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Anemia and Polycythemia Michael Billet Robin R. Hemphill  ANEMIA Anemia is a common medical problem, affecting approximately one quarter of the world’s population, especially children, pregnant and premenopausal women, the elderly, and the chronically ill.1-4 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 (RBC) destruction. PATHOPHYSIOLOGY Anemia is a reduced concentration of RBCs. In healthy persons, nor mal 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 bone marrow cannot produce new cells to replace those lost ( Table 231-1). 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). Reference RBC values for adults vary between genders, with smaller variations for ethnicity and age (Table 231-2). Anemia reduces the oxygen-carrying capacity of a given volume of blood. The body responds to anemia in ways to minimize the effect of this reduction in oxygen-carrying capacity. Mechanisms vary depend ing on the rapidity of onset, the degree of anemia, and the underly ing condition of the patient. The cardiovascular response typically manifests with vasoconstriction in the peripheral vasculature and vasodilation in the central vasculature to help preserve blood flow to vital organs. As anemia worsens, systemic small-vessel vasodilation will occur, increasing blood flow to tissues. These processes result in decreased systemic vascular resistance, increased cardiac output, and often tachycardia. In addition, RBCs enhance their ability to release oxygen to the tissues by a shift of the oxyhemoglobin dissociation curve. 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. CLINICAL FEATURES The severity of signs and symptoms depends on the rate of develop ment of anemia; the degree of anemia; and the age, comorbidities, and general condition of the patient. Otherwise healthy patients may tolerate significant anemia with minimally altered vital signs until they become profoundly fatigued, whereas physiologic compensation will be more challenging in those with medical comorbidities. Most adults will be symptomatic when hemoglobin levels decrease below 7 grams/dL; however, some patients with chronic anemia may have no complaints even with hemoglobin levels as low as 5 grams/dL. Patients with chronic anemia may note weakness, fatigue, dizziness, dyspnea with exertion, palpitations, and orthostatic symptoms. Additional manifestations may depend on comorbid illnesses, such as worsened chest pain in a patient with preexisting angina. Specific historical features can be helpful in the identification and diagnosis of anemia, such as recent trauma, hematochezia, melena, hemoptysis, hematemesis, hematuria, or menorrhagia.

ptoms. Additional manifestations may depend on comorbid illnesses, such as worsened chest pain in a patient with preexisting angina. Specific historical features can be helpful in the identification and diagnosis of anemia, such as recent trauma, hematochezia, melena, hemoptysis, hematemesis, hematuria, or menorrhagia. More subtle historical features include relevant comorbidities such as peptic ulcer disease, chronic liver disease, and chronic kidney disease. Query regarding the use of antiplatelet agents, anticoagulants, and NSAIDs. Physical exam findings include tachycardia; skin, nail bed, and mucosal pallor; systolic ejection murmur; bounding pulse; and widened pulse pressure. 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. Patients who develop acute, severe anemia may have any of the signs and symptoms noted above. In addition, they may have resting dyspnea, diaphoresis, anxiety, or severe weakness that may progress to lethargy and altered mental status. Loss of >40% of blood volume from traumatic or spontaneous hemorrhage can lead to severe symptoms that are due more to intravascular volume depletion than to anemia. DIAGNOSIS The diagnosis is established by a finding of decreased RBC count, hemoglobin, and hematocrit on the CBC. Further workup initiated in the ED can help expedite a diagnosis and should be started before the transfu sion of packed RBCs whenever possible. The initial evaluation of newly diagnosed anemia includes consid eration for a source of bleeding, including the most common internal sites—GI or uterine bleeding. If there is no physical or historical evidence of bleeding, RBC indices, reticulocyte count, and peripheral blood smear should be reviewed ( Table 231-3). The mean corpuscular volume is the most useful guide to the possible etiology of an anemia and classifies the anemia as microcytic, normocytic, or macrocytic. Other useful diagnostic tests include the red cell distribution width and reticulocyte count. Serum ferritin is the most useful test for the diag nosis of iron deficiency anemia. 7 Following this initial classification, additional tests can lead to a specific diagnosis ( Figures 231-1, 231-2, and 231-3).2-4,7-10 The most common causes of macrocytosis are alcohol abuse, liver disease, vitamin B12 and/or folate deficiency, and hypothyroidism.8 Medications that affect folate absorption or metabolism and produce macrocytosis 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. Sideroblastic anemia can be due to a congenital mutation (X-linked or autosomal recessive), a somatic mutation (as seen in myelodysplas tic syndromes) or from an acquired condition. 10 The most common cause of acquired sideroblastic anemia is alcohol abuse. Pyridoxine deficiency, lead poisoning, copper deficiency, or zinc toxicity can cause CHAPTER Hematologic and Oncologic Disorders SECTION Tintinalli_Sec18_p1461-1522.indd 1461 8/2/19 8:37 PM

odysplas tic syndromes) or from an acquired condition. 10 The most common cause of acquired sideroblastic anemia is alcohol abuse. Pyridoxine deficiency, lead poisoning, copper deficiency, or zinc toxicity can cause CHAPTER Hematologic and Oncologic Disorders SECTION Tintinalli_Sec18_p1461-1522.indd 1461 8/2/19 8:37 PM 1462 SECTION 18: Hematologic and Oncologic Disorders Alcohol abuse Liver disease Hypothyroidism Drug-induced myelodysplastic syndromes Measure serum vitamin B12 level Measure serum folate and/or homocysteine levels MCV Elevated RDW high RDW normal Vitamin B12, or folate deficiency FIGURE 231-1. Evaluation of macrocytic anemia. MCV = mean corpuscular volume; RDW = red cell distribution width. TABLE 231-3 Laboratory Tests in the Evaluation of Anemia Test Interpretation Clinical Correlation Mean corpuscular volume (MVC) Measure of the average red blood cell (RBC) size. Decreased MCV (microcytosis) is seen in chronic iron deficiency, thalassemia, anemia of chronic disease, and lead poisoning. Increased MCV (macrocytosis) can be due to vitamin B 12 or folate deficiency, alcohol abuse, liver disease, reticulocytosis, and some medications (see “Diagnosis” section). Mean corpuscular hemoglobin (MCH) Measure of the amount of hemoglobin in average red blood cell. — Red cell distribution width (RDW) Measures the size variability of the RBC population. In early deficiency anemia (iron, vitamin B 12, or folate), may be increased before the mean corpuscular volume becomes abnormal. Mean corpuscular hemoglobin concentration (MCHC) Measure of hemoglobin concentration in average RBC. Low MCHC can be seen in iron deficiency anemia, defects in porphyrin synthesis, and hemolytic anemia. Ferritin Ferritin is a protein in the body that binds to iron. Serum levels serve as an indication of the amount of iron stored in the body. Low serum ferritin is associated with iron deficiency anemia and helps differentiate this anemia from other causes. Reticulocyte count These RBCs of intermediate maturity are a marker of production by the bone marrow. Decreased reticulocyte count reflects impaired RBC production. Increased counts are a marker of accelerated RBC production. Peripheral blood smear Allows visualization of the RBC morphology. May guide to new diagnosis of diseases such as sickle cell disease. Allows evaluation for abnormal cell shapes. Aids in the diagnosis of entities such as hemolytic anemia. Allows examination of the white blood cells and platelets. May guide the diagnosis of other diseases that cause anemia. Coombs test Direct Coombs test is used to detect antibodies on RBCs. Direct Coombs test is positive in autoimmune hemolytic anemia, transfusion reactions, and some drug-induced hemolytic anemia. Indirect Coombs test is used to detect antibodies in the sera. Indirect Coombs test is routinely used in compatibility testing before transfusion. Abbreviations: MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; RDW = red cell distribution width.

ed hemolytic anemia. Indirect Coombs test is used to detect antibodies in the sera. Indirect Coombs test is routinely used in compatibility testing before transfusion. Abbreviations: MCHC = mean corpuscular hemoglobin concentration; MCV = mean corpuscular volume; RBC = red blood cell; RDW = red cell distribution width. TABLE 231-1 Classification of Anemia Mechanism Example Loss of red blood cells by hemorrhage Acute GI bleeding Increased destruction Sickle cell disease Drug-induced autoimmune hemolytic anemia Impaired production Nutritional deficiency anemia (iron, folate) Aplastic or myelodysplastic anemia Dilutional Rapid IV crystalloid infusion TABLE 231-2 Reference Range Red Blood Cell Values for Adults Male Female Red blood cell count (million/mm3) 4.5–6.0 4.0–5.5 Hemoglobin (grams/dL) 14–17 (140–170 grams/L) 12–15 (120–150 grams/L) Hematocrit or packed cell volume (%) 42–52 36–48 Mean corpuscular volume: MCV (fL) 78–100 78–102 Mean corpuscular hemoglobin: MCH (picograms/cell) 25–35 25–35 Mean corpuscular hemoglobin concentration: MCHC (grams/dL) 32–36 (320-360 g/L) 32–36 (320-360 g/L) Red cell distribution width: RDW (%) 11.5–14.5 11.5–14.5 Reticulocytes (%) 0.5–2.5 0.5–2.5 Note: Normal values may vary depending upon the equipment used, patient’s age, and the altitude of patient residence. sideroblastic anemias. Antimicrobials associated with sideroblastic anemia include linezolid, chloramphenicol, isoniazid, and cycloserine. TREATMENT The treatment of anemia depends on the cause and clinical status of the patient. In the ED, anemia that requires the most urgent attention results from acute blood loss. 5 All patients with ongoing blood loss should have their blood typed and cross-matched for possible transfu sion (see Chapter 238, “Transfusion Therapy”). The decision to trans fuse the anemic patient is individualized, taking into account clinical symptoms, the patient’s age and health, and the likelihood of further Tintinalli_Sec18_p1461-1522.indd 1462 8/2/19 8:37 PM

their blood typed and cross-matched for possible transfu sion (see Chapter 238, “Transfusion Therapy”). The decision to trans fuse the anemic patient is individualized, taking into account clinical symptoms, the patient’s age and health, and the likelihood of further Tintinalli_Sec18_p1461-1522.indd 1462 8/2/19 8:37 PM CHAPTER 231: Anemia and Polycythemia 1463 MCV Normal Reticulocyte count normal Reticulocyte count high RDW highRDW normal Anemia of chronic disease Anemia of renal insufficiency Iron, vitamin B12, or folate deficiency Coombs test positiveC oombs test negative Autoimmune causes Enzymopathies (e.g., glucose-6-phosphate dehydrogenase deficiency) Hemoglobinopathies (e.g., sickle cell disease) Membranopathies (e.g., hereditary spherocytosis) Microangiopathic hemolysis FIGURE 231-2. Evaluation of normocytic anemia. MCV = mean corpuscular volume; RDW = red cell distribution width. MCV Low RDW high Ferritin low Iron deficiency Ferritin normal Anemia of chronic disease Sideroblastic anemia RBC count low RBC count normal or high ThalassemiaAnemia of chronic disease Hypothyroidism Vitamin C deficiency RDW normal FIGURE 231-3. Evaluation of microcytic anemia. MCV = mean corpuscular volume; RBC = red blood cell; RDW = red cell distribution width. blood loss. 11,12 In general, patients who are symptomatic at rest or are hemodynamically unstable and show evidence of tissue hypoxia and/ or limited cardiopulmonary reserve should have RBCs transfused. In most settings, patients with anemia benefit when transfused at hemo globin levels of ≤7 grams/dL (60 to 70 grams/L). Liberal transfusion strategy (defined as a hemoglobin threshold of 9.5 to 10 grams/dL or 95 to 100 grams/L) is not generally associated with clinical benefit. ED patients with lesser degrees of anemia who are hemodynamically stable and have no evidence of tissue hypoxia, typically with hemoglobin levels of ≥8 grams/dL (80 grams/L), do not require immediate transfu sion, and outpatient follow-up is recommended for further hematologic evaluation. 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 B 12 replacement has traditionally been IM because of concern that malabsorption of the vitamin would limit the effectiveness of oral replacement. 13 However, oral doses of 1000 micrograms of vitamin B 12 per day are as effective as the IM route.14,15 DISPOSITION AND FOLLOW-UP Patients with anemia from ongoing blood loss should be admitted to the hospital for further evaluation and treatment. Patients with isolated anemia not related to blood loss do not necessarily require hospital admission if they are asymptomatic and hemodynamically stable, they have minimal comorbid disease, and 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 may require admission.  POLYCYTHEMIA Polycythemia is suggested when an elevated hemoglobin or hematocrit (packed cell volume) is found on CBC testing ( Table 231-5).16 Since hemoglobin and hematocrit values on the CBC are ratios, an eleva tion can be due to either a decrease in plasma volume or an increase in RBC mass. The former is termed relative polycythemia and is most Tintinalli_Sec18_p1461-1522.indd 1463 8/2/19 8:37 PM