Chapter 231: Anemia

Anemia is a common medical problem worldwide, affecting approximately one quarter of the world's population, especially children, pregnant and premenopausal women, the elderly, and the chronically ill.^{1,2,3,4,5,6,7} Anemia is not so much a disease as a sign or symptom. There are three broad causes of anemia: (1) blood loss, (2) decreased red blood cell production, and (3) increased red blood cell destruction.

Anemia is a reduced concentration of red blood cells (RBCs) from the normal ranges based on age, gender, and race.⁸ In healthy persons, normal erythropoiesis ensures that the concentration of RBCs present is adequate to meet the body's demand for oxygen and that the destruction of RBCs balances the production. The average life of the circulating erythrocyte is approximately 110 to 120 days. Any process or condition that results in the loss of RBCs, that impairs RBC production, or that increases RBC destruction will result in anemia if the body cannot produce enough new cells to replace those lost (Table 231-1). It is not uncommon for more than one mechanism to produce anemia in the same individual.

Quantification of the erythrocyte concentration is reflected in (1) RBC count per microliter, (2) hemoglobin concentration, and (3) hematocrit (percentage of RBC mass to blood volume). Normal RBC values for adults vary between genders, with small variations for ethnicity and age (Table 231-2).

The body responds to anemia in several ways in order to blunt the effect of a reduction in the oxygen-carrying capacity. The mechanisms vary, depending on the rapidity of onset, the degree of anemia, and the underlying condition of the patient. In acute forms of anemia that result from intravascular volume loss, the peripheral vasculature compensates by vasoconstriction, while the central vasculature vasodilates to help preserve blood flow to vital organs.⁹ As the condition worsens, systemic small-vessel vasodilation will occur, allowing increased blood flow to tissues. These mechanisms result in decreased systemic vascular resistance, increased cardiac output, and often tachycardia. Along with these changes, the RBCs themselves enhance their ability to release oxygen to the tissues. If the anemia is chronic in nature, there is commonly an increase in plasma volume that maintains total blood volume at a constant level. Finally, anemia will result in the stimulation of erythropoietin as a result of tissue hypoxia and breakdown products from RBC destruction. New immature erythrocytes, known as reticulocytes, will appear in the blood within 3 to 7 days.

The severity of signs and symptoms related to anemia depends on several factors: the rate of development of anemia (acute vs chronic), the extent of anemia that is present, the age and general physical condition of the patient, and other existing comorbidities. Children and young adults, for example, may tolerate a significant decline in RBC volume with minimally altered vital signs until they become acutely hypotensive, whereas elderly patients frequently have other comorbidities that make physiologic compensation challenging.^3,4 Patients with chronic and slowly developing anemia may have no complaints even with hemoglobin levels as low as 5 to 6 grams/dL. Typically, most otherwise healthy adults will be symptomatic when hemoglobin levels decrease to about 7 grams/dL.

Patients with chronic anemia may note weakness, fatigue, dizziness, lethargy, dyspnea with minimal exertion, palpitations, and orthostatic symptoms. Specific historical features can be helpful in the identification and diagnosis of anemia; a history of recent trauma, hematochezia, melena, hemoptysis, hematemesis, hematuria, or menorrhagia suggests possible anemia. More subtle historical features include relevant comorbidities such as peptic ulcer disease, chronic liver disease, and chronic renal disease. Specific inquiries about the use of antiplatelet agents, anticoagulants, and nonsteroidal anti-inflammatory agents should be made.

Physical exam findings that may be present in patients with clinically significant anemia include tachycardia; skin, nail bed, and mucosal pallor; systolic ejection murmur; bounding pulse; and widened pulse pressure (Figure 231-1). Signs of easy bleeding or bruising suggest a coagulation disorder. Evidence of jaundice and hepatosplenomegaly suggests hemolysis. Unusual skin ulcerations, peripheral neuropathy, or neurologic signs such as ataxia or altered mental status may be evidence of nutritional deficiencies. Additional manifestations may depend on comorbid illnesses. For example, a patient with preexisting angina may find that episodes of chest pain are markedly worsened when anemia is present.

Patients who develop an acute, severe anemia may have all the signs and symptoms noted above and, in addition, may have hypotension, resting and exertional dyspnea, palpitations, diaphoresis, anxiety, or severe weakness that may progress to lethargy and altered mental status. They may also complain of thirst and will usually have decreased urine output. Loss of >40% of blood volume from trauma or spontaneous hemorrhage can lead to severe symptoms that are due more to intravascular volume depletion than to anemia.¹⁰ In healthy patients, myocardial oxygen delivery usually is not limited until hemoglobin concentration is 50% or less of normal.

The diagnosis is established by a finding of decreased RBC count, hemoglobin, and hematocrit on the routine CBC. It is rarely essential that a specific cause of anemia be established in the ED. However, appropriate assessment initiated in the ED can help expedite a diagnosis and should therefore be started before the transfusion of packed RBCs.^6,8

The initial evaluation of a patient newly diagnosed with anemia includes several steps. First, look for a source of bleeding, including the most common internal sites—GI or uterine bleeding. If there is no physical or historical evidence of GI or uterine bleeding, then review RBC indices provided with the CBC, reticulocyte count, and peripheral blood smear (Table 231-3). The mean corpuscular volume is the most useful guide to the possible etiology of an anemia and is used to classify the anemic process as microcytic, normocytic, or macrocytic. Other useful diagnostic tests include the red cell distribution width and reticulocyte count. The serum ferritin is the most useful test for the diagnosis of iron deficiency anemia.¹¹ Following this initial classification, additional tests can lead to a specific diagnosis (Figures 231-2, 231-3, and 231-4).^{5,7,8,12,13,14,15}

Macrocytosis can result from multiple causes; most common are alcohol abuse, liver disease, vitamin B₁₂ and/or folate deficiency, and hypothyroidism.^14,15 A variety of medications can affect folate absorption or metabolism and produce macrocytosis. Drugs include phenytoin, valproate, trimethoprim, sulfamethoxazole, and metformin. The reverse transcriptase inhibitors used to treat human immunodeficiency virus infection can also produce macrocytosis, but they do so without causing anemia. Reticulocytes are larger than mature RBCs, so automated blood cell counters can report a mean corpuscular volume value above the normal range when an increased reticulocyte count is present.

The treatment of anemia depends on the etiology, symptoms, and clinical status of the patient. In the ED, anemia that requires the most urgent attention results from acute blood loss.¹⁰ All patients who have ongoing blood loss and anemia should have their blood typed and cross-matched, so that information is available for transfusion, if needed (see chapter 238, "Transfusion Therapy"). The decision to transfuse RBCs must be individualized for each patient, taking into account clinical symptoms, age of the patient, presence of comorbid disease, and the likelihood of further blood loss.^{16,17,18,19,20} In general, patients who are symptomatic and hemodynamically unstable and show evidence of tissue hypoxia and/or limited cardiopulmonary reserve should have RBCs transfused. In most settings, patients with anemia resulting from acute blood loss benefit when transfused at hemoglobin levels of 6 to 8 grams/dL. Liberal transfusion strategy (defined as a hemoglobin threshold of 9.5 to 10 grams/dL) is not associated with clinical benefit, so a hemoglobin value threshold of 6 to 8 grams/dL for RBC transfusion is recommended in most circumstances.²¹

ED patients with chronic anemia or a newly diagnosed anemia of uncertain etiology not caused by acute blood loss may not require immediate transfusion unless they are hemodynamically unstable, hypoxic, or have acidosis or ongoing cardiac ischemia. In a patient with newly diagnosed anemia of uncertain etiology, obtain laboratory studies for hematologic evaluation before transfusion. Consultation with a hematologist may be beneficial to guide this evaluation. The subsequent evaluation of some patients with chronic anemias or anemias of uncertain etiology can be made more difficult by transfusion, so transfusion should not be undertaken unless specifically indicated.

Treatment for nutritional deficiency anemias usually produces a reticulocyte response in 4 to 7 days (Table 231-4). Standard therapy for iron or folate deficiency uses oral replacement. Vitamin B₁₂ replacement has traditionally been intramuscular because of concern that malabsorption of the vitamin, a common predisposing condition for vitamin B₁₂ deficiency, would limit the effectiveness of oral replacement.²² However, oral doses of 2000 micrograms of vitamin B₁₂ per day are as effective as the intramuscular route in achieving the desired clinical response.^23,24

Patients with anemia from ongoing blood loss should be admitted to the hospital for further evaluation and treatment. Patients with isolated anemia that is chronic or newly diagnosed and not related to blood loss do not necessarily require hospital admission if they are asymptomatic and hemodynamically stable, they have minimal comorbid disease, and close follow-up can be arranged. Patients newly diagnosed with anemia who also have abnormalities in the WBC or platelet count should have hematologic consultation and should probably be admitted.