CHAPTER 32
Anemia
Sarah M. Colson, MSN, APRN, NP-C
DEFINITION
The term anemia, from early Greek, literally means “without blood.” Being a culture given to war and philosophy, the Greeks had ample opportunity to view loss of blood and postulate on the effects it had on the human body. From such remote beginnings, science has made great advances in the understanding of blood and the diverse pathology that can lead to anemia. Medically defined, anemia is a deficiency in the red cell component of blood, less than the normal number of red blood cells (RBCs), or less than the normal quantity of hemoglobin per unit volume. Functionally, anemia can also be defined as an insufficient red cell mass to adequately deliver oxygen to peripheral tissues. As red cell mass is not a readily available test, assessment is most often based on levels of hemoglobin (Hgb), hematocrit (Hct), and RBC count (Besa & Krishnan, 2012). Physiologic anemia is a relative reduction in red cell values due to a natural increase in plasma volume, which occurs in the sixth to seventh month of pregnancy. Age and gender are also factors when considering normal levels. The World Health Organization (WHO) has defined anemia within age-related categories:
AGE/GENDER | ANEMIC Hgba (g/dL) |
Children 6–59 months | <11.0 |
Children 5–11 years | <11.5 |
Children 12–14 years | <12.0 |
Nonpregnant women, age 15+ years | <12.0 |
Pregnant women | <11.0 |
Men, age 15+ years | <13.0 |
aWorld Prevalence of Anaemia, 2008.
Adults older than 65 years have been found to have a generally lower hemoglobin level. Some of this decrease can be accounted for by decreased androgen levels in older men. It is undecided if there is more pathology causing anemia in the elderly population or if lower norms are appropriate in this age group (Greer et al., 2009).
There are several limitations on assessing anemia by strict numerical parameters. The following examples illustrate caveats to the usual definition or presentation of anemia:
Plasma volumes change normally in later pregnancy and in abnormal conditions such as with severe burns. In such cases, the relative hemoglobin values are affected.
Chronic obstructive pulmonary disorders (COPD) lead to a sensing of reduced oxygen in the kidneys, in turn stimulating erythropoietin release and subsequent higher RBC production.
High-altitude living (such as in the Andes and the Himalayas) will stimulate an increase in RBC production (Greer et al., 2009; van Patot & Gassmann, 2011). In such cases, a normal hemoglobin level for one person might represent a relative anemia in the previously polycythemic individual.
In acute hemorrhage, hemoglobin values are not immediately reflective of sudden decreases, owing to compensatory vasoconstriction and the redistribution of interstitial fluids. Additionally, fluid resuscitation efforts will alter relative values by hemodilution. Under conditions of hemodynamic shock, the level of acidosis is a good indicator of whether the tissues are receiving oxygen (the prime purpose of adequate circulating RBCs).
Thalassemia, a heritable disorder of globin synthesis, produces a high RBC number and simultaneous low hemoglobin that seems to defy the common standard of anemia.
Anemia is rarely a disease in itself, but almost always a manifestation of an acquired condition or genetic abnormality. Major organ disease states can be adversely affected by concurrent anemia or, in a spiraling phenomenon, cause more anemia, which in turn worsens organ function. Cardiorenal anemia syndrome is a phenomenon that occurs because chronic heart failure, chronic renal insufficiency, and anemia can each cause and be caused by one another. Correcting the primary source of anemia may decrease complications and provide meaningful palliation in serious illness. This chapter is intended as a primary care overview and a framework with which to begin a diagnostic process.
ANATOMY, PHYSIOLOGY, AND PATHOLOGY
The red cell is composed of heme iron and protein chains or globin subunits. One molecule of hemoglobin is comprised of four heme groups embedded within four globin units. Alterations at this structural biochemical level lead to pathology affecting the major function of the RBC, which is to provide transport of oxygen from the lungs to tissues. Oxygen is bound to the iron portion of the porphyrin molecule; some carbon dioxide (<10%) rides on the protein portion of the molecule but does not compete for a gas binding site. Most carbon dioxide making the return journey for excretion from the lungs is dissolved in plasma. Carbon monoxide is an example of a gas that does effectively block oxygen binding sites by preferentially and tightly binding to hemoglobin; this action accounts for its toxicity. Gas tensions allow the bidirectional diffusion of oxygen across the cell membrane (Greer et al., 2009).
The normal RBC is described as a biconcave disc with approximate diameter of 6 to 9 microns when viewed stained under a slide. Mature red cells are without a nucleus, which accounts for the biconcave form. This nuclear extrusion creates an area of central pallor that should represent no more than one third of the whole cell. The flexible RBC structure allows it to deform as needed in circulating through the minute flow space of the capillaries. Immature RBCs are called reticulocytes and are somewhat larger than when fully developed as mature circulating red cells. Reticulocytes still retain some of their RNA nuclear material, which accounts for their darker color and which can be effectively stained, enhancing identification (Greer et al., 2009). Blood loss that stimulates a brisk reticulocytosis in healthy bone marrow will temporarily increase the mean cell volume (MCV) because of the inherently larger size of reticulocytes.
RBCs maintain their cellular integrity for approximately 100 to 120 days. Most iron in the body is conserved by the recycling of senescent RBCs. Only 1 mg of iron per day is lost through tissue sloughing or blood loss, so an equal portion must be effectively absorbed from the duodenal enterocytes to replenish this loss. The spleen functions to filter and remove aged or damaged RBCs and participates in the recycling process. When senescent, RBCs are engulfed by macrophages that break down the cells to component parts. Globin is broken down to constituent amino acids (AAs) for the rebuilding of more complex proteins. The heme portion is broken down to iron and the porphyrin ring. Iron then binds to apotransferrin to form transferrin, a molecule that can transport the iron through the plasma to the bone marrow for erythropoiesis or other tissues for storage. Iron is stored primarily in the liver, the spleen, and the bone marrow. Heme molecules also play an important role in the cytochrome system, in enzyme function, in electron transport, and in energy production. Ribonucleotide reductase is an iron-dependent enzyme that is required for DNA synthesis (Rosenthal & Glew, 2009). Iron deficiency therefore may have a broader impact on physiological function than previously understood.
The kidneys continually monitor for levels of oxygen, secreting the hormone erythropoietin to stimulate production of red cells when oxygen levels are low. With renal failure, the sensing of oxygen is impaired and erythropoietin levels are not adequate to maintain a nonanemic state (Jelkmann, 2011). Where there are elevated levels of erythropoietin without RBC production, lack of essential ingredients such as iron, other nutrients, and protein may be suspected. Nutritional deficiencies may thwart the body’s call for increased production. Alternately, decreased marrow function can effect production if erythropoietin levels are raised, iron is replete, and nutrition is otherwise unimpaired.
EPIDEMIOLOGY
Epidemiology, which identifies the burden of an illness upon a given population, relies upon accurate current data. The prevalence of anemia will vary according to how populations of interest are identified. Epidemiologic variations for anemia exist among age groups, gender, ethnicity, climate, and country. Public health initiatives may have an impact on prevalence of anemia, depending on geopolitical groups. Socioeconomic status, war, famine, and poverty will affect the nutrition and disease factors that determine anemia prevalence in a given geopolitical area. Women and children often bear a disproportionate burden of these deficiencies and consequently by age and gender have a higher incidence of anemia.
There are several hundred types of anemia with innumerable causes and treatments. Some are by far more common in general across the world population. Iron deficiency anemia, for example, is the single most common anemia throughout the world. The causes of iron deficiency anemia vary within population subsets. Iron deficiency is often brought on by loss of blood, either chronic or acute. Within the United States and other first-world Western countries, the most common cause is often a gastrointestinal (GI) loss of blood. In tropical and undeveloped climates, diseases are the most prevalent etiology for anemia. Malaria and helminth infection, poverty, under education, and malnutrition will be the prime contributors to iron deficiency anemia in these areas of the world. Sickle cell disease causing severe anemia is the most common inherited hematologic disease, affecting millions world-wide; this disease. may be found in Africa and countries with African-descent populations.
Thus, for the practitioner, determining the factors affecting the given population of concern will identify the most common presentation of anemia for the area served. It defies the scope of this chapter to list all of these; however, there are resources available for further study. One such comprehensive resource is: Global Burden of Diseases, Injuries, and Risk Factors Study 2010 (GBD 2010, www.healthmetricsandevaluation.org/gbd).
DIAGNOSTIC CRITERIA
Types of Anemia
Each type of anemia may be viewed via several different diagnostic pathways. Iron deficiency anemia can be viewed by cell size as a microcytic anemia, as a hypo-proliferative anemia, or as a nutritional anemia. Reorganizing various anemia subgroups to capture every diagnostic viewpoint is not undertaken, here for the sake of brevity and clarity. The morphologic characteristics and then the general groupings of anemia etiologies are presented in this section.
Anemia Categories by Cell Morphology
RBC size, shape, and count are used as diagnostic pathways to differentiate morphologic classes of anemia. Descriptors of RBC size (such as normocytic, microcytic, or macrocytic) refer to the MCV. Normochromic, hypochromic, or hyperchromic descriptors refer to the mean corpuscular hemoglobin concentration (MCHC), reflecting the amount of hemoglobin within each red cell. Higher hemoglobin concentrations are more deeply pigmented. Hypochromic cells are pale, poorly colored, and iron deficient. A high MCHC, known as hyperchromia, can be found in hereditary spherocytosis, sickle cell disease, and homozygous hemoglobin C disease. Reticulocytes, the youngest circulating RBCs, are somewhat larger and more deeply pigmented than the mature biconcave RBC. Reticulocytes take approximately 24 hours in circulation to condense down into a mature biconcave form. If there is an elevation in RBC production, a high number of reticulocytes will increase the average cell size, raising the MCV. This change is not based on a disease process, but is a normal and temporary variant. Red cell distribution width (RDW) is a measure of the variation in size of the RBC. An elevated RDW is also known as anisocytosis. The RDW is interpreted with the MCV to assist in the diagnostic evaluation.
Some of the more common examples using cell size, shape, and count are often found first in the primary care setting.
Clinical Pearls
If iron can be absorbed well from the GI tract, iron deficiency anemia is very responsive to iron supplementation, all other aspects of hematopoiesis being normal. Alternatively, IV iron can be utilized in cases of refractory absorption, such as in severe Crohn’s disease or ulcerative colitis.
A high to high normal RBC count with microcytic cells and normal RDW may indicate a beta thalassemia, a heritable disorder of globin synthesis. Often this anemia will have been noted medically for years and may have been mistakenly treated with iron supplementation. Thalassemia minor will frequently cause a microcytic anemia without evidence of hemolysis. Thalassemia can be confused with iron deficiency, as cells are extremely microcytic; however, the microcytosis associated with thalassemia will be unresponsive to iron supplementation.
Microcytic hypochromic anemia (small, pale cells), low RBCs, and high RDW often represents iron deficiency, the most common anemia worldwide. A workup to determine a source should be undertaken commensurate with history and physical findings.
Chronic menorrhagia may be substantial enough to outstrip the body’s ability to absorb oral iron, so IV iron can be useful until the menorrhagia state is managed.
Macrocytic anemia with large cell size can be found in B12 and/or folate deficiencies such as pernicious anemia, poor dietary intake, vegan diets, excessive alcohol consumption, use of erythrocyte-stimulating agents (ESAs), drugs affecting DNA synthesis, or liver disease etiologies. Macrocytosis often accompanies treatment with hydroxyurea, for example, and is correlated with an increase in production of hemoglobin F.
A normocytic, normochromic anemia can be found in chronic disease and/or inflammatory states, including rheumatoid arthritis, chronic or end-stage renal disease, heart failure, or chronic infections such as osteomyelitis. Normocytic anemia can also herald the beginning of iron deficiency or other nutritional deficiencies. Uremia, found in later-stage chronic kidney disease, can also contribute to anemia of chronic disease. After a complete workup, often this anemia may be shown to be multifactorial in nature, as several comorbid conditions are often found together.
High RDW may be seen in mixed states of iron deficiency and B12/folate deficiency; it also may be seen in GI absorption problems, malnutrition, and liver disease with chronic blood loss. Pathology smear reviewers should always recall the patient’s recent transfusion history, as a severe iron deficiency anemia may require transfusion support, which will render interpretation of RDW unreliable for a period of time.
Anemia Categories by Production, Destruction, or Loss
Decreased production of cells or ineffective erythropoiesis can be related to any failure in the production process. Nutritional deficits, bone marrow failure, and hereditary or acquired disease can contribute to hematopoietic production problems. Where bone marrow failure syndromes and/or rare anemia disorders are suspected, hematology consults are appropriate for guidance or management. Production problems that are found to be related to nutritional deficits, iron deficit from blood loss, endocrine imbalance, or anemia secondary to major organ dysfunction can often be diagnosed and addressed within the primary care setting. Bone marrow disorders may show chronic decline over years and therefore be monitored and managed in primary care until decision for active treatment must be made.
Iron deficiency anemia is the most common anemia worldwide. Iron deficiency caused by nutritional deficits alone can occur in pregnancy, in young children who have a high intake of cow’s milk, and elders who progressively have less resources for nutrient-rich food preparation. Children and adolescents whose growth needs exceed their iron intake may suffer from iron deficiency leading to anemia. Severe menorrhagia in adolescent and adult females, though not common, can contribute to anemia burden in an otherwise healthy younger population. In the United States, iron deficiency anemia in adults is most often related to chronic GI blood loss. When GI loss is suspected and confirmed with fecal occult blood checks, a progressive GI workup is necessary. A colonoscopy and esophagogastroduodenoscopy (EGD) are needed, and if occult GI bleeding persists, a video capsule endoscopy for small bowel sources may be required. Small bowel bleeding represents a small percentage of all GI bleeding, but of that population blood vessel malformations, AVMs, account for approximately 70% of the cases. The oldest elderly population may not tolerate or may decline this level of workup. The primary care practitioner may be left with palliative support by way of iron infusions or blood transfusions for this small population of patients who persist with a chronic GI bleed but in whom intervention is not possible. Younger adult patients who have severe Crohn’s disease, ulcerative colitis, and gastric bypass surgery may also present with iron deficiency from loss or absorption problems.
Sideroblastic anemia (SA) is due to congenital or acquired defects in heme synthesis and utilization of iron. Sideroblastic anemia in its hereditary form presents as highly variable in the level of anemia manifested (Greer et al., 2009). SA is characterized by microcytic hypochromic red cells in circulation, but severity is variable. As with any hypoxemic state, there is a stimulation of erythropoietin production; however, this does not lead to normal cell production. Iron is delivered to a developing red cell but is sequestered in mitochondrial ferritin, which assumes a classic ring; hence the term ringed sideroblast. Ineffective erythropoiesis leads to erythroblast destruction in the marrow. Erythroid hyperplasia is also noted in the bone marrow. An acquired and usually reversible sideroblastic anemia has been associated with isoniazid (INH) in treatment of tuberculosis. The mechanism appears to be altered vitamin B6 metabolism in INH therapy. Drug cessation and/or large doses of B6 can reverse this acquired SA. Iron overload is a common feature of this anemia and because of the symptomatic hypoxic nature may be incorrectly treated with supplemental iron to improve erythropoiesis (Bottomley, 2012). Hepatosplenomegaly is found in one third to one half of SA patients. With advancing iron overload, after many red cell transfusions for symptomatic anemia, liver and cardiac decompensation become manifest (Greer et al., 2009). Assessment of iron overload includes serial ferritin measurement, liver biopsy or MRI, and cardiac MRI to assess iron overload in these organs. Initiation of a chelation agent is considered at approximately 20 transfused units of RBCs and/or a megaloblastic anemia characterized by impaired RBC production leading to enlarged macrocytic red cells. Macrocytosis may occur with or without anemia, but in either case should prompt an analysis for etiology. B12 and/or folate deficiency is a common finding in macrocytosis. Folate is necessary for thymidilate synthesis and production of DNA. B12 is needed to incorporate circulating folate into developing RBCs. Without these B vitamins, RBC production is impaired, affecting DNA synthesis, cell structure, and function. Hypovitaminosis may result from dietary insufficiency or impaired absorption, such as in pernicious anemia, inflammatory bowel disorders, alcoholism, and some medications.
Alcoholism can lead to poor absorption (particularly of folate), gastric irritation, and liver disease. Excess chronic alcohol consumption can also lead to bone marrow suppression and serous atrophy development within the previously productive bone marrow (Munfus & Menke, 2009).
Pernicious anemia is related to an autoimmune process that damages parietal cells in the gastric mucosa. Without parietal cells, intrinsic factor is greatly reduced and impairs B12 absorption, leading to the megaloblastic formation of RBCs. Some medications affect the absorption of various B vitamins or DNA synthesis. Long-term use of metformin for diabetic management, and proton pump inhibitors may affect absorption of nutrients. Methotrexate is an antifolate drug used in chemotherapy treatment for various cancers and in a variety of autoimmune disorders, including rheumatoid and psoriatic arthritis. Another chemotherapy used in myeloproliferative disorders is hydroxyurea (HU), which consistently creates a macrocytosis (from increased production of hemoglobin F with HU).
Anemia of chronic disease or chronic inflammation (discussed under normocytic anemia) often presents as a mild to moderate-level anemia. The cells are usually normocytic and normochromic, and the blood count will show reduced RBC and reticulocyte counts. There may be several processes contributing simultaneously to this anemia and therefore have differing mechanisms acting to suppress the production of erythrocytes.
Anemia of endocrine origin may result from disorders related to thyroid function, adrenal function, and androgen deficiencies. In such cases, the anemia may not be corrected until the disease or deficiency responsible is under control. Many autoimmune processes that may be found simultaneously may contribute to an anemia. The metabolic deceleration of hypothyroidism may contribute to anemia by creating a hypo-proliferative process (Mehmet, Aybike, Ganidagli, & Mustafa, 2012). Pernicious anemia may be found concurrent with other autoimmune disease, including Hashimoto’s thyroiditis. Hypothyroidism can lead to a normocytic anemia, whereas pernicious anemia, with reduced B12 absorption, will produce a macrocytic state. When found concurrently, there may be a confusingly mixed smear. Elderly males may present with a low testosterone level and on supplementation, the anemia will correct itself as long as iron and protein sources are available. Menorrhagia, sometimes related to thyroid imbalance, can lead to severe iron deficiency anemia, as the loss of blood and thus iron reserves prevents the bone marrow from effective erythropoeisis. On pathology smear review, the finding of acanthocytes, red cells that have a spiculated appearance, can signal hypothyroidism. However, acanthocytosis signifies a derangement in the lipid content and structure of the red cell membrane. This may be found more commonly in lipid abnormalities and severe liver disease and is not necessarily exclusive to thyroid disorders.
Myelophthisic anemia is a result of bone marrow failure where infiltrative lesions replace the hematopoietic areas, causing progressive decreases in production. Pancytopenia, neutropenia, or thrombocytopenia may be observed concurrently with this anemia. Multiple myeloma, leukemias, and metastatic cancers invade the marrow and displace hematopoietic production areas. Myeloproliferative disorders such as polycythemia vera may lead eventually to a postproliferative myelofibrosis, or primary myelofibrosis may present de novo. Fibrosis can be observed in the stained core sample under the microscope as tiny filaments. Progressively, the numerous filaments encircle areas of cell production, effectively slowing or trapping cells from proceeding into the circulation. All cell lines may be affected in this process. Marrow failure or secondary cancer development may occur as a long-term consequence of past chemotherapy and radiation treatment. Additionally, the diagnoses of myeloproliferative and myelodysplastic disorders carry a higher risk for transformation to an acute leukemic process than in populations without these disorders. Patients with myelodysplastic syndrome and myelofibrosis are reported to have shorter survival times than those without these features (Algarni, Akhtari, & Fu, 2012).
Aplastic anemia (AA) may be acquired or congenital. The primary life-threatening problem is bone marrow failure, the development of myelodysplasia, and possible evolution to acute myelogenous leukemia (AML). In most cases, acquired AA behaves as an immune-mediated disease that leads to bone marrow failure (Young, Scheinberg, & Caladro, 2008).
CLINICAL WARNING:
Severe AA is a medical emergency requiring prompt referral for workup, treatment, and aggressive supportive care (Greer et al., 2009).
The difference between AA and myelodysplasia (myelodysplastic syndrome, MDS) as a bone marrow failure disorder is that on examination of bone marrow, aplastic or hypoplastic anemia reveals a severe lack of proliferating cells. By contrast, in MDS there is often a hypercellular marrow with abnormal dysplastic forms in the bone marrow and in circulation.
A congenital form of AA is known as Fanconi’s anemia (FA), a rare autosomal recessive disorder found with higher incidence in people of Afrikaner descent and within the Ashkenazi Jewish population. DNA repair is affected in FA, which has a significant impact on cell division and therefore bone marrow production of cells. Life expectancy is shortened with FA, which within the last decade has been approximately 30 years. A majority of patients with FA also frequently have concurrent congenital defects such as lack of thumbs at birth, microcephaly, cognitive and developmental defects, and renal and endocrine abnormalities.
In acquired aplastic anemia, toxic exposure to chemicals, chemotherapy, and/or radiation treatment can be implicated. Several sources attribute the death of Madame Curie to an aplastic anemia thought to be caused by her chronic exposure to radiation in her lifetime work with radium.
Autoimmune processes and infectious etiologies have also been associated. Paroxysmal nocturnal hemoglobinuria (PNH) presents more frequently in patients with AA (but not exclusively) and adds the threat of hemolysis to an already bleak bone marrow failure condition. PNH is an acquired clonal disease characterized by chronic intravascular hemolysis, cytopenias related to bone marrow failure, and increased tendency to thrombosis. Hemoglobinuria presents as a marked discoloration of the urine after awakening from sleep and resolves over the course of the waking hours. Hemoglobinuria is not noted as an initial finding in most cases, however. If signs of hemolysis are found concurrent with known aplastic anemia, there should be strong clinical suspicion for PNH, as there is a dual presentation in a high percentage of aplastic anemia patients.
Myelodysplastic syndrome or MDS was formerly called preleukemia for the increased frequency with which it transformed to acute myelogenous leukemia. MDS is a class of blood-forming disorders affecting the myeloid lineage of cells. Approximately 10,000 cases are diagnosed in the United States each year. The presentation and progression can be variable and may first be suspected when a blood smear shows dysplastic forms in circulation and cell line decreases including anemia. Most of the morbidity associated with MDS comes not from transformation to AML but from the progressive cytopenias, multiple transfusions, and related complications. Iron overload is common in transfusion-dependent MDS patients. The International Prognostic Scoring System (IPSS) is most frequently utilized in predicting outcomes. MDS is monitored and managed most frequently in the hematology–oncology setting, as the diagnostic process and treatment will involve advanced care and decision making with the patient. Bone marrow biopsies, cytogenetic testing, transfusion support, chelation, and treatment with hypomethylating agents such as azacitadine or decitabine may be part of hematology management. In some cases, bone marrow transplantation may be undertaken, but this disorder is frequently found in an elderly population who may not be candidates for transplant due to age, comorbidities, frailty, or finances. Though such management is a hematology function, primary care should continue to maintain a close patient relationship and manage all other comorbidities that have an impact on patient health. The cost of treatment may be prohibitive for many individuals; if this is the case, the primary care provider (PCP) may be called on to manage the patient’s palliative care needs with transfusion and chelation support.
Pure red cell aplasia (PRCA), a rare disorder, may be acquired or congenital. Congenital PRCA (Diamond–Blackfan syndrome) presents in infancy with a severe macrocytic anemia and results in a shortened life expectancy. A benign transient childhood PRCA may develop after a viral infection and then spontaneously resolve. Acquired idiopathic PRCA is the most common presentation in the adult population. Autoimmune causes have been ascribed, such as erythropoietin antibody development from ESA use. PCRA has also been associated with lupus, rheumatoid, and diabetic-related autoimmune diseases. Thymoma, T-cell, and/or B-cell deficiencies may account for up to 15% of PRCA cases. A small percentage of idiopathic PRCA cases are refractory to treatment, may evolve into leukemia, and are classified as myelodysplastic (Greer et al., 2009).
Anemia Caused by Cellular Destruction or Hemolysis
The normal lifespan of RBCs is approximately 120 days. There is a natural hematopoietic balance between the normal senescence and death of RBCs and continuing RBC renewal in the bone marrow. When the lifespan of RBCs is abnormally shortened in the hemolytic process, the reduced RBC state triggers stimulation of the bone marrow to produce more RBCs. This increased production can be noted in an increased reticulocyte count as long as there is no problem with the bone marrow or supplies of nutrients. Haptoglobin in plasma will combine with the free hemoglobin liberated from the red cell when it is broken, either from normal senescence and death or hemolysis. When there is an elevated level of free hemoglobin from hemolytic destruction, haptoglobin levels will be low. Because of the lysed red cells, unconjugated bilirubin and lactic dehydrogenase (LDH) levels will also be elevated. Except in patients with liver disease, increased indirect serum bilirubin, increased LDH, and decreased haptoglobin are characteristic of hemolysis (Koury & Rhodes, 2012). A complete blood count assessment may cause the automated blood counter to flag for a high count of fragmented RBC forms. The manual smear review may reveal schistocytes, helmet cells, or other abnormal forms and fragments. The presence of a high number of spherocytes or ovalocytes may point toward a hereditary etiology. Sickle cells or the small, pale red cells of thalassemia, both hereditary-based diseases of hemoglobin synthesis, may be present in a smear review.
Sickle Cell Disease
Sickle cell disease is the most common inherited hematologic disease, affecting millions worldwide. There is a single substitution of one amino acid for another (valine instead of glutamine) which leads to polymerization and deformation in hemoglobin S. These sickle cells are found in the homozygous (SS) but not the heterozygous (Ss) or carrier state. Morphologically, cells are misshapen, sickled, and rigid. Sickle cells tend to occlude small vessels, leading to painful vaso-occlusive episodes. Cell fragility causes hemolysis, leading to severe anemic states. Clinical finding may range from acute to chronic symptoms. Repeated vaso-occlusive episodes may lead to stroke, splenic infarcts with eventual auto-splenectomy, blindness, heart, and renal failure. Ankle ulcers, bone and joint crises, and abdominal crises all create pain management challenges. Hemoglobin S may co-occur with other hemoglobinopathies such as hemoglobin C, alpha and beta thalassemia. Patients and their families should be educated to avoid precipitants to a sickle cell crisis, such as dehydration, infection, stress, high altitudes, and exercising to exhaustion. A multidisciplinary approach to management is required in this very complex disease process. Prevention of crises can reduce morbidity. Beneficial effects of hemoglobin F production with hydroxyurea have been noted in treatment of sickle cell disease as well as thalassemia intermedia (Karimi, 2009).
Acquired Hemolytic Anemia
In addition to hereditary disease, hemolysis may arise from acquired causes such as infection, medications, and various immune processes. RBC destruction may be categorized as extravascular or intravascular hemolysis and may present as an acute or chronic condition. Hemolysis can be found alone or with other comorbid conditions, which together may contribute to a complex etiologic basis for anemia. If anemia is multifactorial, the levels of unconjugated bilirubin, LDH, the peripheral smear review, and haptoglobin level should still mark hemolysis as a contributor to the existing anemia.
There are numerous causes of hemolysis related to factors extrinsic to the red cell. Mechanical damage to the red cell membrane can be caused by extracorporeal oxygenation during surgery, by artificial heart valves, or by hemodialysis. Some hemolysis has been associated with high-level exercise such as marathon training. Deep thermal burns can cause any number of mechanisms for anemia, including hemolysis. The passage of erythrocytes through damaged small blood vessels causes mechanical injury of the cell with fragmentation. Microangiopathic hemolytic anemia of this type is seen in disorders such as thrombotic thrombocytopenic purpura, hemolytic–uremic syndrome, and disseminated intravascular dissemination (DIC; George & Charania, 2013).
Hereditary Spherocytosis and Hereditary Elliptocytosis
Hereditary spherocytosis and HE are two of the most common hemolytic disorders related to hereditary abnormalities of the red cell membrane (Salomao et al., 2010). Hemolysis from spherocytosis occurs because of increased red cell membrane fragility and increased destruction of abnormal cells as they pass through the spleen. Symptoms and severity can vary. Diagnosis can be from the early neonatal period to late adulthood. Patients may have mild pallor, intermittent jaundice, mild to moderate fatigue, and an enlarged spleen. Family history may often reveal a similar set of symptoms in other family members. Splenectomy may eventually have to be undertaken, and consequences of splenectomy and following changes in anemia may involve primary care management over years of HE. The HE syndrome variants are clinically and hematologically heterogeneous, sharing the features of elliptocytes on a peripheral smear (Greer et al., 2013). One common form of HE may manifest with no anemia, no hypersplenism, and normal red cell survival even though the peripheral smear shows up to 100% elliptocytes. Often this form of HE is found incidentally and is surprising when a smear review indicates such a high number of elliptocytes. Homozygous HE may present with variable clinical severity and moderate to severe hemolysis (Greer et al., 2013). Mild to moderate levels of anemia from hemolysis in these diseases may be tolerated for many years, but may become problematic if splenic enlargement evolves or comorbid contribution to anemia worsens the patient’s medical condition.
Glucose-6-Phosphate Dehydrogenase Deficiency
Glucose-6-phosphate dehydrogenase deficiency can be related to acute periods of hemolysis with striking drops in hemoglobin given certain exposures. With G6PD deficiency there may be no anemia and no increased reticulocytosis in the steady state (Greer et al., 2009). G6PD-deficient erythrocytes have a structure variably susceptible to oxidative stress. When exposed to oxidants (dietary, infectious, or medication/chemical), the biochemical cell changes make the cell vulnerable to destruction in the splenic and liver reticuloendothelial system. Massive extravascular and intravascular hemolysis can ensue. Clinical signs may include pallor from the 3 to 4 g drop in hemoglobin, jaundice, dark urine, abdominal, and/or back pain. Primary care management will involve prompt recognition of the diagnosis, investigation, and cessation of the offending agent where possible, as well as supportive care. Dietitian involvement is recommended to educate patients on foods to avoid, such as legumes. Complete drug and food listings should be supplied to patients diagnosed with this disorder with periodic updates and reviews.
Immune-Mediated Hemolysis
Immune-mediated hemolysis is precipitated by immunoglobulin binding to the surface of red cells and causing subsequent attack by the immune system. There are warm- and cold-mediated variants to immune hemolysis. Microspherocytes may be found on a peripheral smear review and the direct antiglobulin test (DAT) will be positive. Alloimmune hemolysis occurs when a there is an A-B-O incompatibility during transfusion. A transfusion reaction may occur immediately, within minutes, or may be delayed until 3 to 10 days after completion of the transfusion. Autoimmune hemolysis or autoimmune hemolytic anemia (AIHA) has a particular diagnostic pathway and may be precipitated by medications (a-methyldopa, penicillin); by the presence of a non-Hodgkin’s lymphoma, as in chronic lymphocytic leukemia; or by other autoimmune diseases (systemic lupus, rheumatoid arthritis, ulcerative colitis). Infectious etiologies include mycoplasma or viral pneumonias, mononucleosis, or other respiratory infections. The workup and treatment should be managed with a hematologist consult, as there are multiple possible etiologies of AIHA. Treatment pathways will be dependent on the severity and the presence of underlying disease requiring treatment (such as a lymphoma). Steroid treatment, splenectomy, monoclonal antibody, or chemotherapy administration may also be considered through a hematologist consultation. Long-term steroid therapy with associated risks should not be undertaken for mild manifestations of immune-mediated hemolysis where the bone marrow may be able to compensate for the hemolytic loss. Acute hemolytic crises may require transfusion support as a temporizing stabilization until other treatments can take effect.
Clinical Presentation of Anemia
As noted earlier, anemia is not an end diagnosis in itself but a condition that merits a thorough diagnostic workup to uncover the etiologic basis. Primary care clinicians see many diseases, syndromes, and conditions that can contribute to anemic states. Anemia may be detected incidentally in a general physical examination or preoperative assessment. The presentation of anemia may vary from vague symptoms of malaise to a much more pronounced level of fatigue, dyspnea with exertion, pale mucous membranes, and cardiac symptoms. Chest pain and dyspnea on exertion may become more frequent in patients with coronary artery disease. Heart failure is exacerbated by anemia but at the same time may contribute to anemia. Hemolytic anemia may contribute to jaundice of skin, mucous membranes, and conjunctiva.
