-soluble B complex vitamin and essential for RBC production and maturation. The human body depends on dietary intake of folate, with the average adult requiring 50 to 200 mcg/day. Folate is absorbed within the small intestine and transported to the liver, where it is stored. Pregnant and lactating patients need increased folic acid intake, as folic acid transfers through the placenta to the fetus. Folate-deficiency anemia during pregnancy is teratogenic, leading to significant fetal abnormalities and neural tube defects. A fetus has higher folate requirements than a pregnant patient, rendering pregnancy a maternal folate-depleting condition, with repeated pregnancies depleting maternal folate stores. Folate deficiency is such a significant contributor to neural tube defects that folate has been added to grains in the US to prevent these congenital disabilities (Khan & Jialal, 2022).

The most common cause of folate deficiency is inadequate dietary intake and chronic malnourishment. Therefore, this condition frequently affects older adults and those living in poverty or chronically abusing alcohol. Less commonly, folate deficiency is caused by impaired absorption due to celiac disease or other gastrointestinal malabsorption disorders. The symptoms of folate-deficiency anemia resemble those of pernicious anemia, except for the neurological manifestations, which generally do not occur with this condition. Some clinical manifestations specific to folate deficiency include severe cheilosis (scales and fissures of the lips and corners of the mouth), as well as inflammation and ulceration of the mouth and tongue. Gastrointestinal symptoms are also common, such as increased flatulence, watery diarrhea, and dysphagia (i.e., difficulty swallowing; McCance & Huether, 2019).

Anemia of Chronic Disease 

ACD, also called anemia of inflammation, is the second most common type of anemia worldwide, following IDA. It is usually multifactorial in etiology, as a diagnosis requires the presence of a chronic inflammatory condition, autoimmune disease, or other chronic illnesses such as kidney disease, hypothyroidism, or cancer. Classic features consist of microcytic or normocytic anemia and a low reticulocyte count. Serum iron is typically low or normal, while ferritin can be normal or elevated. ACD may partly be caused by reduced EPO response in the bone marrow and the suppression of bone marrow from medications used to treat chronic conditions. In cancer treatment, bone marrow is suppressed due to chemotherapy, and as a result, normal RBC death occurs without the production of new RBCs (Madu & Ughasoro, 2017).

Anemia is highly prevalent among patients with CHF. Patients with anemia and CHF usually experience more severe symptoms, significantly worsening functional capacity, and reduced survival rates. The comorbid condition most frequently present in patients with CHF is CKD. CHF and CKD share many common causes (i.e., hypertension), clinical features (i.e., impaired performance status due to deconditioning), and risk factors (i.e., older age, obesity, poor lifestyle choices). The significant factors contributing to CHF-related anemia include CKD, renin-angiotensin system, iron deficiency, chronic inflammation, and hemodilution (Madu & Ughasoro, 2017; McCance & Huether, 2019).

In CHF, the reduced cardiac output from impaired heart function leads to hypoxia, which causes reduced renal perfusion and subsequent renal damage. While hypoxia initially stimulates EPO production as a compensatory mechanism, patients with CKD—especially those on dialysis—often have anemia due to a lack of EPO. Renal EPO synthesis declines when the glomerular filtration rate drops below 30 mL/min/1.73 m² to 40 mL/min/1.73 m². As highlighted earlier, EPO is generated by healthy kidneys and fuels RBC growth. When the kidneys fail, they no longer produce enough EPO; without enough EPO, fewer RBCs are generated.

Aplastic Anemia 

Aplastic anemia is a critical condition that develops when the bone marrow fails to produce essential cells, leading to a deficiency in circulating RBCs. Its etiology can be traced back to an injury to an immature stem cell, which may be related to exposure to ionizing radiation or toxic agents, viral infection, or it may be idiopathic. Aplastic anemia is relatively rare, with 2 to 5 cases per 1,000,000 people annually. Generally, it affects young adults between the ages of 15 and 25 and adults older than 60. The onset can be rapid, and the presentation depends on which cell type is most affected. CBC results often reveal pancytopenia, a reduction in the RBCs, WBCs (leukopenia), and platelets (thrombocytopenia). Many patients present with abnormal bleeding or hemorrhage due to thrombocytopenia and have a high risk of death related to infection or bleeding. In addition to bleeding, common symptoms may include fever, fatigue, and weakness, with dyspnea and hypoxemia occurring in more severe cases. On physical examination, patients often exhibit pallor, petechiae, purpura, ecchymosis, and ulceration of oral mucosa. Splenomegaly and neurological manifestations are not typical. A bone marrow biopsy is indicated to diagnose this condition accurately, and findings often demonstrate the replacement of marrow-forming cells with adipose (fat) cells (Ignatavicius et al., 2018; McCance & Huether, 2019).

Sickle Cell Anemia

Sickle cell disease affects approximately 100,000 individuals within the US. It most often occurs in non-Hispanic black individuals at a rate of about 1 in every 365 births and Hispanic individuals at a rate of 1 in every 16,300 births. Approximately 1 in every 13 non-Hispanic black babies is born with the sickle cell trait. All newborns in the US are now tested for the disease. Sickle cell disease can be identified before birth by testing a sample of amniotic fluid or tissue from the placenta (SCT; Ashorobi & Bhatt, 2021; Bender, 2021; CDC, 2022). Sickle cell disease is the most inherited blood disease in the US. Sickle cell disease is an autosomal-recessive genetic disorder that affects the RBCs and changes the body's Hb structure, causing it to become defective and misshaped. The disease alters the normal hemoglobin A (HbA) molecule, with two alpha and beta amino acid chains, to the abnormal hemoglobin S (HbS) molecule, composed of abnormal beta chains (see Figure 4). When RBCs consisting of many HbS molecules are exposed to an area of low oxygen, the abnormal beta chains contract, creating a distorted, sickle shape (NHLBI, 2022b).

Figure 4

Structure of Hemoglobin 

(CCCOnline, n.d.)

The malformed Hb in individuals with sickle cell disease causes the RBCs to become fragile and break down faster than usual, resulting in anemia. Symptoms of sickle cell disease are varied and include jaundice, shortness of breath, fatigue, and delayed growth. Patients may describe joint pain that resembles arthritis pain, and chronic neuropathic pain is also common. Infants born with sickle cell disease may not show symptoms immediately but typically begin by 4 months of age. Patient symptoms may wax and wane with periods of extensive sickling leading to a crisis. The rigid, sickle-shaped structure of the RBCs makes the cells sticky, causing them to stick to the blood vessel walls and clump together, blocking blood flow. This clumping increases a patient's risk of developing clots. See Figure 5 for a graphic representation of this process. This disruption of blood flow is referred to as a vaso-occlusive crisis, which can be exacerbated by dehydration, pain, infection, or changes in the weather. This process can cause severe pain, organ failure, pulmonary hypertension, priapism (extended penile erection), acute chest syndrome, or stroke, depending on the affected area. The pain experienced during a crisis is often brought on by hypoxemia and typically affects the joints, limbs, and abdomen. Crisis frequency varies from every other week to annually and can last hours to days. Long-term effects of sickle cell disease can range from mild to severe. Sickle cell disease increases the risk of blood clots, strokes, and life-threatening infections (Ashorobi & Bhatt, 2021; Bender, 2021; CDC, 2022; Hockenberry et al., 2019; Ignatavicius et al., 2018).  

 

Figure 5

Sickle-Cell Anemia 

(Grib, 2015)

Thalassemia   

Thalassemia is an inherited blood disorder in which the body produces an inadequate amount of normal Hb. Since the condition is caused by a defect in two major proteins that make up normal Hb—alpha-globin and beta-globin, as seen in Figure 4—the two major types of thalassemia are named after the defects within these proteins. Alpha thalassemia is related to a mutation in the alpha-globin protein, whereas beta-thalassemia is related to a gene defect in the beta-globin protein. In general, the condition is inherited in an autosomal-recessive manner. Alpha thalassemia presents with two clinically relevant forms: hemoglobin Bart hydrops fetalis (Hb Bart) syndrome, caused by the deletion or inactivation of all four alpha-globin genes, and hemoglobin H (HbH) disease, most frequently caused by the deletion or inactivation of three alpha-globin genes. Hb Bart is the most severe form of alpha thalassemia and is autosomal recessive, requiring the inheritance of a defective gene from both parents. Symptoms typically include generalized edema, congestive heart failure, and marked hepatosplenomegaly. Infants diagnosed with this condition usually die shortly before or after birth. HbH usually presents in the first years of life, although milder cases may present in adulthood. Most commonly, HbH disease presents with splenomegaly, mild jaundice, and bone changes. Infections or exposure to oxidant medications may result in acute episodes of hemolysis. They may also experience gallstones (Longo, 2017; Tamary & Dgany, 2020)

Males and females are affected by beta-thalassemia in equal proportions. Most severe forms are usually diagnosed in early childhood and are lifelong conditions. Most people affected by beta-thalassemia have a mutation in one copy of the beta globulin gene, are considered carriers, and are asymptomatic. This is referred to as beta thalassemia minor, or trait, and patients may be unaware that they are a carrier. Thalassemia intermedia presents later in life with milder anemia. Beta thalassemia major is the most severe form of beta-thalassemia and is often referred to as Cooley's anemia. Signs and symptoms usually occur within the first 2 years of life. Patients typically develop severe microcytic hypochromic anemia and other health problems, such as a pale and listless appearance, anorexia and weight loss, and dark urine secondary to hemolysis. Other clinical manifestations include slowed growth, delayed puberty, jaundice, hepatosplenomegaly, and cardiomegaly. Many of these patients also experience bone problems, such as osteoporosis. The clinical severity of symptoms varies depending on the degree to which globin synthesis is affected. A peripheral blood smear will generally demonstrate target cells (codocytes), nucleated red blood cells, teardrop cells (dacrocytes), and hemoglobin analysis will result in reduced amounts of hemoglobin A. RBC indices typically indicate microcytosis (HbA; Longo, 2017; Means & Brodsky, 2022; NHLBI, 2022c; Origa, 2021)

Clinical Presentation

Anemia is most commonly recognized by abnormal screening laboratory test results when the Hb and/or hematocrit is reduced below the normal range. Additionally, it is often suspected based on a patient's history and physical examination findings (Jameson et al., 2018).

Health History

Obtaining a detailed health history is critical as it provides important clues to help determine the diagnosis and etiology of the condition. Symptoms of deep, sighing respirations with activity and a sensation of a rapid heart rate are vital indicators of decreased oxygen-carrying capacity of the blood. Patients should be asked about acute blood loss, blunt trauma, injury, or abnormal bruising. Healthcare professionals (HCPs) should inquire about any rectal bleeding, including bright red blood per rectum or black or tarry stools. Female patients should be asked about menstrual cycle regularity and heaviness of flow, as well as any abnormal vaginal bleeding (Ignatavicius et al., 2018).

The clinical presentation of anemia can be highly variable based on severity and the body's ability to compensate for hypoxia. Symptoms can range from mild fatigue to dyspnea on exertion or reduced cognitive performance. Anemia that is mild and develops gradually is usually more easily compensated for and may induce symptoms only with physical exertion. However, as anemia becomes more prominent and Hb levels continue to decline, the associated symptoms, alterations of specific organs, and compensatory effects become more pronounced. Symptoms are more notable for patients with preexisting limitations in cardiopulmonary reserve and those with rapidly developing anemia (Braunstein, 2022; McCance & Huether, 2019).

Signs and Symptoms

The initial signs and symptoms of anemia often affect the cardiovascular system. Common signs and symptoms patients report include generalized fatigue or an overall loss of energy, weakness, dyspnea on exertion, chest pain, dizziness, difficulty concentrating, headaches, lightheadedness, cold intolerance, leg cramps, and insomnia. More severe but less common symptoms include angina, syncope, vertigo, amenorrhea (loss of menstrual cycle), loss of libido (loss of sex drive), and pulsatile tinnitus (ringing or thumping sound in the ear). In the most severe cases, heart failure or symptoms of shock can develop in those with severe tissue hypoxia or hypovolemia. Anginal symptoms commonly affect patients with coronary artery disease (Braunstein, 2022; Jameson et al., 2018).

Physical Examination

On physical exam, patients with anemia may have a few abnormal findings, or they may exhibit several. A complete cardiac examination should be performed to evaluate for any murmur or enlargement of the heart, which may provide evidence of the duration and severity of the anemia. A hemic (i.e., early systolic) murmur may be present in response to increased blood flow over the heart valves. An irregular, rapid heart rate is common, in addition to neurological findings such as paresthesia (stocking-glove neuropathy), cold hands and feet, or poor balance. The skin, mucous membranes, lips, nail beds, and conjunctivae may appear pale (pallor). Additional skin changes such as jaundice (yellowing of the skin), scleral icterus (yellowing of the whites of the eyes), spider nevi, purpura (non-blanchable purple or red spots on the skin), palmar erythema, and nail defects can occur. Also, patients may develop coarseness of the hair, weight loss, malnutrition, thinning of the lateral aspects of the eyebrows, an unusually prominent venous pattern on the abdominal wall, and splenomegaly. Splenomegaly is more common in patients with hemolytic anemia because of RBC destruction. However, splenomegaly may also develop in response to anemias of chronic inflammatory etiology, such as connective tissue disease, myeloproliferative disorder, infection, or cancer. These conditions can suppress bone marrow activity and enlarge the spleen. For patients who present following blunt trauma, abdominal distention could suggest acute hemorrhage or splenic rupture (Braunstein, 2022).

Diagnostic Tests

When anemia is suspected or identified on routine laboratory tests, a more comprehensive workup to evaluate the etiology of anemia is indicated. The initial anemia workup often consists of a series of blood tests, including several or all of the following listed in Table 2. Reference ranges are compiled from the American Board of Internal Medicine (ABIM, 2019).

Table 2 

Anemia: Common Laboratory Tests with Reference Ranges 

Complete blood count (CBC) Hemoglobin female: 12–16 g/dL male: 14–18 g/dL Hematocrit female: 37%–47% male: 42%–50% WBC: 4000–11,000/μL Platelet: 150,000–450,000/μL RBC indices mean corpuscular volume (MCV): 80–98 fL mean corpuscular hemoglobin (MCH): 28–32 pg mean corpuscular hemoglobin concentration (MCHC): 33–36 g/dL red blood cell distribution width (RDW): 9.0%–14.5%

Reticulocyte count (0.5%–1.5% of red cells; 25,000–100,000/µL)

Cell morphology: evaluation of peripheral blood smear under a microscope for: hemoglobin count anisocytosis: variations in cell size poikilocytosis: variations in cell shape polychromasia: reticulocytes prematurely released from the bone marrow in response to EPO stimulation or architectural damage

Iron studies serum iron level: 50–150 μg/dL total iron-binding capacity (TIBC): 250–310 μg/dL serum ferritin female: 11–307 ng/mL male: 24–336 ng/mL serum transferrin: 200–400 mg/dL transferrin saturation: 20%–50% Serum folate: 1.8-9.0 ng/mL

Serum vitamin B12: 200–800 pg/mL

Bone marrow aspiration and biopsy may be indicated based on the extent of anemia and the associated clinical presentation

(ABIM, 2019; Braunstein, 2022; Longo, 2017)

Subsequent diagnostic tests are ordered and performed based on the results from the laboratory assessments listed in Table 2 and the patient's clinical presentation. Clinicians may order a stool guaiac test to evaluate for the presence of blood in the stool when acute blood loss is suspected. A heme-positive stool guaiac is a common sign of anemia due to gastrointestinal bleeding. An ultrasound of the spleen may also be ordered to evaluate for splenomegaly (Chaparro & Suchdev, 2019).

Complete Blood Count 

When evaluating patients with anemia, the CBC components provide essential clues toward the classification and origin of anemia. Hb and hematocrit usually exist in a 1:3 ratio, so 1 g of Hb is equivalent to 3% of hematocrit. The body's hydration status influences the hematocrit level: in severe dehydration, hematocrit is falsely elevated, but in overhydration, hematocrit is falsely reduced. Mean corpuscular volume (MCV) is a measure of the average size of erythrocytes. When the MCV is low, the RBC size is abnormally small and is referred to as microcytic or microcytosis. When the MCV is high, the RBC size is abnormally large, known as macrocytosis or macrocytic anemia. The MCH refers to the average amount (content) of Hb found in each RBC. Since Hb provides the RBCs with their characteristic red color, the suffix "-chromic" is used. Therefore, an RBC with a normal MCH has a typical red color and is called "normochromic," whereas an RBC with a low MCH is a pale red color and termed "hypochromic." The MCHC is Hb's average weight (concentration) based on the RBC volume. Variations in MCH and MCHC values can indicate defects in Hb synthesis. The RDW measures how many RBCs vary in size and volume. It reflects the degree of variation in RBC size and is often reported as anisocytosis on RBC morphology results. A wide variation in RBC size leads to an elevated RDW, indicating the cells were produced under varying conditions. Minor variations in cell size are expected, so the RDW is only considered increased when it is greater than 15%. An elevated RDW is commonly seen with IDA (Longo, 2017). The RBC indices, particularly the MCV, can help narrow down the differential diagnosis of deficient erythropoiesis and help determine what further testing is necessary (McCance & Huether, 2019).

Cell Morphology

Anemias are commonly classified by their causes or according to changes in their cellular morphology, such as the erythrocytes' size, shape, or Hb content. Anemia types are classified as microcytic, normocytic, or macrocytic (McCance & Huether, 2019).

Microcytic Anemia

RBCs are considered microcytic if the MCV is below 80 fL. Microcytic anemias usually result from deficient or defective Hb synthesis, as Hb is a significant contributor to cell size, such as in IDA. This can be confirmed by testing iron stores. Since Hb gives RBCs their red color, microcytic RBCs are generally hypochromic (i.e., low MCH). Additional causes of microcytic anemia include thalassemia, lead poisoning, and ACD (Braunstein, 2022; Longo, 2017; Means & Brodsky, 2022).

Normocytic Anemia

Normal RDW and normochromic indices characterize normocytic anemias. This suggests that the erythrocytes were made under healthy conditions with sufficient EPO and no defects in Hb synthesis. The most common etiologies of normocytic anemia include acute blood loss and ACD, resulting from inflammation, neoplasm, renal failure, endocrine, or bone marrow dysfunction (Longo, 2017; Yilmaz & Shaikh, 2022). Alternative etiologies of normocytic anemia include IDA, vitamin B12 or folate deficiency, drug-induced anemia, liver disease, alcohol use disorder, hemolysis, and hypothyroidism (Means & Brodsky, 2022)

Macrocytic Anemia

Macrocytic anemia, or macrocytosis, is abnormally large erythrocytes as reflected by an MCV greater than 100 fL. The most common cause of macrocytosis is impaired ribonucleic acid (RNA) and DNA synthesis. Vitamin B12 and folate deficiencies significantly contribute to RNA and DNA in developing erythrocytes. Therefore, vitamin B12 or folate deficiency typically leads to macrocytic anemia, referred to as megaloblastic anemia. Since Hb synthesis is not affected by these deficiencies, macrocytic cells are typically normochromic, maintaining their healthy red color. Aside from vitamin B12 and folate deficiency, macrocytic anemia may also be related to alcohol use disorder, drug use, copper deficiency, myelodysplastic syndrome, and liver disease. Some patients with hypothyroidism have macrocytic RBC indices (Braunstein, 2022; Longo, 2017; Means & Brodsky, 2022).

Reticulocytes  

As noted earlier, reticulocytes are immature erythrocytes. When Hb levels drop, and anemia develops, the body's normal response is to increase reticulocyte production (reticulocytosis) to increase the body's Hb level. If this value is high, the underlying etiology may be hemolysis, recovery following blood loss, the recent removal of a bone marrow suppressant (e.g., drug, infection), or recent correction of a deficiency (e.g., iron, folic acid, vitamin B12). If reticulocytopenia is present in the setting of anemia, consideration should be given to lack of EPO, significant blood loss (within 5 days), or bone marrow failure. This may be related to nutritional deficiency (iron, folate, vitamin B12, or copper), a medication that suppresses bone marrow function, or primary marrow disorder (e.g., myelodysplastic syndrome, myelofibrosis, or leukemia). The reticulocyte production index (RPI) indicates how rapidly new RBCs are produced and mature. This is a formula calculation using a correction factor. In summary, an RPI value over 3 indicates adequate hematological and bone marrow responses to anemia, whereas below 2 indicates an inadequate response. The RBC indices, particularly the MCV, can help narrow down the differential diagnosis of deficient erythropoiesis and help determine what further testing is necessary (McCance & Huether, 2019; Means & Brodsky, 2022).

Iron Studies

Routine iron studies include serum iron, serum ferritin, TIBC (i.e., transferrin), and transferrin saturation. Serum iron refers to the total iron concentration in circulation. It is directly related to total iron intake over the last 24 to 48 hours, so it can be falsely elevated due to recent high dietary or iron supplement intake. Ferritin is the body's major iron storage protein. The first biochemical change seen in iron deficiency anemia is a low ferritin level (< 30 ng/mL), which occurs before serum iron is decreased and before morphologic changes are seen in RBCs. Serum ferritin is an essential indicator of IDA and ACD, as ferritin is low in these conditions. Serum ferritin reflects the body's iron stores if the patient does not have liver disease or an acute inflammatory reaction. About 15% to 20% of iron is stored within ferritin, but serum ferritin does not reflect bone marrow stores. The TIBC is a measure of transferrin, a plasma protein that combines with iron. Up to one-third of transferrin may be saturated with iron. If iron stores are depleted, transferrin levels in the blood increase. When more transferrin is available for binding, the TIBC level increases, indicating iron deficiency. The transferrin/TIBC may be measured directly (and typically referred to as a transferrin level) or indirectly/calculated by combining the unsaturated iron-binding capacity (UIBC) and the serum iron. Transferrin saturation (TSAT) or iron saturation is the percentage of iron bound to transferrin, calculated by dividing the serum iron level by the TIBC. TSAT values below 19% indicate IDA, while vales over 50% indicate iron overload (Longo, 2017; McCance & Huether, 2019; Means & Brodsky, 2022).

Serum Folate

Folate (folic acid) is an essential vitamin for erythrocyte production and maturation and comes solely from dietary intake (Longo, 2017; McCance & Huether, 2019; Means & Brodsky, 2022).

Treatment/Management

Iron Deficiency Anemia

When devising a treatment plan for IDA, the HCP's priority is to identify any source of blood loss and correct it, as treatment will be ineffective in the setting of ongoing bleeding. IDA may be treated with oral or intravenous (IV) iron replacement therapy. For IDA caused by nutritional deficits, oral iron replacement therapy (IRT) is highly effective and considered a first-line treatment. Ferrous sulfate (Slow Fe) is the most common oral option, as it is the most readily absorbed and the best tolerated, as well as effective and inexpensive (McCance & Huether, 2019). The recommended daily dose of oral IRT for adults is 100 mg to 200 mg of ferrous sulfate (Slow Fe) administered in divided daily doses. Oral IRT is considered the gold standard of treatment for mild to moderate anemia and is safe for use in pregnant patients. For patients undergoing oral IRT, serum ferritin measurements are useful in monitoring the response to therapy and determining when iron therapy should be discontinued. A normal hemoglobin level does not necessarily indicate that the body's iron stores have been replenished. Therefore, serum ferritin assays should be performed at 3- to 4-week intervals until the level rises above 50 ng/mL, which indicates iron stores of around 400 mg. While on therapy, patients often report a rapid decline in fatigue, dyspnea on exertion, and other symptoms. A treatment duration of 3 to 6 months is typically required to replete iron stores and normalize serum ferritin levels. Patients should be advised to take oral IRT without food. Vitamin C enhances iron absorption when taken simultaneously, so patients may be counseled to take their oral IRT with half an orange, 4 oz of orange juice, or another food source rich in vitamin C. Side effects of oral IRT include nausea, constipation, diarrhea, or a metallic taste. Patients should be advised that their stools may appear darker or even black, but this is a common side effect and does not indicate the presence of blood in the stool (Auerbach, 2022; DeLoughery, 2017; Garzon, 2020).

Additional nursing considerations regarding oral IRT include counseling patients on common drug interactions. Patients should be advised to separate oral IRT and antacids by at least 2 hours due to interference with iron absorption. Antacids neutralize stomach acid and contain ingredients such as aluminum, calcium, magnesium, or sodium bicarbonate, which act as bases to counteract stomach acid and neutralize the pH. Similarly, patients should avoid caffeine within 2 hours of oral IRT due to decreased absorption. Oral IRT may reduce the efficacy of certain antibiotics such as fluoroquinolones (ciprofloxacin [Cipro], levofloxacin [Levaquin]) and tetracyclines (doxycycline [Vibramycin]). Some antihypertensives such as angiotensin-converting enzyme (ACE) inhibitors (lisinopril [Zestril], ramipril [Altace]) and thyroid hormones (levothyroxine [Synthroid]) may also be affected. Many of these medications need to be separated from IRT by at least 6 hours to ensure there is no interaction, and patients should be more closely monitored after starting oral IRT to assess for the need to adjust medication dosages (Auerbach, 2022; Brant, 2020).

Parenteral iron replacement is the treatment of choice for patients who cannot tolerate or have failed oral IRT, those with malabsorption disorders or inflammatory bowel disease, or those with severe IDA without the presence of cardiovascular symptoms. IV iron replacement is preferred when a rapid increase in Hb level is needed, such as for patients with chronic kidney disease (CKD) who are receiving hemodialysis. This approach is more effective and increases Hb levels quicker than oral IRT, bypassing the issues associated with iron absorption within the gastrointestinal system (Auerbach, 2022; Longo, 2017).

There are several parenteral formulations of iron replacement, but the most common options consist of sodium ferric gluconate (Ferrlecit), iron sucrose (Venofer), ferumoxytol (Feraheme), and ferric carboxymaltose (Injectafer). Traditionally, IV iron infusions have posed a risk for hypersensitivity reactions and anaphylaxis, primarily related to a previously utilized high-molecular-weight iron dextran (DexFerrum, INFeD). However, newer agents are biochemically structured to significantly decrease the risk of hypersensitivity reactions, increasing their utility. Patients receiving IV iron replacement should be counseled on the potential side effects (e.g., nausea, vomiting, pruritus, flushing, and headaches). While the risk of hypersensitivity allergic reactions is reduced with the newer iron formulations, patients may experience infusion reactions within 24 to 48 hours of their infusion. Symptoms can include flu-like reports of myalgias, arthralgias, and pain in the chest and back. For patients who experience any acute flushing, discomfort, or abnormal reactions during an IV iron infusion, the infusion should be stopped immediately, and the patient monitored closely. Once the patient is clinically stable, the infusion can be safely resumed, but the infusion rate should be slowed. Premedication with an antihistamine such as diphenhydramine (Benadryl) is not advised due to the risk of hypotension and tachycardia (Auerbach, 2022).

Another treatment option for patients with IDA is erythropoiesis-stimulating agents (ESAs), such as epoetin alfa (Procrit) and darbepoetin alfa (Aranesp). These agents are approved by the US Food & Drug Administration (FDA) for treating anemia resulting from CKD, chemotherapy, or HIV treatments. ESAs are colony-stimulating factors that function similarly to the body's natural EPO by stimulating the bone marrow to make RBCs. They are administered by subcutaneous injection into the arm, thigh, or abdomen. Data compiled from numerous randomized clinical trials have indicated that ESAs are associated with an increased risk of tumor progression, tumor recurrence, and shortened overall survival for patients with certain types of cancer. In addition, the prescribing information of these injectable ESAs notes an increased risk of myocardial infarction, stroke, venous thromboembolism, thrombosis of vascular access, and death. As a result, the FDA placed injectable ESAs on a Risk Evaluation and Mitigation Strategy (REMS) program to ensure that prescribers and patients understand the risks and benefits of their use. In 2017, the REMS requirement was lifted. However, the risk of developing a severe complication remains, and HCPs must continue to discuss the risks and benefits of ESAs with patients before initiating use and periodically during therapy (FDA, 2017).

Patients should receive blood transfusions to manage more severe IDA if associated with cardiovascular symptoms such as heart failure or angina. This approach rapidly corrects the cardiovascular compromise and associated hypoxia in conjunction with correcting the IDA. One unit of packed red blood cells (PRBCs) is equivalent to approximately 200 mg of iron. With PRBCs, the gastrointestinal system does not have to absorb the iron, thereby enhancing systemic absorption and treatment efficacy (Auerbach, 2022; Longo, 2017).

Pernicious Anemia

Treatment for pernicious anemia requires the prompt initiation of vitamin B12 therapy. While oral and injectable options for treatment exist, injectable formulations are preferred due to their heightened efficacy and enhanced absorption over oral agents. Only about 10 mcg of a 500 mcg oral supplement is absorbed in healthy adults. A manufactured vitamin B12 called cyanocobalamin is administered as an intramuscular injection. There are varied recommendations for treating pernicious anemia in adults, but in general, evidence-based guidelines recommend an initial dose of 1000 mcg of cyanocobalamin. Some sources recommend repeat injections daily for 6 to 7 days or until clinical improvement, and reticulocyte response on laboratory testing are seen. Other sources advise repeat doses at monthly intervals (Longo, 2017; NIH, 2022b).

Patients generally respond quickly to injectable vitamin B12 therapy, with reticulocytosis occurring within 5 to 7 days and anemia resolving typically within 2 months. Symptoms often improve rapidly with treatment; however, neurological manifestations can be long-lasting or permanent based on the severity and length of deficiency. Patients should be tested for concomitant folate deficiency, and folic acid replacement should occur with vitamin B12 therapy to ensure optimal outcomes. During the first week of vitamin B12 replacement therapy, patients should be monitored for hypokalemia. Hypokalemia is common during B12 replacement therapy for severe anemia due to intracellular potassium shifts during reticulocytosis. Oral potassium replacement is generally sufficient to correct the hypokalemia caused by vitamin B12 replacement. Patients should additionally be counseled on the importance of strict compliance with treatment, as pernicious anemia cannot be cured, and patients will require maintenance dosing with cyanocobalamin 1000 mcg monthly (Longo, 2017; McCance & Huether, 2019).

Folate-Deficiency Anemia 

All individuals of childbearing age that can become pregnant are strongly advised to consume folate-rich foods and receive at least 0.4 mg per day of supplemental folic acid to prevent pregnancy-related complications and fetal abnormalities in the event of an unplanned pregnancy. Pregnant patients should take a daily prenatal vitamin containing sufficient folic acid to meet daily requirements. Individuals who cannot tolerate prenatal vitamins due to nausea or other side effects may safely take oral supplementation with folic acid 1 mg daily, in addition to increasing folate-rich foods within their diet (Khan & Jialal, 2022; McCance & Huether, 2019). Folic acid supplementation at a dose of 1 mg daily is usually sufficient to prevent folic acid deficiency in other high-risk patients, such as those undergoing bariatric surgery or chronic alcohol use. If left untreated, folate deficiency can lead to neuropsychiatric manifestations such as depression, irritability, insomnia, cognitive decline, and psychosis (Khan & Jialal, 2022).

Oral folic acid supplementation (1 mg to 5 mg) daily is sufficient to treat folate deficiency in otherwise healthy adults. However, persons with alcohol use disorder may require up to 5 mg of folic acid supplementation daily (Khan & Jialal, 2022; McCance & Huether, 2019). All patients with folate deficiency should be encouraged to eat a diet rich in fruits and green leafy vegetables and counseled on the importance of compliance with daily supplementation. The response to folic acid therapy is usually rapid, with reticulocytosis peaking at 7 to 10 days after the initiation of treatment. A patient's hematocrit level typically increases by 4% to 5% each week during therapy and reaches normal limits within a month. If left untreated, folate deficiency can lead to neuropsychiatric manifestations such as depression, irritability, insomnia, cognitive decline, and psychosis (Khan & Jialal, 2022).

Anemia of Chronic Disease 

Treatment of ACD should focus on reversing the underlying disorder, and injectable ESAs may be indicated. Before starting any treatment for anemia in these patients, guidelines recommend screening for any other causes of anemia, such as active bleeding, hemolysis, vitamin B12 or folate deficiency, or malignant processes (Madu & Ughasoro, 2017; McCance & Huether, 2019).

Aplastic Anemia

The management of aplastic anemia is more complex than other types of anemias. Based on laboratory values and clinical symptoms, patients are treated with supportive therapies as needed. They often require blood transfusions for anemia and platelet transfusions for thrombocytopenia and to control bleeding. Immunosuppressive treatment with medications such as steroids (e.g., prednisone [Deltasone]) or immunosuppressants (e.g., cyclosporine [Sandimmune]) may be prescribed to suppress the immune system's attack on the bone marrow. Infrequently, splenectomy (surgical removal of the spleen) may be necessary for some patients (Sun et al., 2018).

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potential cure for aplastic anemia. An allogeneic HSCT uses hematopoietic stem cells taken from a donor source and transplanted into the affected patient to replace defective stem cells with healthy, functioning stem cells. These cells can be obtained directly from an individual's bone marrow or bloodstream. When obtained from the bloodstream, hematopoietic stem cells are referred to as peripheral blood stem cells (PBSCs). Another source of hematopoietic stem cells is the umbilical cord after delivery (Saad et al., 2020; Sun et al., 2018). For more information, see the NursingCE course on Hematopoietic Cell Transplantation. 

Sickle Cell Disease

Early diagnosis of sickle cell disease is critical. Prevention efforts aim to educate the patient about and control potential triggers for vaso-occlusive crises, such as aggressively managing infections and hydration needs and implementing aggressive pain management. Blood transfusions and hydroxyurea (Hydrea) are interventions available for chronic management of sickle cell disease to prevent long-term effects. Hydroxyurea (Hydrea) is a myelosuppressive agent that suppresses DNA synthesis, increasing RBC water content and altering their adhesion to the vascular endothelium. It works by making the RBCs more flexible, thereby reducing pain and the need for blood transfusions to manage acute issues such as acute chest syndrome. It is the only drug shown to reduce the frequency of crisis episodes in patients with sickle cell. Hydroxyurea (Hydrea) can decrease the rate of painful episodes by 50%. The most common side effects of hydroxyurea (Hydrea) are bone marrow suppression (i.e., neutropenia), anorexia, nausea, vomiting, elevated liver function enzymes, and infertility. Unfortunately, hydroxyurea has not been shown to significantly decrease sickle cell mortality rates and is not approved by the FDA for use in children (Ashorobi & Bhatt, 2021; Bender, 2021).

In 2019, the FDA approved voxelotor (Oxbryta) to treat sickle cell disease, but this drug is not available to children under 4. It binds to HbS, decreasing polymerization and increasing oxygen affinity. It is dosed at 1500 mg once daily in adults but should be reduced to 1000 mg in those with hepatic dysfunction class C. Children 4-11 should be dosed based on weight (600-1500 mg daily). Common side effects include headache, fever, diarrhea, nausea, vomiting, and abdominal pain, but it has been reported to cause hypersensitivity reactions and pulmonary embolism (Ashorobi & Bhatt, 2021; Bender, 2021).  

Crisis management is guided by supportive treatment and aggressive fluid resuscitation. Although opioids are not an appropriate treatment for the chronic pain that some sickle cell patients may experience, vaso-occlusive crises are acute pain episodes with significant evidence supporting the use of opioids during these periods. An HSCT is currently the only cure for sickle cell disease. This procedure is only used for patients with severe sickle cell disease with complications such as stroke, recurrent pain crises, nephropathy, retinopathy, priapism, and osteonecrosis of multiple joints. HSCT is unavailable for all patients diagnosed with sickle cell disease due to its significant risks, including graft-versus-host disease and death (Ashorobi & Bhatt, 2021; Bender, 2021).  

Thalassemia

Rarely, Hb Bart syndrome may benefit from intrauterine transfusions or HSCT. HbH disease typically requires minimal treatment, with the exception of occasional transfusions during hemolytic or aplastic crises (Tamary & Dgany, 2020). Mild forms of beta thalassemia generally do not require treatment and often do not shorten the lifespan. Those with more severe forms often require frequent blood transfusions to manage moderate to severe anemia. Regular blood transfusions can cause iron overload, a condition in which iron builds up in the blood, damaging organs and tissues, especially the heart and liver. It is managed with iron chelation therapy to remove excess iron from the body. Severe thalassemia can also cause early death due to heart failure. While thalassemia intermedia does not require regular treatment with blood transfusions, these individuals are still at risk for iron overload secondary to increased intestinal absorption of iron as a result of ineffective erythropoiesis. In severe cases, HSCT is also an alternative to traditional transfusion and chelation therapy. Cord blood transplantation from a related donor balances a high probability of cure with a reduced risk for graft-vs-host disease (NHLBI, 2022c; Origa, 2021).

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