Melissa A. Tscheiner
Anemia is defined as a decrease in the number of circulating red blood cells, with a concomitant decrease in the capacity of the blood to carry oxygen to tissues. Anemia is a manifestation of disease rather than a diagnostic entity in and of itself.
Anemia can be classified into disorders of decreased red cell production, disorders of increased red cell destruction, and anemia resulting from blood loss (1–3). Each of these diagnostic groups has its own clinical presentation and differential diagnosis (Table 200.1) and, in general, requires its own approach to emergency department (ED) evaluation and management.
TABLE 200.1
Differential Diagnosis of Anemia
Anemia of any cause may present acutely or chronically, and the aggressiveness of intervention and management depends on the acuteness of onset and on the severity of the clinical presentation. For example, anemia secondary to acute gastrointestinal blood loss may require vigorous fluid resuscitation, transfusion therapy, and intensive care management; anemia secondary to chronic occult gastrointestinal bleeding leads to a well-compensated iron-deficiency anemia that can be evaluated and treated on an outpatient basis (4,5).
Defective red blood cell production may be due to interruption in the availability or synthesis of any of the three moieties of the hemoglobin molecule: iron, heme, and globin. Hence, anemia may result from iron deficiency, from toxins or enzymatic deficits that interfere with heme synthesis, or from genetic defects in globin synthesis. Disorders and deficiencies that affect the proliferation of erythroid stem cells in the bone marrow may also result in anemia from decreased red cell production (6–8).
Red cell destruction may result from either intrinsic or extrinsic causes. Intrinsic abnormalities of hemoglobin, enzymes, or red cell membranes may result in hemolytic anemia. Extrinsic destruction may be due to immunologic, mechanical, or environmental causes or to hypersequestration (hypersplenism) (1–3,8).
Blood loss resulting in anemia may be acute or chronic and may originate from intraperitoneal, retroperitoneal, pelvic, pleural, gynecologic, or gastrointestinal sources (3).
CLINICAL PRESENTATION
Patients with anemia secondary to acute blood loss present with hypovolemia. A source of blood loss may be readily identifiable on clinical evaluation; menstrual and gastrointestinal tract blood loss are the most common reasons for occult bleeding (9). A history of underlying disease (e.g., cirrhosis, bleeding diathesis, malignancy, or infection) or of medication use (e.g., use of salicylates, nonsteroidal anti-inflammatory drugs, or anticoagulants) may be useful in guiding initial evaluation and management. Hypovolemia may be relatively well tolerated in the young patient without underlying disease but can be a significant stress to elderly or chronically ill individuals whose compensatory mechanisms may be overwhelmed and whose tissue perfusion may be marginal at baseline (10,11).
Patients with anemia secondary to chronic blood loss or to decreased red cell production often present with signs and symptoms involving several systems due to hypoperfusion and decreased oxygen-carrying delivery:
• Constitutional symptoms—progressive fatigue, malaise, or dizziness
• Integumentary symptoms—pallor of the skin or mucous membranes, jaundice (from hemolysis), petechiae or purpura (with thrombocytopenia), or glossitis (from vitamin deficiency) (1,2,12)
• Pulmonary symptoms—dyspnea on exertion or decreased exercise tolerance
• Gastrointestinal symptoms—anorexia or nausea, hepatomegaly (from extramedullary hematopoiesis, sequestration or autoimmune process) (1,3,13)
• Cardiovascular symptoms—angina pectoris, claudication, syncope, tachycardia with widened pulse pressure, hyperdynamic precordium from increased cardiac output, or systolic ejection murmur (1,2,14,15)
• Genitourinary symptoms—dark urine (from hemolysis) or decreased urine output (16)
• Neurologic symptoms—focal neurologic deficits, stocking glove anesthesia or impaired position or vibratory sense (due to vitamin B12 deficiency) (6,12)
Other important historic information includes ethnicity and family history (predisposition to certain hemoglobinopathies and pernicious anemia), drug use, dietary history, use of ethanol, recent hospitalization (anemia of chronic disease is common in hospitalized patients), and history of underlying disease (renal, hepatic, thyroid, collagen vascular, or neoplastic disease; previous anemia; or recurrent jaundice) (3,17). Chronic rheumatologic, endocrine, hepatic, or neoplastic disease may manifest with lymphadenopathy, rash, thyromegaly, myxedema, or the stigmata of liver failure (15,16).
The symptoms, signs, and laboratory findings of anemia may be the initial presenting manifestations of pancytopenia (1). The etiology of pancytopenia is multifactorial. Pancytopenia is most commonly idiopathic (50%) but may result from chemical and physical agents, autoimmunity, or vitamin B12 or folic acid deficiency. Pancytopenia may follow viral illness, including upper respiratory infection, hepatitis, Epstein–Barr infection, and human immunodeficiency virus infection (1,18). It may also be associated with hypersplenism, myelodysplasia, bone marrow failure, or marrow replacement (3). Clinically, pancytopenia may present as a viral illness, preceding the symptomatic presentation of anemia over several weeks, or as an insidious presentation of anemia with clinical evidence of thrombocytopenia (petechia, purpura, or mucous membrane bleeding) (1).
Patients with anemia secondary to acute hemolysis are likely to present with signs and symptoms similar to those seen with mild chronic anemia. In more severe presentations, there may be jaundice and dark urine. Fever, prostration, abdominal and back pain, and hemoglobinuria suggest acute intravascular hemolysis, similar to that associated with transfusion reaction (1,8). A family history of anemia suggests an intrinsic cause of hemolysis, whereas exposure to drugs or toxins suggests an extrinsic cause (1,3). Immunologic destruction of red blood cells may be due to autoantibodies (8). Mechanical destruction is seen in some patients with prosthetic heart valves (3). Disseminated intravascular coagulation leading to microangiopathic hemolytic anemia is suggested by diffuse bleeding (13,15).
DIFFERENTIAL DIAGNOSIS
A complete differential diagnosis is presented in Table 200.1.
ED EVALUATION
Patients presenting to the ED with hypovolemic shock due to acute blood loss need to be rapidly evaluated and stabilized. Cases of chronic anemia can be evaluated on a less emergent basis, and some patients may continue their evaluation as an outpatient. In-patient evaluation may include further laboratory evaluation for specific diseases as well as a bone marrow biopsy in some cases (3).
Potential diagnostic errors of importance include the following:
• Not suspecting acute blood loss and impending hypovolemic shock with any unexplained normocytic normochromic anemia
• Confusing anemia with other entities that also cause constitutional symptoms (e.g., uremia, collagen vascular disease, fluid and electrolyte imbalance, infections, drug effects)
• Confusing iron-deficiency anemia, which presents with low iron, increased total iron-binding capacity (TIBC), and low ferritin, with anemia of chronic disease, which presents with low iron, low TIBC, and normal ferritin associated with a chronic disease or recent hospitalization (1,3,10)
• Confusing hemolytic anemia with other entities that also cause acute jaundice (particularly acute hepatitis)
• Overlooking pancytopenia by focusing on a clinical picture of anemia and low hemoglobin while neglecting findings of leukopenia and thrombocytopenia
KEY TESTING
Initial testing in the ED should include the following:
• Complete blood count
• Red blood cell indices and reticulocyte count
• Peripheral smear (hemolyzed cells, basophilic stippling, ringed sideroblasts, or hypersegmented leukocytes may be seen) (1,4,7,16)
• Additional focused laboratory analysis for specific conditions
• Serum iron, TIBC, and serum ferritin for hypochromic microcytic anemia (3)
• Folate and vitamin B12 levels, liver-function tests, and thyroid-function tests for macrocytic anemia (3,12)
• Indirect Coombs tests, fractionated serum bilirubin count, and lactate dehydrogenase (LDH) and haptoglobin levels in hemolytic anemia (8,12,19)
ED MANAGEMENT
Anemia of pregnancy is treated with prenatal vitamins (one daily) and iron replacement (ferrous sulfate 325 mg three times per day), and hypochromic microcytic anemia associated with an identified source of blood loss (presumed to be due to iron-deficiency anemia) is treated similarly, with iron replacement therapy (5,10,20). These patients should be re-evaluated after 4 to 6 weeks to assess the adequacy of the therapeutic response (5,10).
In megaloblastic anemia, presumed to be due to folic acid or vitamin B12 deficiency, treatment may be initiated with 1 mg/d of oral folic acid or with vitamin B12 intramuscularly at a dose of 1 mg weekly for 8 weeks (6,10,12,17,18). High doses of oral vitamin B12 daily for 90 to 120 days (1 to 2 mg) have been shown to be as effective and safe as intramuscular administration (12). In mild or asymptomatic anemia of chronic disease, therapy is generally directed to control the underlying disease (3).
For severe or sympatomatic anemia, transfusion may be indicated, sometimes in the ED. There is still uncertainty regarding the “transfusion threshold” for critically ill or septic patients or patients experiencing a STEMI. Recent literature suggests that a threshold hemoglobin of 7 may be associated with better outcomes for critically ill adults and children and for patients with acute myocardial infarction (MI) (19,21,22).
In many cases of newly identified anemia, drug therapy and other interventions including the use of erythropoietin have been shown to be beneficial but are frequently not indicated in the ED setting, and patients are referred to a consultant for further evaluation and management (5,7,9,14,16,18,23).
In children, the most common causes of anemia are nutritional deficiencies or hereditary or acquired primary hematologic disorders (3). Treatment is directed toward the underlying cause (2).
CRITICAL INTERVENTIONS
• Recognize clinical signs and symptoms of anemia
• Initiate laboratory investigation for the underlying etiology of anemia
DISPOSITION
Consultation or referral for follow-up, in most cases, is to the patient’s primary care physician. Most anemic adult patients have iron-deficiency anemia, vitamin B12- or folic-acid–deficiency anemia, or anemia of pregnancy; these cases can be treated and followed up on an outpatient basis. Children who are symptomatic or severely anemic should receive a transfusion and be admitted to the hospital for further evaluation (2). Stable patients or those with mild anemia may be treated on an outpatient basis.
Urgent consultation and hospital admission should be sought for the following indications (3,10,17):
1. Hypovolemia or ongoing bleeding
2. Need for urgent transfusion, generally because of a hemoglobin level <7 g/dL in a bleeding or symptomatic patient (19,21), or to hemoglobin of 10 g/dL in septic patients in the first 6 hours or patients with acute MI (19,21)
3. Severe symptoms (e.g., chest pain, dyspnea, syncope) that impair the patient’s ability to function at home
4. Pancytopenia requiring diagnostic evaluation (1,18)
5. Anticipated need for extensive diagnostic or therapeutic intervention
Unless active bleeding is present or the patient is hemodynamically unstable, there is usually no contraindication to routine transfer for specialized evaluation.
Common Pitfalls
• Failure to suspect and identify bleeding and hypovolemia.
• Failure to appreciate the possibility of anemia from the clinical presentation and, hence, not ordering a hemoglobin or hematocrit determination. This is especially likely in hemolytic anemia or when chest pain, dyspnea, dizziness, or claudication is the presenting complaint.
• Failure to identify and treat the underlying cause of the anemia.
• Failure to ensure referral or appropriate follow-up for evaluation of therapeutic response or the need for additional diagnostic testing.
ACKNOWLEDGMENT
The authors gratefully acknowledge the contributions of Louis S. Binder to the contents of this chapter.
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