Introduction
Background
Microcytic anemia.
Microcytic anemia.
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Microcytic anemia.
Microcytic anemia.
Peripheral smear showing ovalocytes, macrocytes, ...
Peripheral smear showing ovalocytes, macrocytes, and a hypersegmented polymorphonuclear leukocyte.
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Peripheral smear showing ovalocytes, macrocytes, ...
Peripheral smear showing ovalocytes, macrocytes, and a hypersegmented polymorphonuclear leukocyte.
Anemia, like a fever, is a symptom of disease that requires investigation to determine the underlying etiology. Often, practicing physicians overlook mild anemia. This is similar to failing to seek the etiology of a fever. The purpose of this article is to provide a method of determining the etiology of an anemia.
Anemia is strictly defined as a decrease in red blood cell (RBC) mass. Methods for measuring RBC mass are time consuming, are expensive, and usually require transfusion of radiolabeled erythrocytes. Thus, in practice, anemia is usually discovered and quantified by measurement of the RBC count, hemoglobin (Hb) concentration, and hematocrit (Hct). These values should be interpreted cautiously because they are concentrations affected by changes in plasma volume. For example, dehydration elevates these values, and increased plasma volume in pregnancy can diminish them without affecting the RBC mass.
For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Anemia.
Pathophysiology
Erythroid precursors develop in bone marrow at rates usually determined by the requirement for sufficient circulating Hb to oxygenate tissues adequately. Erythroid precursors differentiate sequentially from stem cells to progenitor cells to erythroblasts to normoblasts in a process requiring growth factors and cytokines. This process of differentiation requires several days. Normally, erythroid precursors are released into circulation as reticulocytes.
Reticulocytes remain in the circulation for approximately 1 day before reticulin is excised by reticuloendothelial cells with the delivery of the mature erythrocyte into circulation. The mature erythrocyte remains in circulation for about 120 days before being engulfed and destroyed by phagocytic cells of the reticuloendothelial system.
Erythrocytes are highly deformable and increase their diameter from 7 µm to 13 µm when they traverse capillaries with a 3-µm diameter. They possess a negative charge on their surface, which may serve to discourage phagocytosis. Because erythrocytes have no nucleus, they lack a Krebs cycle and rely on glycolysis via the Embden-Meyerhof and pentose pathways for energy. Many enzymes required by the aerobic and anaerobic glycolytic pathways decrease within the cell as it ages. In addition, the aging cell has a decrease in potassium concentration and an increase in sodium concentration. These factors contribute to the demise of the erythrocyte at the end of its 120-day lifespan.
RBCs contain fluid Hb encased in a lipid membrane supported by a cytoskeleton. Abnormalities of the membrane, the chemical composition of the Hb, or certain glycolytic enzymes can reduce the lifespan of RBCs to cause anemia. Basically, only 3 causes of anemia exist: blood loss, increased RBC destruction (hemolysis), and decreased production of RBCs. Each of these 3 causes includes a number of etiologies that require specific and appropriate therapy. Often, the etiology can be determined if the RBCs are altered in either size or shape or if they contain certain inclusion bodies. For example, Plasmodium falciparum malaria is suggested by the presence of more than one ring form in an RBC and produces pan-hemolysis of RBCs of all ages.
Frequency
United States
The prevalence of anemia in population studies of healthy nonpregnant people depends on the Hb concentration chosen for the lower limit of normal values. The World Health Organization chose 12.5 g/dL for both adult males and females. In the United States, limits of 13.5 g/dL for men and 12.5 g/dL for women are probably more realistic. Using these values, approximately 4% of men and 8% of women have values lower than those cited. A significantly greater prevalence is observed in patient populations. Less information is available regarding studies using RBC or Hct.
International
The prevalence of anemia in Canada and northern Europe is believed to be similar to that in the United States. In underprivileged countries, limited studies of purportedly healthy subjects show the prevalence of anemia to be 2-5 times greater than that in the United States. Although geographic diseases, such as sickle cell anemia, thalassemia, malaria, hookworm, and chronic infections, are responsible for a portion of the increase, nutritional factors with iron deficiency and, to a lesser extent, folic acid deficiency play major roles in the increased prevalence of anemia. Populations with little meat in the diet have a high incidence of iron deficiency anemia because heme iron is better absorbed from food than inorganic iron.
A recent study in Iran, however, demonstrated that once-weekly low-dose iron supplementation can be effective in improving iron status and in treating iron deficiency anemia.1 Mozaffari-Khosravi et al randomly selected and assigned 193 adolescent girls aged 14-16 years to receive either 150 mg ferrous sulfate once weekly for 16 weeks or no iron supplementation. Both before and after intervention, the percentage of anemia, iron deficiency anemia, and iron deficiency were measured in both groups of girls.
Although the parameters measured before the intervention were not significantly different, at the end of 16 weeks, the group that received the ferrous sulfate had significant improvement in the same parameters.1 In addition, all cases of iron deficiency anemia were resolved in the gropu receiving the low-dose iron supplementation.
Mortality/Morbidity
* The morbidity and mortality of anemias vary greatly depending on the etiology.
o Acute hemorrhage has variable mortality depending on the site of bleeding (80% with aortic rupture, 30-50% with bleeding esophageal varices, approximately 1% with benign peptic ulcers).
o Anemia from gastrointestinal bleeding may be the first evidence of an intestinal malignancy.
o Sickle cell disease may be associated with frequent painful crises and a shortened lifespan, or patients with sickle cell disease may remain relatively asymptomatic with a nearly normal lifespan.
o Most patients with beta-0 homozygous thalassemia die during the second or third decade of life unless they undergo bone marrow transplantation.
o Hereditary spherocytosis either may present with a severe hemolytic anemia or may be asymptomatic with compensated hemolysis.
o Similarly, glucose-6-phosphate dehydrogenase (G-6-PD) deficiency may manifest as chronic hemolytic anemia or exist without anemia until the patient receives an oxidant medication.
o The 2-year fatality rate for severe aplastic anemia is 70% without bone marrow transplantation or a response to immunosuppressive therapy.
* Many symptoms associated with anemia are not caused by diminished RBC mass. Patients with pernicious anemia are often asymptomatic when they are detected incidentally with an Hb of 6 g/dL. In contrast, ice chewing, calf cramps, and diminished capability to perform muscular work occur in iron-deficiency anemia with an Hb of 10-11 g/dL because of depletion of iron-containing proteins other than Hb.
* In addition, tolerance of anemia is proportional to the anemia's rate of development. Symptoms and mortality associated with rapidly developing anemia are more profound than in slowly developing anemia.
Race
* Certain races and ethnic groups have an increased prevalence of genetic factors associated with certain anemias. Examples are hemoglobinopathies, thalassemia, and G-6-PD deficiency. Each of these disorders has different morbidity and mortality in different populations due to differences in the genetic abnormality producing the disorder. For example, G-6-PD deficiency and thalassemia have less morbidity in African Americans than in Sicilians because of differences in the genetic fault. Conversely, sickle cell anemia has a greater morbidity and mortality in African Americans than among Saudi Arabians.
* Race is a factor in nutritional anemias and anemia associated with chronic untreated illnesses to the extent that socioeconomic advantages are distributed along racial lines in a given area.2 Socioeconomic advantages affect diet and the availability of health care and lead to a decreased prevalence of these types of anemia.3,4,5 For instance, iron deficiency anemia is much more prevalent in third world populations who have little meat in their diets than it is in populations of the United States and northern Europe. Similarly, anemia of chronic disorders is commonplace in populations with a high incidence of chronic infectious disease (eg, malaria, tuberculosis, AIDS), and this is at least in part worsened by the socioeconomic status of these populations and their access to adequate health care.
Sex
* Overall, anemia is twice as prevalent in females as in males. This difference is significantly greater during the childbearing years due to pregnancies and menses.
* Approximately 65% of body iron is incorporated into circulating Hb. Each gram of Hb contains 3.46 mg of iron (1 mL of blood with Hb of 15 g/dL = 0.5 mg of iron). Each healthy pregnancy depletes the mother of approximately 500 mg of iron. While a man must absorb about 1 mg of iron to maintain equilibrium, a premenopausal woman must absorb an average of 2 mg daily. Further, because women eat less food than men, they must be more than twice as efficient as men in the absorption of sufficient iron to avoid iron deficiency.
* Women have a markedly lower incidence of anemia from X-linked anemias, such as G-6-PD deficiency and sex-linked sideroblastic anemias.
Age
* Severe genetically acquired anemias (eg, sickle cell disease, thalassemia, Fanconi syndrome) are more commonly found in children because they do not survive to adulthood.
* During the childbearing years, women are more likely to become iron deficient.
* Neoplasia increases in prevalence with each decade of life and can produce anemia from bleeding, from the replacement of bone marrow with tumor, or from the development of anemia associated with chronic disorders. Use of aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), and Coumadin increases with age and can produce gastrointestinal bleeding.
Clinical
History
Carefully obtain a history and perform a physical examination in every patient with anemia because the findings usually provide important clues to the etiology of the underlying disorder. From the standpoint of the investigation of the anemia, asking questions in addition to those conventionally explored during a routine examination is important. Areas of inquiry found valuable are briefly described below.
* Often, the duration of anemia can be established by obtaining a history of previous blood examination and, if necessary, by acquiring those records. Similarly, a history of rejection as a blood donor or prior prescription of hematinics provides clues that anemia was detected previously.
* Obtain a careful family history not only for anemia but also for jaundice, cholelithiasis, splenectomy, bleeding disorders, and abnormal Hbs. Carefully document the patient's occupation, hobbies, prior medical treatment, drugs (including over-the-counter medications and vitamins), and household exposures to potentially noxious agents. Patients are unlikely to volunteer exposures to tranquilizers, insecticides, paints, solvents, and hair dyes unless specifically queried.
* In searching for blood loss, carefully document pregnancies, abortions, and menstrual loss. Estimates of menstrual losses are notoriously inaccurate if only routine inquiry is made.
* Often, patients do not appreciate the significance of tarry stools. Changes in bowel habits can be useful in uncovering neoplasms of the colon.
* Hemorrhoidal blood loss is difficult to quantify, and it may be overlooked or overestimated from one patient to another. Obviously, seek a careful history of gastrointestinal complaints that may suggest gastritis, peptic ulcers, hiatal hernias, or diverticula.
* Abnormal urine color can occur in renal and hepatic disease and in hemolytic anemia.
* A thorough dietary history is important in a patient who is anemic. This history must include foods that the patient both eats and avoids as well as an estimate of their quantity.
o A meal-by-meal description is necessary to obtain appropriate estimates.
o Even then, patients frequently attempt to deceive the physician because of embarrassment regarding dietary idiosyncrasies or financial restrictions. In these circumstances, a close and concerned family member participating in the dietary history can often be helpful because this person is usually more objective than the patient.
o Specifically question patients regarding consumption of either clay or laundry starch. This history will not be provided spontaneously. These substances render iron less absorbable.
o Changes in body weight are important with regard to dietary intake and can suggest the presence of malabsorption or an underlying wasting disease of infectious, metabolic, or neoplastic origin.
* Nutritional deficiencies may be associated with unusual symptoms that can be elicited by a history.
o Patients with iron deficiencies frequently chew or suck ice (pagophagia). Occasionally, they complain of dysphasia, brittle fingernails, relative impotence, fatigue, and cramps in the calves on climbing stairs that are out of proportion to their anemia.
o In vitamin B-12 deficiency, early graying of the hair, a burning sensation of the tongue, and a loss of proprioception are common.
o Suspect a loss of proprioception if the patient stumbles in the dark or must look in order to put on pants in the morning.
o Paresthesia or unusual sensations frequently described as pain also occur in pernicious anemia.
o Patients with folate deficiencies may have a sore tongue, cheilosis, and symptoms associated with steatorrhea.
o Color, bulk, frequency, and odor of stools and whether the feces float or sink can be helpful in detecting malabsorption. More sensitive questions to detect steatorrhea include whether the toilet needs to be flushed more than once to rid it of stool and whether an oily substance is floating on the water surface after the first flush.
* Obtain a history of fever or identify the presence of fever because infections, neoplasms, and collagen vascular disease can cause anemia. Similarly, the occurrence of purpura, ecchymoses, and petechiae suggest the occurrence of either thrombocytopenia or other bleeding disorders; this may be an indication either that more than one bone marrow lineage is involved or that coagulopathy is a cause of the anemia because of bleeding.
* Cold intolerance can be an important symptom of hypothyroidism or lupus erythematosus, paroxysmal cold hemoglobinuria, and certain macroglobulinemias.
* The relation of dark urine to either physical activity or time of day can be important in march hemoglobinuria and paroxysmal nocturnal hemoglobinuria.
* Explore the presence or the absence of symptoms suggesting an underlying disease, such as cardiac, hepatic, and renal disease; chronic infection; endocrinopathy; or malignancy.
Physical
Too often, the physician rushes into the physical examination without looking at the patient for an unusual habitus or appearance of underdevelopment, malnutrition, or chronic illness. These findings can be important clues to the underlying etiology of disease and provide information related to the duration of illness. The skin and mucous membranes are often bypassed so that pallor, abnormal pigmentation, icterus, spider nevi, petechiae, purpura, angiomas, ulcerations, palmar erythema, coarseness of hair, puffiness of the face, thinning of the lateral aspects of the eyebrows, nail defects, and a usually prominent venous pattern on the abdominal wall are missed in the rush to examine the heart and the lungs.
* Examine optic fundi carefully but not at the expense of the conjunctivae and the sclerae, which can show pallor, icterus, splinter hemorrhages, petechiae, comma signs in the conjunctival vessels, or telangiectasia that can be helpful in planning additional studies.
* Perform systematic examination for palpable enlargement of lymph nodes for evidence of infection or neoplasia. Bilateral edema is useful in disclosing underlying cardiac, renal, or hepatic disease, whereas unilateral edema may portend lymphatic obstruction due to a malignancy that cannot be observed or palpated.
* Carefully search for both hepatomegaly and splenomegaly. Their presence or absence is important, as are the size, the tenderness, the firmness, and the presence or the absence of nodules. In patients with chronic disorders, these organs are firm, nontender, and nonnodular. In patients with carcinoma, they may be hard and nodular. The patient with an acute infection usually has a palpably softer and more tender organ.
* A rectal and pelvic examination cannot be neglected because tumor or infection of these organs can be the cause of anemia.
* The neurologic examination should include tests of position sense and vibratory sense, examination of the cranial nerves, and testing for tendon reflexes. The heart should not be ignored because enlargement may provide evidence of the duration and the severity of the anemia, and murmurs may be the first evidence of a bacterial endocarditis that could explain the etiology of the anemia.
Causes
Causes of anemia are numerous and multifaceted. A family history may be useful in detecting hereditary etiology. Diet and exposure to drugs and chemicals can be useful. A geographic history and a thorough knowledge of the patient's health can be important in establishing an etiology.
* Genetic
o Hemoglobinopathies
o Thalassemias
o Enzyme abnormalities of the glycolytic pathways
o Defects of the RBC cytoskeleton
o Congenital dyserythropoietic anemia
o Rh null disease
o Hereditary xerocytosis
o Abetalipoproteinemia
o Fanconi anemia
* Nutritional
o Iron deficiency
o Vitamin B-12 deficiency
o Folate deficiency
o Starvation and generalized malnutrition
* Hemorrhage
* Immunologic - Antibody-mediated abnormalities
* Physical effects
o Trauma
o Burns
o Frostbite
o Prosthetic valves and surfaces
* Drugs and chemicals
o Aplastic anemia
o Megaloblastic anemia
* Chronic diseases and malignancies
o Renal disease
o Hepatic disease
o Chronic infections
o Neoplasia
o Collagen vascular diseases
* Infections
o Viral - Hepatitis, infectious mononucleosis, cytomegalovirus
o Bacterial - Clostridia, gram-negative sepsis
o Protozoal - Malaria, leishmaniasis, toxoplasmosis
* Thrombotic thrombocytopenic purpura and hemolytic uremic syndromeDifferential Diagnoses
Aplastic Anemia
Myelophthisic Anemia
Cooley Anemia
Pernicious Anemia
Hemolytic Anemia
Sickle Cell Anemia
Iron Deficiency Anemia
Spur Cell Anemia
Low LDL Cholesterol (Hypobetalipoproteinemia)
Thalassemia, Alpha
Megaloblastic Anemia
Thalassemia, Beta
Workup
Laboratory Studies
The first step in the diagnosis of anemia is detection with reliable accurate tests so that important clues to underlying disease are not overlooked and patients are not subjected to unnecessary tests for and treatment of nonexistent anemia. Detection of anemia involves the adoption of arbitrary criteria.
* The World Health Organization's criterion for anemia in adults is Hb values less than 12.5 g/dL. Children aged 6 months to 6 years are considered anemic at Hb levels less than 11 g/dL, and children aged 6-14 years are considered anemic when Hb levels are less than 12 g/dL. The disadvantage of such arbitrary criteria is that a few healthy individuals fall below the reference range, and some people with an underlying disorder fall within the reference range for Hb concentration.
* Usually, US values are slightly higher. Anemia is suggested in males with Hb levels less than 13.5 g/dL and in females with Hb levels less than 12.5 g/dL. Higher values are anticipated in individuals living in altitudes significantly above sea level. Conditions with an increase in plasma volume, such as during the last trimester of pregnancy, are associated with lower values without an existent anemia because the red cell mass is normal.
Once the existence of anemia is established, investigate the pathogenesis. If an adequate history has been taken and a physical examination has been performed, the etiology may be obvious, and confirmatory studies and appropriate therapy can be undertaken with a minimum of investigation. If this is not the case, initiate a definite plan of investigation considering the cost to the patient along with a determination of the etiology of the abnormality.
A rational approach is to begin by examining the peripheral smear and laboratory values obtained on the blood count. If the anemia is either microcytic (mean corpuscular volume [MCV], <84) or macrocytic (MCV, >96) or if certain abnormal RBCs or WBCs are observed in the blood smear, the investigative approach can be limited (see Table 1, Table 2, and Table 3).
Presently, RBC cellular indices are computer calculated and automatically placed on laboratory reports. The formulae for calculating these values follow (reference ranges are in parentheses). RBC is per million cells.
* MCV = Hct X 10/RBC (84-96 fL)
* Mean corpuscular Hb (MCH) = Hb X 10/RBC (26-36 pg)
* Mean corpuscular Hb concentration (MCHC) = Hb X 10/Hct (32-36%)
A rapid method of determining whether cellular indices are normocytic and normochromic is to multiply the RBC and Hb by 3. The RBC multiplied by 3 should equal the Hb, and the Hb multiplied by 3 should equal the Hct. Deviation from the calculated values suggests microcytosis, macrocytosis, or hypochromia versus the presence of spherocytes (MCHC, >36).
Table 1. Microcytic Hypochromic Anemia (MCV, <83; MCHC, <31)
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Table
Condition
Serum Iron Total Iron-Binding Capacity (TIBC) Bone Marrow Iron Comment
Iron deficiency ↓ ↑ 0 Responsive to iron therapy
Chronic inflammation ↓ ↓ ++ Unresponsive to iron therapy
Thalassemia major ↑ N ++++ Reticulocytosis and indirect bilirubinemia
Thalassemia minor N N ++ Elevation of A of fetal hemoglobin, target cells, and poikilocytosis
Lead poisoning N N ++ Basophilic stippling of RBCs
Sideroblastic ↑ N ++++ Ring sideroblasts in marrow
Hemoglobin N N ++ Hemoglobin electrophoresis
Condition
Serum Iron Total Iron-Binding Capacity (TIBC) Bone Marrow Iron Comment
Iron deficiency ↓ ↑ 0 Responsive to iron therapy
Chronic inflammation ↓ ↓ ++ Unresponsive to iron therapy
Thalassemia major ↑ N ++++ Reticulocytosis and indirect bilirubinemia
Thalassemia minor N N ++ Elevation of A of fetal hemoglobin, target cells, and poikilocytosis
Lead poisoning N N ++ Basophilic stippling of RBCs
Sideroblastic ↑ N ++++ Ring sideroblasts in marrow
Hemoglobin N N ++ Hemoglobin electrophoresis
↓ = decreased; ↑ = increased; 0 = absent; +'s indicate the amount of stainable iron in bone marrow specimens, on a scale of 0-4; N = normal.
Table 2. Macrocytic Anemia (MCV, >95)
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Table
Megaloblastic bone marrow Deficiency of vitamin B-12
Deficiency of folic acid
Drugs affecting DNA synthesis
Inherited disorders of DNA synthesis
Nonmegaloblastic bone marrow Liver disease
Hypothyroidism and hypopituitarism
Accelerated erythropoiesis (reticulocytes)
Hypoplastic and aplastic anemia
Infiltrated bone marrow
Megaloblastic bone marrow Deficiency of vitamin B-12
Deficiency of folic acid
Drugs affecting DNA synthesis
Inherited disorders of DNA synthesis
Nonmegaloblastic bone marrow Liver disease
Hypothyroidism and hypopituitarism
Accelerated erythropoiesis (reticulocytes)
Hypoplastic and aplastic anemia
Infiltrated bone marrow
Table 3. Various Forms of RBCs
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Table
Macrocyte Larger than normal (>8.5 µm diameter). See Table 2.
Microcyte Smaller than normal (<7 µm diameter). See Table 1.
Hypochromic Less hemoglobin in cell. Enlarged area of central pallor. See Table 1.
Spherocyte Loss of central pallor, stains more densely, often microcytic. Hereditary spherocytosis and certain acquired hemolytic anemias.
Target cell Hypochromic with central "target" of hemoglobin. Liver disease, thalassemia, hemoglobin D, postsplenectomy.
Leptocyte Hypochromic cell with a normal diameter and decreased MCV. Thalassemia.
Elliptocyte Oval to cigar shaped. Hereditary elliptocytosis, certain anemias (particularly vitamin B-12 and folate deficiency).
Schistocyte Fragmented helmet- or triangular-shaped RBCs. Microangiopathic anemia, artificial heart valves, uremia, malignant hypertension.
Stomatocyte Slitlike area of central pallor in erythrocyte. Liver disease, acute alcoholism, malignancies, hereditary stomatocytosis, and artifact.
Tear-shaped RBCs Drop-shaped erythrocyte, often microcytic. Myelofibrosis and infiltration of marrow with tumor. Thalassemia.
Acanthocyte Five to 10 spicules of various lengths and at irregular interval on surface of RBCs.
Echinocyte Evenly distributed spicules on surface of RBCs, usually 10-30. Uremia, peptic ulcer, gastric carcinoma, pyruvic kinase deficiency, preparative artifact.
Sickle cell Elongated cell with pointed ends. Hemoglobin S and certain types of hemoglobin C and l.
Macrocyte Larger than normal (>8.5 µm diameter). See Table 2.
Microcyte Smaller than normal (<7 µm diameter). See Table 1.
Hypochromic Less hemoglobin in cell. Enlarged area of central pallor. See Table 1.
Spherocyte Loss of central pallor, stains more densely, often microcytic. Hereditary spherocytosis and certain acquired hemolytic anemias.
Target cell Hypochromic with central "target" of hemoglobin. Liver disease, thalassemia, hemoglobin D, postsplenectomy.
Leptocyte Hypochromic cell with a normal diameter and decreased MCV. Thalassemia.
Elliptocyte Oval to cigar shaped. Hereditary elliptocytosis, certain anemias (particularly vitamin B-12 and folate deficiency).
Schistocyte Fragmented helmet- or triangular-shaped RBCs. Microangiopathic anemia, artificial heart valves, uremia, malignant hypertension.
Stomatocyte Slitlike area of central pallor in erythrocyte. Liver disease, acute alcoholism, malignancies, hereditary stomatocytosis, and artifact.
Tear-shaped RBCs Drop-shaped erythrocyte, often microcytic. Myelofibrosis and infiltration of marrow with tumor. Thalassemia.
Acanthocyte Five to 10 spicules of various lengths and at irregular interval on surface of RBCs.
Echinocyte Evenly distributed spicules on surface of RBCs, usually 10-30. Uremia, peptic ulcer, gastric carcinoma, pyruvic kinase deficiency, preparative artifact.
Sickle cell Elongated cell with pointed ends. Hemoglobin S and certain types of hemoglobin C and l.
In microcytic hypochromic anemia, seek a source of bleeding. The appropriate laboratory tests are serum iron level and TIBC and either serum ferritin level or stain of bone marrow specimen for iron. If the serum iron level is decreased and TIBC is increased, a diagnosis of iron deficiency can be made, therapy can be initiated, and a search for the cause of the iron deficiency can be started. If this cannot be demonstrated, suspect each of the other causes of a microcytic anemia listed in Table 1, and the order of investigation can be influenced by findings in the history, physical examination, or peripheral smear.
Similarly, a reasonable approach with macrocytic anemia is to determine if the bone marrow aspirate is megaloblastic. If so, attempt to incriminate either vitamin B-12 or folic acid deficiency with appropriate laboratory studies. Similar to the establishment of a diagnosis of iron deficiency anemia, a diagnosis of vitamin B-12 or folic acid deficiency does not stop with an abnormal laboratory value for one of these vitamins. Prompt treatment can be instituted, but a continued search for an underlying cause of the vitamin deficiency is indicated (see Pernicious Anemia).
When a normocytic normochromic anemia is encountered, classify the anemia into 3 possible etiologies (ie, blood loss, hemolysis, decreased production). In most anemias, one of these causes is the dominant factor. However, in certain anemias, more than a single cause may play an important role. For example, pernicious anemia is predominantly due to decreased production of erythrocytes, but hemolysis adds significantly to the severity of anemia.
Blood loss
* Obviously, significant hemorrhage produces anemia. Immediately after blood loss, the Hct cannot be used as a reliable method to determine the quantity of lost blood because the patient loses plasma as well as RBCs. After acute hemorrhage, the Hct falls for 24-48 hours until the plasma volume is replaced. At that time, anemia is normochromic and normocytic with normal cellular indices because the cells in the peripheral blood have been produced prior to bleeding (see Iron Deficiency Anemia).
* If the patient had adequate iron stores, accelerated production of RBCs occurs, so that 1 week after bleeding, a larger than normal number of young RBCs and reticulocytes are circulating in the peripheral blood. Because reticulocytes and young RBCs have a larger volume (MCV of approximately 120), macrocytes may be observed in the peripheral smear, and a slight increase in the MCV occurs.
* If hemorrhage was sufficient to deplete iron stores (1-2 L of blood, 500-1000 mg of iron), newly formed erythrocytes are microcytic and hypochromic and gradually replace normal erythrocytes in the circulation that were produced prior to the induction of iron deficiency. Because RBCs normally survive for 120 days in circulation, maximal changes in the MCV and MCHC are not observed until that time. Iron deficiency and the depletion of iron stores can be detected several weeks after bleeding by measurements of the serum iron level and TIBC and/or special stains of bone marrow specimens showing an absence of storage iron.
* Diagnosis of iron deficiency anemia in an adult in the United States should be attributed to bleeding unless other causes can be proven. Aside from recent multiparity, other causes are relatively uncommon and include prolonged dietary idiosyncrasies (eg, clay eating, laundry starch consumption, protein deprivation for several years), urinary loss of iron due to intravascular hemolysis (eg, artificial aortic valves, paroxysmal nocturnal hemoglobinuria), gastrectomy, and other upper gastrointestinal surgery or disease.
* Diagnosis of iron deficiency anemia is made by demonstrating that the patient has low serum iron levels and elevated TIBC, absence of stainable iron in a bone marrow specimen, or both. A low serum ferritin level provides confirmation of the diagnosis. The presence of microcytosis and hypochromia is helpful but not diagnostic.
* Microcytic hypochromic anemia is observed with conditions other than iron deficiency anemia. Certain types of these disorders are iron-overloading states in which the administration of iron can be deleterious to the patient (see Table 1). Similarly, low serum iron levels can be observed in chronic inflammatory states with normal body stores of iron. However, in the latter, the TIBC is usually decreased rather than increased, and stainable iron can be demonstrated in bone marrow aspirates. Whenever the diagnosis of iron deficiency anemia is in doubt, follow-up blood work after administration of iron to show correction of the anemia can be helpful in confirming the diagnosis.
* The patient notices hemorrhage from most body organs. Epistaxis, hemoptysis, or hematuria of sufficient degree to cause anemia is usually reported to the physician long before iron deficiency ensues. However, bleeding from either the uterus or the gastrointestinal tract may be disregarded by the patient or be totally undetected until anemia becomes profound and symptomatic.
* Menstrual bleeding among healthy females varies monthly from 10-250 mL. Unless the patient observes a change in menses, she relates that menses are normal unless specific questions are asked. The presence of clots, abdominal cramps, excessive gushing of blood upon removal of tampons, the need for both tampons and pads, and the use of an unusual number of pads or tampons can be used to determine if menstrual bleeding may be sufficient to induce iron deficiency anemia.
* Gastrointestinal bleeding is the other occult cause of anemia due to blood loss. If hemorrhage is profuse, it is usually detected before evidence of iron deficiency anemia occurs because hematochezia or melena causes the patient to seek medical attention. However, if the bleeding occurs slowly, it is usually undetected until anemia ensues because stools appear normal.
* Every patient with iron deficiency anemia should have a stool examination for occult blood. A positive result necessitates a careful search of the gastrointestinal tract to identify the site of bleeding. Unfortunately, a negative result does not exclude gastrointestinal blood loss because bleeding can be intermittent and require several examinations for detection. Also, less than 20-30 mL of blood in the stool per day may go undetected due to the insensitivity of the test. The 2 methods used to detect small daily losses of blood from the gut are as follows: (1) placing the patient on a meat-free diet for several days and using more sensitive methods, such as a benzidine test, and (2) labeling the patient's RBCs with chromium 51 and collecting stool specimens for the detection of the radioisotope.
* Investigate gastrointestinal bleeding by endoscopy and radiographic studies (see Procedures).
Hemolysis (increased RBC destruction)
* A normal RBC survives in the circulation for 120 days. If the erythrocytic lifespan is shortened significantly (<40 d), the patient has a hemolytic disorder that may be demonstrated by showing increased production of erythrocytes, increased destruction, or both. The former is revealed most readily by the presence of sustained reticulocytosis and the latter by the occurrence of indirect bilirubinemia (see Table 4, below).
* Other laboratory tests are available to detect hemolysis, but they are either more expensive or less reliable.
Table 4. Classification of the Hemolytic Disorders
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Table
Hereditary Acquired
Intracorpuscular defect Hereditary spherocytosis
Hereditary elliptocytosis
Hemoglobinopathies
Thalassemias
Congenital dyserythropoietic anemias
Hereditary RBC enzymatic deficiencies
Rarer hereditary abnormalities Vitamin B-12 and folic acid deficiency
Paroxysmal nocturnal
Hemoglobinuria
Severe iron deficiency
Extracorpuscular defect
Physical agents: Burns, cold exposure
Traumatic: Prosthetic heart valves, march hemoglobinemia, DIC, graft rejection
Chemicals: Drugs and venoms
Infectious agents: Malaria, toxoplasmosis, mononucleosis, hepatitis, primary atypical pneumonia, clostridial infections, bartonellosis, leishmaniasis
Hepatic and renal disease
Collagen vascular disease
Malignancies: Particularly hematologic neoplasia
Transfusion of incompatible blood
Hemolytic disease of the newborn
Cold hemagglutinin
disease
Autoimmune hemolytic anemia Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
Hereditary Acquired
Intracorpuscular defect Hereditary spherocytosis
Hereditary elliptocytosis
Hemoglobinopathies
Thalassemias
Congenital dyserythropoietic anemias
Hereditary RBC enzymatic deficiencies
Rarer hereditary abnormalities Vitamin B-12 and folic acid deficiency
Paroxysmal nocturnal
Hemoglobinuria
Severe iron deficiency
Extracorpuscular defect
Physical agents: Burns, cold exposure
Traumatic: Prosthetic heart valves, march hemoglobinemia, DIC, graft rejection
Chemicals: Drugs and venoms
Infectious agents: Malaria, toxoplasmosis, mononucleosis, hepatitis, primary atypical pneumonia, clostridial infections, bartonellosis, leishmaniasis
Hepatic and renal disease
Collagen vascular disease
Malignancies: Particularly hematologic neoplasia
Transfusion of incompatible blood
Hemolytic disease of the newborn
Cold hemagglutinin
disease
Autoimmune hemolytic anemia Thrombotic thrombocytopenic purpura (TTP) and hemolytic uremic syndrome (HUS)
Anemia solely due to hemolysis does not occur until RBCs are being destroyed at 6-8 times the normal rate, reducing the mean RBC lifespan to less than 20 days because of the bone marrow's capacity to undergo 6-fold hypertrophy and hyperplasia. Thus, if the clinician relies on the presence of anemia to detect hemolytic states, the clinician misses most of them and, perhaps, an important clue to an underlying disorder. On the contrary, if reticulocytosis and indirect bilirubinemia are used to detect hemolytic states, they are usually found when the mean lifespan is less than 40-50 days. More sophisticated methods, such as measurements of RBC lifespan, are required to detect less severe shortening of erythrocyte lifespan (50-100 d) and are only occasionally needed in clinical practice.
All patients with both reticulocytosis and indirect bilirubinemia have a hemolytic disorder. All patients with sustained reticulocytosis have a hemolytic disorder. Unfortunately, the contrary is not the case, and significant hemolysis can occur without reticulocytosis if the bone marrow is unable to produce cells at an accelerated rate (eg, pernicious anemia, leukemia, aplasia). A single demonstration of an elevated reticulocyte count is insufficient to establish a diagnosis of hemolysis because transient reticulocytosis may occur without hemolysis (eg, in the treatment of iron deficiency anemia).
Almost all patients with indirect bilirubinemia have a hemolytic disorder. In adults, the exception is patients with Gilbert disease. These patients can be distinguished from those with hemolytic disorders and those who have no other obvious stigmata of hemolysis (eg, anemia, reticulocytosis, Coombs test) by having the patient fast for 3 days. In Gilbert disease, indirect bilirubin doubles with starvation, whereas in hemolytic disorders, it does not. Once the presence of hemolysis has been established, the etiology of the increased rate of RBC destruction can be sought.
All causes of hemolytic disorders are either hereditary or acquired. Similarly, they are due to either an intrinsic abnormality of the RBC (intracorpuscular defect) or external factors that shorten the erythrocyte lifespan (extracorpuscular). Using this nomenclature, only 4 groups of hemolytic disorders are possible—hereditary intracorpuscular, hereditary extracorpuscular, acquired intracorpuscular, and acquired extracorpuscular.
All hereditary hemolytic disorders are due to intracorpuscular defects, and most acquired disorders are due to extracorpuscular abnormalities (see Table 4). Hereditary etiologies of hemolytic disease are suggested strongly in any patient with a family history of anemia, jaundice, cholelithiasis, or splenectomy. Whenever possible, family members, particularly parents, siblings, and children, should undergo a hematologic examination, including hemogram with reticulocyte count, indirect bilirubin determination, and careful examination of the peripheral smear.
If a specific hereditary hemolytic disorder (eg, hereditary spherocytosis, hemoglobinopathy) is suggested in a patient, examine blood from family members for that entity by appropriate laboratory methods. Establishment of a hemolytic defect in other closely related family members permits a presumptive diagnosis of hereditary intracorpuscular hemolytic disorder in the patient. Showing a similar RBC abnormality (eg, spherocytes, abnormal Hb, G-6-PD deficiency) among family members establishes the basic etiology. Once the probability of a hereditary hemolytic disorder is established, a planned approach to determine the definitive abnormality is usually simple.
A careful examination of the peripheral smear may reveal spherocytes in hereditary spherocytosis; ovalocytes in hereditary elliptocytosis; sickle cells in patients with major hemoglobinopathies associated with sickle Hb; target cells in patients with Hb C or E disease; and marked poikilocytosis with target cells, microcytes, and hypochromic RBCs in thalassemia.
Even in certain rare disorders, abnormal erythrocyte morphology may provide an important clue. Examples are acanthocytosis in abetalipoproteinemia, stomatocytosis in the hereditary disorder of this name, and numerous target cells in lecithin cholesterol acyltransferase deficiency. Other laboratory studies of value in the hereditary hemolytic disorders include the following:6
* Hereditary spherocytosis - MCHC greater than 36%, incubated osmotic fragility studies autohemolysis in oxalate, and detection of the underlying molecular defect
* Hemoglobinopathies - Sickle cell preparation, Hb electrophoresis at one or more pH, heat denaturation test for unstable Hbs, oxygen disassociation for Hbs with abnormal oxygen affinity
* Thalassemia - A2 and fetal Hb, Hb electrophoresis, characterization of the molecular defect, quantification of alpha and beta chains
* Congenital dyserythropoietic anemias - Demonstration of abnormalities of erythroid precursors in bone marrow aspirates, positive acid hemolysis (Ham) test with normal result of sucrose hemolysis test in one form of this disease (hereditary erythroblastic multinuclearity with a positive acidified serum test [HEMPAS])
* Hereditary RBC enzymatic deficiencies - Specific RBC enzyme assay
In clinical practice, approximately 90% of hereditary RBC enzymatic deficiencies with significant clinical manifestations are either G-6-PD deficiencies or abnormalities of pyruvic kinase. The age at which a hemolytic disorder is detected is not always helpful in determining whether the disorder is hereditary. Although the abnormality is inherited, congenital manifestations may be unusual. An infant with sickle cell anemia or beta thalassemia appears healthy at birth. Clinical manifestations usually do not occur in infants younger than 6 months because fetal Hb has not been replaced by adult Hb until that age. Most patients with G-6-PD deficiency have no manifestations of the erythrocyte enzymatic abnormality until they receive an oxidant drug.
Usually, thalassemia minor is not detected until a routine hemogram is performed, and, then, it is often mistaken for iron deficiency anemia because of the microcytosis and hypochromia. Thus, the physician dealing with adult patients must be as aware of these disorders as the pediatrician.
The most commonplace of the hereditary disorders is G-6-PD deficiency because it occurs in 10% of the African American population living in the United States. In this population, G-6-PD deficiency usually remains undetected until oxidant drugs are administered. Then, it produces a mild-to-moderate hemolytic anemia that is transient in nature. In white populations of Mediterranean derivation, G-6-PD deficiency can produce a chronic hemolytic anemia without exposure to drugs. Exposure to oxidant drugs can produce lethal hemolysis.
Acquired hemolytic disorders occur in a large number of disease states and can vary considerably in severity. In addition, hemolysis may be observed as a result of physical injury to the RBC or following exposure to drugs, chemicals, or venoms. In many patients, the etiology of the hemolytic disorder is apparent because of other manifestations of the disease (eg, infections, collagen vascular disease).
A confirmed positive Coombs test result can be extremely helpful in this group of disorders. It provides assurance that the hemolytic disorder is an acquired extracorpuscular defect and limits it to the group of disorders associated with autoimmune hemolytic anemia. They include the following:
* Drug-dependent antibodies (eg, to penicillin, quinidine, alpha methyldopa)
* Coexistence of an underlying disease (eg, hematologic malignancies, lupus erythematosus, certain viral infections)
* Idiopathic groups in which an underlying disease cannot be demonstrated
Usually, the acquired hemolytic disorders with intracorpuscular defects are not difficult to diagnose. Vitamin B-12 and folic acid deficiencies are associated with macrocytic anemia, the presence of hypersegmented polymorphonuclear leukocytes in the peripheral smear, megaloblastic bone marrow, physical findings of the underlying cause of the deficiency state, and abnormal serum levels for the deficient vitamin.
Iron deficiency in the United States is rarely of sufficient severity to cause significant hemolysis and is merely mentioned herein for the sake of completeness.
Paroxysmal nocturnal hemoglobinuria is diagnosed only if the physician considers it in the differential diagnosis, and it may manifest by either a pancytopenia or a hemoglobinuria. However, a sugar-water test can help exclude this cause of hemolysis.
The major diagnostic problem encountered with hemolytic disorders is when the known causes for hemolysis have been excluded by history, physical examination, and laboratory studies; the Coombs test result is negative; and not enough family members can be tested to differentiate between hereditary intracorpuscular hemolytic disorders and acquired extracorpuscular defects.
A donor cell chromium survival study can be helpful in differentiating between a hereditary hemolytic disorder and an acquired hemolytic disorder. Labeled RBCs from a healthy blood donor of a compatible blood group allow for a normal survival rate in patients with hereditary hemolytic disease and a shortened lifespan in those with an acquired extracorpuscular defect.
Decreased RBC production
Diminished production of RBCs is suggested in all patients without evidence of either blood loss or hemolysis. Thus, a patient with anemia without evidence of bleeding or iron deficiency with normal indirect bilirubin and normal or decreased reticulocyte count probably has a defect in the production of erythrocytes. Many of these patients have pancytopenia or other abnormalities of the leukocytes or the platelets that can be detected with an examination of a peripheral smear. When this group of disorders is suspected, the most important laboratory test is a bone marrow biopsy and aspiration (see Procedures). The bone marrow biopsy permits categorization of these disorders into 3 separate groups, as shown in the image below: (1) aplastic or hypoplastic, (2) hyperplastic, and (3) bone marrow replaced with nonhematopoietic elements (infiltration of bone marrow).
Anemia. Decreased production of red blood cells i...
Anemia. Decreased production of red blood cells is suggested in certain patients with anemia. Bone marrow biopsy specimen allows categorization of patients with anemia without evidence of blood loss or hemolysis into 3 groups: aplastic or hypoplastic disorder, hyperplastic disorder, or infiltration disorder. Each category and its associated causes are listed in this image.
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Anemia. Decreased production of red blood cells i...
Anemia. Decreased production of red blood cells is suggested in certain patients with anemia. Bone marrow biopsy specimen allows categorization of patients with anemia without evidence of blood loss or hemolysis into 3 groups: aplastic or hypoplastic disorder, hyperplastic disorder, or infiltration disorder. Each category and its associated causes are listed in this image.
Drugs or chemicals commonly cause the aplastic and hypoplastic group of disorders. Certain types of these causative agents are dose related and others are idiosyncratic. Any human exposed to a sufficient dose of inorganic arsenic, benzene, radiation, or the usual chemotherapeutic agents used for treatment of neoplastic diseases develops bone marrow depression with pancytopenia. Conversely, among the idiosyncratic agents, only an occasional human exposed to these drugs has an untoward reaction resulting in suppression of 1 or more of the formed elements of bone marrow (1:100 to 1:millions). With certain types of these drugs, pancytopenia is more common, whereas with others, suppression of one cell line is usually observed. Thus, chloramphenicol may produce pancytopenia, whereas a granulocytopenia is more frequently observed with toxicity to sulfonamides or antithyroid drugs.
The idiosyncratic causes of bone marrow suppression include multiple drugs in each of the categories that can be prefixed with anti- (eg, antibiotics, antimicrobials, anticonvulsants, antihistamines). The other idiosyncratic causes of known etiology are viral hepatitis and paroxysmal nocturnal hemoglobinuria. In approximately one half of patients presenting with aplastic anemia, a definite etiology cannot be established, and the anemia must be regarded as idiopathic.
Whenever possible, a cause for the aplastic anemia should be uncovered because cessation of exposure may lead to recovery. Identification of the offending agent is likewise important in determining the prognosis.
Chances of survival are poorer for patients with idiosyncratic aplasia caused by chloramphenicol and viral hepatitis and better when paroxysmal nocturnal hemoglobinuria or anti-insecticides are the probable etiology. The prognosis for idiopathic aplasia lies between these 2 extremes, with an untreated mortality rate of approximately 60-70% within 2 years after diagnosis.
Rare causes of anemia due to a hypoplastic bone marrow include familial disorders and the acquired pure red cell aplasias. The latter are characterized by a virtual absence of erythroid precursors in the bone marrow with normal numbers of granulocytic precursors and megakaryocytes.
Among patients with a hyperplastic bone marrow and decreased production of RBCs, one group has an excellent prognosis, and the other is unresponsive, refractory to therapy, and has a relatively poor prognosis. The former includes patients with disorders of relative bone marrow failure due to nutritional deficiency in whom proper treatment with vitamin B-12, folic acid, or iron leads to a correction of anemia once the appropriate etiology is established. Drugs acting as an antifolic antagonist or inhibitor of DNA synthesis can produce similar effects. The second group includes patients with an idiopathic hyperplasia that may respond partially to pyridoxine therapy in pharmacologic doses but, more frequently, does not. These patients have ringed sideroblasts in the bone marrow indicating an inappropriate use of iron in the mitochondria for heme synthesis.
Certain patients with marrow hyperplasia may have refractory anemia for years, but some of the group eventually develop acute myelogenous leukemia.
Rare causes of diminished erythrocyte production with hyperplastic bone marrow include hereditary orotic aminoaciduria and erythremic myelosis.
Infiltration of the bone marrow with fibrous tissue, neoplastic cells, or other cells that replace normal hematopoietic tissue can diminish the production of RBCs, granulocytes, and platelets.7 The diagnosis of myelofibrosis or neoplastic involvement of bone marrow is often suggested by evidence of myeloid metaplasia in the peripheral smear (ie, erythroid and granulocyte precursors). Replacement of bone marrow with nonhemopoietic cells leads to activation of fetal sites of blood production in organs, such as the liver and the spleen, with release of abnormally shaped erythrocytes and normoblasts, immature granulocytes and normoblasts, immature granulocytes, and large platelets into the peripheral blood. Myeloid metaplasia does not occur in aplastic disease. Thus, its presence in a patient who is anemic suggests bone marrow infiltration, even before the biopsy specimen is obtained.
Imaging Studies
Imaging studies are useful in the workup for anemia when a neoplastic etiology is suggested. They permit discovery of the neoplasm or centrally located adenopathy. Occasionally, they are useful in detecting or confirming the existence of splenomegaly.
Procedures
* Investigate gastrointestinal bleeding by endoscopy and radiographic studies to identify the bleeding site. However, even these methods may leave a source of gastrointestinal bleeding undetected because these procedures do not detect the bleeding site or the lesion if small. Examples of these causes include coagulation abnormalities induced by aspirin or platelet dysfunction, hookworm infestation, hemangiomas of the small bowel, lymphosarcoma and other tumors, adenomas of the gallbladder, and self-administration of anticoagulants.
* Bone marrow aspirates and biopsy findings are particularly useful in establishing the etiology of anemia in patients with decreased production of RBCs. They help differentiate aplasia; megaloblastic hyperplasia; and infiltration of marrow with neoplasia, myelodysplasia, and myelofibrosis. In addition, they lead to a definitive histologic diagnosis of leukemias, lymphomas, myelomas, and metastatic carcinomas. These procedures are less useful in detecting hemolytic anemia (except to detect lymphoma or leukemia), and they are less useful in diagnosing congenital dyserythropoietic anemia, in which they reveal the multinuclearity of erythroid precursors. Iron stains of the bone marrow aspirate can be used to document the existence of iron deficiency anemia or the sideroblastic anemias.Treatment
Medical Care
The purpose of establishing the etiology of an anemia is to permit selection of a specific and effective therapy.
* Transfusion of packed RBCs should be reserved for patients who are actively bleeding and for patients with a severe and symptomatic anemia.8 Transfusion is palliative and should not be used as a substitute for specific therapy. In chronic diseases associated with anemia of chronic disorders, erythropoietin may be helpful in averting or reducing transfusions of packed RBCs.
* The appropriate treatment of anemia due to blood loss is correction of the underlying condition and oral administration of ferrous sulfate until the anemia is corrected and for several months afterward to ensure that body stores are replete with iron. Relatively few indications exist for the use of parenteral iron therapy, and blood transfusions should be reserved for the treatment of shock or hypoxia.
* Nutritional therapy is used to treat deficiency of iron, vitamin B-12, and folic acid. Pyridoxine may be useful in the treatment of certain patients with sideroblastic anemia, even though this is not a deficiency disorder.
* Corticosteroids are useful in the treatment of autoimmune hemolytic anemia.
* Treatment of aplastic disorders includes removal of the offending agent whenever it can be identified, supportive therapy for the anemia and thrombocytopenia, and prompt treatment of infection. Avoid transfusion in patients with a potential bone marrow donor because transfusion worsens the probability of cure from transplantation. Certain patients seem to develop a salutary response with immunosuppressive therapy (ie, antithymocyte globulin, cyclosporin). Splenectomy may provide sufficient improvement for patients with hypoplastic, but not totally aplastic, marrow so that transfusion is not necessary, and platelet and granulocyte counts increase to less dangerous levels (see Surgical Care).
* Therapy and medical care vary considerably in the group of hereditary disorders. Splenectomy has been advantageous in hereditary spherocytosis and hereditary elliptocytosis, in some of the unstable hemoglobinopathies, and in certain patients with pyruvic kinase deficiency. It has little value in most other hereditary hemolytic disorders (see Surgical Care).
* Patients with beta-thalassemia major and the major hemoglobinopathies associated with sickle Hb usually require medical attention at frequent intervals for the treatment of anemia, infection, pain, and leg ulcers because of the serious nature of these illnesses. Conversely, many of the other hereditary abnormalities have minimal or no clinical manifestations; the patient only requires reassurance.
* Drugs and chemicals capable of producing aplasia or a maturation arrest of erythroid precursors should be discontinued and avoided. Similarly, diseases known to be associated with anemia should be appropriately treated.
* Guidelines related to the treatment of chemotherapy-associated anemia and CME related to these guidelines are available.
Surgical Care
* Surgery is useful to control bleeding in patients who are anemic. Most commonly, bleeding is from the gastrointestinal tract, the uterus, or the bladder. Patients should be hemodynamically stable before and during surgery. A blood transfusion may be needed.
* Splenectomy is useful in the treatment of autoimmune hemolytic anemias and in certain hereditary hemolytic disorders (ie, hereditary spherocytosis and elliptocytosis, certain unstable Hb disorders, pyruvic kinase deficiency). Improvement in survival rates has been reported in patients with aplastic anemia, but splenectomy is not the preferential therapy. Leg ulcers have shown improvement in some patients with thalassemia. Prior to splenectomy, patients should be immunized with polyvalent pneumococcal vaccine. Preferably, this should be administered more than 1 week prior to surgery.
* Bone marrow and stem cell transplantation have been used in patients with leukemia, lymphoma, Hodgkin disease, multiple myeloma, myelofibrosis, and aplastic disease. Survival rates improved, and hematologic abnormalities were corrected. Allogeneic bone marrow transplantation successfully corrected phenotypic expression of sickle cell disease and thalassemia and provided enhanced survival in patients who survive transplantation.
Consultations
* Surgical consultation is indicated to control bleeding, for splenectomy when necessary, and for biopsies to establish the presence of neoplasia.
* Consultation with gastroenterologists is frequently sought to identify a bleeding site in the gut.
* Urologic consultation may be needed to investigate hematuria.
Diet
* Iron deficiency anemia is prevalent in geographic locations where little meat is in the diet. Many of these locations have sufficient dietary inorganic iron to equal the iron content in persons residing in countries in which meat is eaten. However, heme iron is more efficiently absorbed than inorganic food iron.
* A strict vegetarian diet requires iron and vitamin B-12 supplementation.
* Folic acid deficiency occurs among people who consume few leafy vegetables.
* Coexistence of iron and folic acid deficiency is common among Third World nations.
Activity
* The activity of patients with severe anemia should be curtailed until the anemia is partially corrected. Transfusion can often be avoided by ordering bed rest, while therapy is initiated for a patient with correctable anemia (eg, pernicious anemia).
* March hemoglobinuria is a rare hemolytic disorder usually observed in young males. Individuals develop hemoglobinuria after marching or running on hard surfaces. Curtailing the precipitating exercise (ie, running on grass rather than concrete) and using shoes with reinforced soles are helpful in preventing hemoglobinuria.
Medication
Documentation of the etiology of anemia is essential in the selection of therapy. All microcytic anemias are not caused by iron deficiency; some are iron-overloading disorders. Similarly, all megaloblastic anemias are not associated with either vitamin B-12 deficiency or folic acid deficiency. Hereditary hemolytic disorders do not improve with corticosteroid therapy. Specific therapy for anemia is discussed in articles describing the different causes of anemia (see Differential Diagnoses)Follow-up
Further Outpatient Care
Patients with chronic anemia can usually be cared for on an outpatient basis. Follow-up care is necessary to ensure that therapy is being continued and to assess the efficacy of treatment.
Transfer
* Patients with a benign etiology for anemia usually do not require transfer to another institution.
* Occasionally, transfer is necessary to establish the etiology of the anemia or to provide a treatment that is not locally available.
* If patients are being transferred for diagnostic reasons, transferring them before transfusion is helpful. If the transfusion is necessary before transfer to achieve hematopoietic stability, consult with the receiving physician to determine laboratory tests that should be performed before transfusion.
* Patients who are hemodynamically unstable should not be transported.
Complications
* The most serious complications of severe anemia arise from tissue hypoxia. Shock, hypotension, or coronary and pulmonary insufficiency can occur. This is more common in older individuals with underlying pulmonary and cardiovascular disease.
* Hemolytic transfusion reactions and transmission of infectious disease are risks of blood product transfusions. Patients with autoimmune antibodies against RBCs are at greater risk of a hemolytic transfusion reaction because of difficulty in cross-matching the blood.
* Occasionally, the blood of patients with autoimmune hemolytic anemia cannot be cross-matched in vitro. These patients require in vivo cross-matching in which incompatible blood is transfused slowly, and periodic determinations are made to ensure the patient is not developing hemoglobinemia. This method should only be used in patients with either significant hypoxia from the anemia or evidence of coronary insufficiency.
Prognosis
Usually, the prognosis depends on the underlying cause of the anemia. However, the severity of the anemia and the rapidity with which it developed can play a significant role. Similarly, the age of the patient and the existence of other comorbid conditions influence outcome.
Patient Education
* Inform patients of the etiology of their anemia, the significance of their medical condition, and the therapeutic options available for treatment.
* Because no effective specific treatment of the underlying disease exists, educate patients requiring periodic transfusions about the symptoms that herald the need for transfusion. Likewise, they should be aware of the potential complications of transfusion.
Miscellaneous
Medicolegal Pitfalls
* Negligence in transfusion of either incompatible blood or blood containing a potentially identifiable infectious agent
* Failure to recognize a hemolytic transfusion reaction and to initiate prompt and appropriate therapy
* Delayed diagnosis, investigation, and treatment of a neoplastic disorder because the etiology of an anemia was not pursued in a timely manner
* Failure to provide appropriate therapy and to ensure that the patient has adequate follow-up care
* Underestimating the potential severity of an anemia (This usually occurs in patients who are bleeding or have an autoimmune hemolytic anemia.)
