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Sumana Devata

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date: 26 January 2022

  1. A. Introduction. Anemia is commonly encountered in clinical practice.

    1. a. Definition. Anemia is defined as a reduced absolute number of circulating red blood cells (RBCs). Because RBC mass is not practical to measure, other RBC measurements including hemoglobin, hematocrit, and RBC count are often utilized. Anemia is a manifestation of disease, not a disease in and of itself.

    2. b. Normal values are gender dependent. Slight variations are seen depending on age and ethnicity.

      1. i. Men: hemoglobin <13.5 g/dL or hematocrit <41%

      2. ii. Women: hemoglobin <12 g/dL or hematocrit <36%

    3. c. Clinical manifestations of anemia. Some patients may be asymptomatic, while others may exhibit fatigue, dyspnea on exertion, or exertional angina. Signs and symptoms of the underlying disorder may also be present.

    4. d. Classification. Anemia is classified as microcytic, normocytic, or macrocytic based on the mean corpuscular volume (MCV).

      1. i. The normal MCV is 80–100 fL.

      2. ii. If more than one disorder is present, the MCV may be an average of the different populations of RBCs, producing a normal MCV. However, in mixed disorders, the red cell distribution width (RDW) will be increased.

      3. iii. Other classification schemes stratify anemias based on increased RBC loss (due to bleeding or hemolysis) or impaired production. The reticulocyte index (RI, a measure of the rate of production of new RBCs) helps differentiate between states of hypoproliferation (RI <2) or hyperproliferation (RI >2).

        1. 1. The RI is a function of the reticulocyte percent, patient’s hematocrit, normal hematocrit, and reticulocyte maturation time (RMT).

        2. 2. The specific formula is:

          RI = (% Reticulocytes × Patient’s hematocrit) ÷ (Normal hematocrit × RMT)

          Where the normal hematocrit is 45 and the RMT depends on the patient’s hematocrit, per Table 62.1.

          Table 62.1 Correlation Between Hematocrit and Reticulocyte Maturation Time

          Patient’s Hematocrit

          Reticulocyte Maturation Time







          15 and below


  2. B. Microcytic Anemia (MCV <80 fL)

    1. a. Causes of microcytic anemia

      1. i. Iron deficiency is a common cause of microcytic anemia and is important to identify as it may indicate an underlying gastrointestinal problem such as malignancy or malabsorption.

      2. ii. Thalassemia are characterized by various defects in hemoglobin production, often resulting in a microcytic anemia. The severity of anemia is variable based on the type of hemoglobin defect present. Patients with alpha or beta thalassemia minor, for example, may present with microcytosis without anemia.

      3. iii. Anemia of chronic disease (ACD) is associated with inflammatory diseases (e.g., rheumatoid arthritis, serious infection, carcinoma, chronic renal insufficiency). Thus, some refer to this entity as anemia of active inflammation.

      4. iv. Sideroblastic anemias are a heterogeneous group of disorders that have in common various defects in the porphyrin pathway that lead to an increase in cellular iron uptake. Congenital sideroblastic anemia causes microcytosis, whereas other etiologies may lead to a variable MCV. Causes of sideroblastic anemia include:

        1. 1. Heredity (e.g., X-linked, erythropoietic protoporphyria)

        2. 2. Drugs and toxins (e.g., Lead, Isoniazid, Ethanol [LIE]). Heavy metal exposures should be evaluated.

        3. 3. Malignancy (e.g., myelodysplasia [refractory anemia with ringed sideroblasts])

    2. b. Approach to the patient. It is important to differentiate iron deficiency from the other causes of microcytic anemia.

      1. i. Iron deficiency versus thalassemia. Iron studies are typically diagnostic for iron deficiency (decreased transferrin saturation and decreased ferritin), but iron deficiency can also be distinguished from thalassemia using the thalassemia index (i.e., the MCV [measured in fL] divided by the RBC count [measured in cells × 106/μ‎L]). A thalassemia index <13 suggests thalassemia; an index >13 suggests iron deficiency.

      2. ii. Iron deficiency versus other etiologies

        1. 1. Determine the probability of iron deficiency. The pretest probability is based on clinical factors. By estimating the pretest probability and using likelihood ratios for a given ferritin level (Table 62.2), you can estimate the posttest probability (see Chapter 2).

          Table 62.2 Serum Ferritin Values and Corresponding Likelihood Ratios

          Serum Ferritin (µL)

          Likelihood Ratio




          Not helpful





          Based on data from Guyatt GH, Oxman AD, Ali M, Willan A, McIlroy W, Patterson C. Laboratory diagnosis of iron-deficiency anemia: an overview. J Gen Intern Med 1992;7(2):145–153.

        2. 2. Laboratory studies

          • a. Serum ferritin. This test may be less helpful in patients with liver disease or other chronic inflammatory states because ferritin is an acute phase reactant. Like most tests, ferritin is most useful when the pretest probability is approximately 50%.

            • i. If the serum ferritin is <15 ng/mL, it practically guarantees that the patient has iron deficiency.

            • ii. Similarly, a value >100 ng/mL makes iron deficiency improbable.

          • b. Serum transferrin receptor is occasionally helpful because it is usually elevated in iron deficiency and decreased in ACD. However, pregnancy and oral contraceptives can also elevate transferrin levels.

          • c. Total iron-binding capacity is normal to high in iron-deficient states.

          • d. Platelet count can be elevated due to iron deficiency.

        3. 3. Bone marrow biopsy remains the gold standard test to diagnose iron deficiency.

          Hot Key

          All forms of the microcytic anemias described here are hypoproliferative (i.e., RI <2).

    3. c. Treatment

      1. i. Iron deficiency anemia therapy involves treating the underlying cause of blood loss and replacing lost iron. Oral iron is most commonly used; side effects include constipation, abdominal discomfort, and black discoloration of stools. Achlorhydria (i.e., in patients on proton pump inhibitors or those status post gastric bypass patients) or celiac disease may limit the ability to absorb iron; these patients can be given iron intravenously. With therapy, reticulocytosis should occur within a few days and the hemoglobin should rise in 1–2 months.

      2. ii. Thalassemia treatment varies with disease severity. Patients may require no treatment or may require frequent transfusions. To prevent iron overload, Iron chelation therapy may be required for those patients receiving frequent blood transfusions to prevent iron overload. Severe disease can be treated successfully with bone marrow transplantation, but significant morbidity and mortality limit its widespread use.

  3. C. Macrocytic Anemia (MCV >100 fL)

    1. a. Megaloblastic anemias are caused by various defects in DNA synthesis that lead to hematologic abnormalities. Causes of megaloblastic anemia include:

      1. i. Vitamin B12deficiency

      2. ii. Folate deficiency

      3. iii. Drugs (e.g., hydroxyurea, methotrexate, azathioprine, zidovudine)

      4. iv. Miscellaneous. Other rare conditions that can cause a megaloblastic anemia are Lesch-Nyhan syndrome and thiamine- or pyridoxine-responsive anemias

        Hot Key

        The finding of hypersegmented polymorphonuclear neutrophils (PMNs) on the peripheral blood smear strongly suggests megaloblastic anemia.

    2. b. Chronic liver disease causes a macrocytosis as a result of ineffective erythropoiesis.

    3. c. Alcoholism produces erythrocyte membrane abnormalities, leading to macrocytic anemia.

    4. d. Hypothyroidism causes macrocytic anemia by an unclear mechanism.

    5. e. Reticulocytosis. An MCV greater than 110 fL is usually not due to reticulocytosis alone.

    6. f. Myelodysplasia. (See Chapter 70.)

      Hot Key

      Practically all HIV-infected patients taking zidovudine and all patients receiving hydroxyurea will have an elevated MCV. Therefore, this finding can aid in gauging compliance with medications.

  4. D. Normocytic Anemia

    An absolute reticulocyte count is the initial test to order in a patient with normocytic anemia because the RI allows the anemia to be classified as hyperproliferative or hypoproliferative (Figure 62.1).

    Figure 62.1 Determining the cause of normocytic anemia. ACD = anemia of chronic disease; AIHA = autoimmune hemolytic anemia; DIC = disseminated intravascular coagulation; G6PD = glucose-6-phosphate dehydrogenase; HELLP = Hemolysis, Elevated Liver enzymes, and Low Platelet count syndrome; HTN = hypertension; HUS/TTP = hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; MAHA = microangiopathic hemolytic anemia; PNH = paroxysmal nocturnal hemoglobinuria; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell.

    Figure 62.1 Determining the cause of normocytic anemia. ACD = anemia of chronic disease; AIHA = autoimmune hemolytic anemia; DIC = disseminated intravascular coagulation; G6PD = glucose-6-phosphate dehydrogenase; HELLP = Hemolysis, Elevated Liver enzymes, and Low Platelet count syndrome; HTN = hypertension; HUS/TTP = hemolytic uremic syndrome/thrombotic thrombocytopenic purpura; MAHA = microangiopathic hemolytic anemia; PNH = paroxysmal nocturnal hemoglobinuria; PT = prothrombin time; PTT = partial thromboplastin time; RBC = red blood cell; WBC = white blood cell.

    1. a. Hyperproliferative normocytic anemia is characterized by erythrocyte loss.

      1. i. Hemolysis. Clues that hemolysis may be present include an elevated lactate dehydrogenase (LDH), increased indirect and total bilirubin level. If hemolysis is a concern, the peripheral smear must be examined. The cause of hemolytic anemia can be determined based on the morphology of the erythrocytes (e.g., schistocytes, spherocytes, sickle cells). Two important causes of hemolysis include autoimmune hemolytic anemia (AIHA) and microangiopathic hemolytic anemia (MAHA).

        1. 1. AIHA is caused by antibodies binding to RBCs. Immunoglobulin G (IgG) autoantibodies are termed “warm” antibodies, and IgM autoantibodies are termed “cold” antibodies. Underlying etiologies include collagen vascular disorders, malignancy, infection (e.g., Mycoplasma, mononucleosis), drugs, prior allogeneic bone marrow or transplantation. AIHA may also be idiopathic in etiology.

          • a. Peripheral smear may show spherocytes.

          • b. Laboratory analysis often reveals an elevated reticulocyte count, LDH, and indirect bilirubin in addition to decreased plasma haptoglobin. Coombs test (direct antiglobulin test [DAT]) is positive.

        2. 2. MAHA is characterized by intravascular shearing of RBCs, which leads to schistocyte formation seen on peripheral smear. A few of the important causes of MAHA are listed here.

          • a. Disseminated intravascular coagulation (DIC). In acute DIC, the major concern is bleeding, whereas in chronic DIC, thrombosis is more of a problem.

            MNEMONIC: Causes of DIC (“MOIST”)


            Obstetric complications




          • b. Hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). The triad of HUS is hemolysis, uremia, and thrombocytopenia. TTP can contain the findings of HUS plus fever and neurologic changes (although having all five findings is extremely rare). In certain patients, the neurologic abnormalities are the predominant feature and renal insufficiency is minimal; these patients are prototypical for TTP. Other patients will present with profound diarrhea and acute renal failure but with minimal neurologic changes; these patients likely have HUS. However, there are many patients that overlap the spectrum of these two conditions. A diagnostic test for TTP is ADAMTS13 activity, as a value of 10% or lower ADAMTS13 activity is suggestive of TTP in the correct clinical context.

            Hot Key

            TTP is a clinical diagnosis. Plasma exchange should not be delayed awaiting the results of ADAMTS13 activity.

          • c. Heart valve abnormalities

          • d. Hemangiomas (e.g., Kasabach-Merritt syndrome)

          • e. Malignant hypertension

      2. ii. Hemorrhage. If hemorrhage is suspected, the source of the blood loss (e.g., the gastrointestinal tract) must be determined.

    2. b. Hypoproliferative normocytic anemia

      1. i. Pure red cell aplasia

      2. ii. Anemia of chronic disease

      3. iii. Renal failure

    3. c. Therapy

      1. i. AIHA. Primary treatment includes steroids and/or splenectomy. Occasionally, immunosuppressive chemotherapy or immunotherapy (e.g., rituximab) may be required.

      2. ii. MAHA treatment should be aimed at correcting the underlying disorder if possible. Immediate therapy for TTP is critical and includes plasmapheresis. If unavailable, the patient can be temporized with fresh-frozen plasma until transferred to a hospital with plasmapheresis capability. Additional therapy with steroids, rituximab, or chemotherapy may also be required in refractory cases.

      3. iii. Anemia of chronic disease or renal disease. If anemia is profound enough to require intermittent transfusions, a trial of recombinant erythropoietin can be given. Erythropoietin dosing should be titrated so as to raise the hemoglobin to 11 g/dL, and concurrent iron supplementation should be given if the ferritin is depressed.

Suggested Further Readings

Berentsen S. Cold agglutinin disease. ASH Education Program Book 2016;2016:226–31.Find this resource:

Camaschella C. Iron-deficiency anemia. N Engl J Med 2015;372:1832–43.Find this resource:

George JN, Nester CM. Syndromes of thrombotic microangiopathy. N Engl J Med 2014;371:654-66.Find this resource:

Kalfa TA. Warm antibody autoimmune hemolytic anemia. ASH Education Program Book 2016;2016:690-7.Find this resource:

Rund D, Rachmilewitz E. β‎-Thalassemia. N Engl J Med 2005;353:1135–46.Find this resource: