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Anemia can occur in isolation, or as a consequence of a process causing pancytopenia, the reduction of all 3 cell lines (white blood cells [WBCs], platelets, and red blood cells [RBCs]). This chapter focuses on the approach to isolated anemia, although a brief list of causes of pancytopenia appears in Figure 6-1. The first step in determining the cause of anemia is to identify the general mechanism of the anemia and organize the mechanisms using a pathophysiologic framework:
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Acute blood loss: this is generally clinically obvious.
Underproduction of RBCs by the bone marrow; chronic blood loss is included in this category because it leads to iron deficiency, which ultimately results in underproduction.
Increased destruction of RBCs, called hemolysis.
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Patients should always be assessed for signs and symptoms of acute blood loss.
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Signs of acute blood loss
Hypotension
Tachycardia
Large ecchymoses
Symptoms of acute blood loss
Hematemesis
Melena
Rectal bleeding
Hematuria
Vaginal bleeding
Hemoptysis
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After excluding acute blood loss, the next pivotal step is to distinguish underproduction from hemolysis by checking the reticulocyte count:
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Low or normal reticulocyte counts are seen in underproduction anemias.
High reticulocyte counts occur when the bone marrow is responding normally to blood loss; hemolysis; or replacement of iron, vitamin B12, or folate.
Reticulocyte measures include:
The reticulocyte count: the percentage of circulating RBCs that are reticulocytes (normally 0.5–1.5%).
The absolute reticulocyte count; the number of reticulocytes actually circulating, normally 25,000–75,000/mcL (multiply the percentage of reticulocytes by the total number of RBCs).
The reticulocyte production index (RPI)
Corrects the reticulocyte count for the degree of anemia and for the prolonged peripheral maturation of reticulocytes that occurs in anemia.
(1) Normally, the first 3–3.5 days of reticulocyte maturation occurs in the bone marrow and the last 24 hours in the peripheral blood.
(2) When the bone marrow is stimulated, reticulocytes are released prematurely, leading to longer maturation times in the periphery, and larger numbers of reticulocytes present at any given time.
(3) For a HCT of 25%, the peripheral blood maturation time is 2 days, and for a HCT of 15%, it is 2.5 days; the value of 2 is generally used in the RPI calculation.
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The normal RPI is about 1.0. In the setting of anemia, values < 2.0 indicate underproduction; those > 2.0 indicate hemolysis or an adequate bone marrow response to acute blood loss or replacement of iron or vitamins.
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The first steps in evaluating anemia are looking for acute blood loss and checking the RPI in patients who are not acutely bleeding.
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After determining the general mechanism, the next step in diagnosing the cause of anemia is to determine the cause of the underproduction or increased destruction. Traditionally, the differential diagnosis for underproduction anemia is framed using the cell size. While this is a useful way to organize the differential, and may at times provide useful clues, it is important to keep in mind that the mean corpuscular volume (MCV) is not specific and should not be used to rule in or rule out a specific cause of anemia.
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Use the MCV to organize your thinking, not to diagnose the cause of an anemia.
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Microcytic anemias (MCV < 80 mcm3)
Iron deficiency
Thalassemia
Anemia of inflammation/chronic disease (more often normocytic)
Sideroblastic anemia (congenital, lead exposure, medications)—rare
Copper deficiency or zinc poisoning—rare
Macrocytic anemias (MCV > 100 mcm3)
Megaloblastic anemias (due to abnormalities in DNA synthesis; hypersegmented neutrophils also occur)
Vitamin B12 deficiency
Folate deficiency
Antimetabolite drugs, such as methotrexate or zidovudine
Nonmegaloblastic anemias (no hypersegmented neutrophils)
Alcohol abuse
Liver disease
Hypothyroidism
Myelodysplastic syndrome (often causes pancytopenia)
Normocytic anemias
Anemia of inflammation/chronic disease (chronic kidney disease, infection, inflammation, malignancy, aging)
Early iron deficiency
Bone marrow suppression
Invasion by malignancy or granulomas
Acquired pure red cell aplasia (parvovirus B19, HIV, medications [mycophenolate mofetil, trimethoprim-sulfamethoxazole, phenytoin, recombinant human erythropoietins], thymoma, other malignancies, immune disorders)
Aplastic anemia (often causes pancytopenia)
Endocrine (hypopituitarism or hypothyroidism)
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The framework for hemolytic anemias is pathophysiologic:
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Hereditary
Enzyme defects, such as pyruvate kinase or glucose-6-phosphate dehydrogenase (G6PD) deficiency
Hemoglobinopathies, such as sickle cell anemia
RBC membrane abnormalities, such as spherocytosis
Acquired
Hypersplenism
Immune
Autoimmune: warm IgG, cold IgM, cold IgG
Drug induced: autoimmune or hapten
Mechanical
Macroangiopathic (marching, prosthetic valves)
Microangiopathic: disseminated intravascular coagulation (DIC), thrombotic thrombocytopenic purpura (TTP), and hemolytic uremic syndrome (HUS)
Infections, such as malaria
Toxins, such as snake venom and aniline dyes
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Figure 6-1 outlines the approach to evaluating anemia, assuming acute bleeding has been excluded.
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Mrs. A has a past medical history of obesity, reflux, depression, asthma, and osteoarthritis. She comes to your office complaining of feeling down, with progressive fatigue for the last 2 months. She has no chest pain, cough, fever, weight loss, or edema. Her only GI symptoms are poor appetite and her usual reflux symptoms; she has had no vomiting, melena, or rectal bleeding. She still has regular menses that are occasionally heavy. She brought in her medication bottles, which include ranitidine, sertraline, tramadol, cetirizine, and a fluticasone inhaler. Her physical exam shows a depressed affect, clear lungs, a normal cardiac exam, a nontender abdomen, guaiac-negative stool, no edema, and no pallor.
How reliable is the history and physical for detecting anemia?
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Symptoms in chronic anemia are due to decreased oxygen delivery to the tissues.
Fatigue is a common but not very specific symptom.
Dyspnea on exertion often occurs.
Exertional chest pain occurs most often in patients with underlying coronary artery disease or severe anemia or both.
Palpitations or tachycardia can occur.
Edema is sometimes seen.
It is due to decreased renal blood flow leading to neurohormonal activation and salt and water retention, similar to that seen in heart failure.
However, in contrast to the low cardiac output seen in patients with heart failure, the cardiac output in patients with anemia is high.
Mild anemia is often asymptomatic.
Symptoms of hypovolemia occur only in acute anemia caused by large volume blood loss.
Conjunctival rim pallor
Present when the anterior rim of the inferior palpebral conjunctiva is the same pale pink color as the deeper posterior aspect, rather than the normal bright red color of the anterior rim.
The presence of conjunctival rim pallor strongly suggests the patient is anemic (LR+ 16.7).
However, the absence of pallor does not rule out anemia.
Palmar crease pallor has an LR+ of 7.9.
Pallor elsewhere (facial, nail bed) is not as useful, with LR+ < 5.
No physical sign rules out anemia.
The overall sensitivity and specificity of the physical exam for anemia is about 70%.
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Order a CBC if patients have symptoms that suggest anemia, even without physical exam signs, or if you observe conjunctival rim or palmar crease pallor.
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Mrs. A's initial laboratory test results show a WBC of 7100/mcL, RBC of 2.6 million/mcL, Hgb of 6.7 g/dL, HCT of 23.3%, and MCV of 76 mcm3. Her platelet count is normal. A CBC 6 months ago showed an Hgb of 12 g/dL, HCT of 36%, and MCV of 82 mcm3.
At this point, what is the leading hypothesis, what are the active alternatives, and is there a must not miss diagnosis? Given this differential diagnosis, what tests should be ordered?