First assess the reticulocyte count and rule out stress erythro- poiesis, as in bleeding or hemolysis. Reticulocytes are larger than senescent red cells; consequently, increased reticulocyte numbers elevate the MCV but generally not above 110 -115 fL. Macrocytic anemias may be non-megaloblastic or megaloblastic (Table 4).
Anemia • 145
Table 3. Differential Diagnosis of Microcytic Anemia
Disease Notes
Iron deficiency anemia Anemia with hypochromia, microcytosis, and increased RDW. Usually due to menstrual or GI blood loss; less commonly, celiac disease or chronic intravascular hemolysis. Serum ferritin concentration and transferrin saturation usually low; serum transferrin receptor concentration usually increased. Search for a source of chronic blood loss.
␣-thalassemia trait Mild anemia with normal RDW due to homozygous single ␣-globin gene deletion or heterozygous double ␣-globin gene deletion. Seen in individuals of African, Mediterranean, Middle Eastern and Southeast Asian ancestry. Normal serum ferritin concentration and transferrin saturation. On electrophoresis, normal percentage of hemoglobin A2and hemoglobin F. Usually a diagnosis of exclusion.
-thalassemia trait Mild anemia with normal RDW due to reduced expression of -globin gene. Seen in individuals of African, Mediterranean, Middle Eastern and Southeast Asian ancestry. Normal serum ferritin concentration and transferrin saturation. On electrophoresis, increased percentage of hemoglobin A2(3.6%-8%) and normal to slightly increased percentage of hemoglobin F (1%-3%). -thalassemia intermedia Hemoglobin 7-10 g/dL due to reduced but not absent expression of both -globin genes. Typically, there is evidence of ineffective
erythropoiesis with a low serum haptoglobin and increased levels of indirect bilirubin and LDH in the setting of normal
reticulocyte count and increased iron stores. Increased serum ferritin concentration and transferrin saturation. On electrophoresis, increased percentage of hemoglobin A2(5.4%-10%) and hemoglobin F (20%-80%).
Sickle-+ thalassemia Seen in persons of African, Middle Eastern, Mediterranean, or Indian ancestry. Serum ferritin and transferrin saturation usually normal. Hemoglobin electrophoresis shows predominantly hemoglobin S but also variable amounts of hemoglobin A (5-30%); hemoglobin A2increased (>3.5%); hemoglobin F normal to variably increased (2-10%).
Hemolysis
When laboratory assessments suggest hemolysis (see Table 2), consider cause by type (spherocytic or non-spherocytic), site (intramedullary or extramedullary; intravascular or extravascular), and mechanism (immune-mediated or non-immune-mediated; intrinsic versus extrinsic to the red cell). For example, spherocyt- ic hemolytic anemia implicates a membrane defect, either acquired as in warm autoimmune hemolytic anemia or congenital as in hereditary spherocytosis. Non-spherocytic hemolytic anemias include bite cell hemolysis (as in oxidant stress) and fragmentation
hemolysis (as in thrombotic microangiopathies). Intramedullary hemolysis is seen in a variety of disorders associated with ineffective erythropoiesis, including thalassemia. Extramedullary hemolysis may be extravascular (as in hemolysis mediated by the spleen) or intravascular (as in hemolysis associated with cold agglutinin dis- ease or thrombotic microangiopathies). Immune-mediated hemol- ysis is distinguished by the Coombs’ test. Hemolytic disorders “intrinsic” to the red cell include membrane defects, enzy- mopathies, and hemoglobinopathies. Table 5 summarizes various causes of hemolytic anemia. In all cases, examining the peripheral
146 • Hematology
Table 5. Differential Diagnosis of Hemolytic Anemia*
Disease Notes
Membrane defect (e.g., Suspected due to family history, splenomegaly, and spherocytes or elliptocytes on smear. Confirmed by osmotic fragility (and hereditary spherocytosis, negative) direct Coombs’ test.
hereditary elliptocytosis)
Enzymopathies (G6PD Common forms of G6PD deficiency usually have only episodic moderate hemolysis, precipitated by oxidant drugs or infection. and pyruvate kinase Variable blood smear findings include bite cells, spherocytes, rarely fragments, and often little erythrocyte abnormality other than deficiency) polychromasia (from reticulocytosis). Pyruvate kinase deficiency is rare with moderately severe anemia, with acanthocytes. Hemoglobinopathies Chronic or episodic hemolysis. Hemoglobin A2levels are increased with -thalassemias (hemoglobin F may be). No structural
(hemoglobins S and C, hemoglobin abnormality is detectable with ␣-thalassemias; these are diagnosed based on hematocrit, MCV, smear, and family thalassemias, and study. Abnormal hemoglobins such as E and D are uncommon in the United States. Blood smear changes suggest certain hereditary unstable hemoglobinopathies; hemoglobin electrophoresis reveals the abnormal hemoglobin.
hemoglobins; see Chapter 40)
Autoimmune hemolytic Spherocytes on the blood smear; erythrocyte agglutination is seen with cold agglutinin disease. Confirmed by direct and indirect anemias (AIHA) (warm Coombs’ tests, and cold agglutinin titer. Most cases of warm AIHA are associated with an underlying disorder (i.e., systemic and cold) lupus and lymphoproliferative disorders, or drug-induced). Cold AIHA is direct Coombs’ positive for C3 and is also frequently
associated with underlying disorders including transient postinfectious (i.e., Mycoplasma pneumoniae) and systemic lupus. Erythrocyte fragmentation TTP usually presents with neurologic symptoms and severe fragmentation anemia and thrombocytopenia. With HUS (children), syndromes (TTP, HUS, renal abnormalities predominate and anemia and thrombocytopenia are milder. In other causes of microangiopathic anemia, the DIC; see Chapter 41) anemia and thrombocytopenia are usually mild to moderate; these disorders include DIC, malignant hypertension, and
scleroderma renal crisis and are diagnosed by peripheral blood smear in the proper clinical context.
Infections (malaria, Symptoms of infection, particularly fevers, usually dominate. Splenomegaly is the rule with malaria; babesiosis produces a usually babesiosis) milder malaria-like illness unless patients are asplenic. Finding intraerythrocyte parasites on blood smear is diagnostic.
Hypersplenism Splenomegaly of any etiology can cause hemolysis; hypersplenism may also lower leukocytes, platelets, or any combination of (see Chapter 22) cell lines. Hypersplenism produces no erythrocyte morphologic changes, but the smear may show changes related to the
underlying etiology (e.g., target cells with liver disease).
*Go to www.acponline.org/essentials/hematology-section.html to see examples of peripheral blood smears illustrating findings associated with these conditions.
AIHA = autoimmune hemolytic anemia; DIC = diffuse intravascular coagulation; G6PD = glucose-6-phosphate dehydrogenase; HS = hereditary spherocytosis; HUS = hemolytic uremic syndrome; TTP = thrombotic thrombocytopenic purpura.
Table 4. Differential Diagnosis of Megaloblastic Anemia (Macrocytosis, Hypersegmented Neutrophils, Macroovalocytes)
Disease Notes
Folate deficiency Morphologically indistinguishable from vitamin B12deficiency and drug-induced megaloblastosis. Inquire about excessive alcohol use, quality of diet, history of small bowel disease. Do serum antibody test for celiac disease (anti–tissue transglutaminase).
Vitamin B12deficiency Morphologically indistinguishable from folate deficiency. Loss of vibration or position sense favors vitamin B12deficiency. However, neurologic disease due to vitamin B12deficiency may occur without anemia or macrocytosis.
Drug-induced changes Numerous drugs prescribed for cancer, HIV infection, psoriasis, lupus, rheumatoid arthritis, and immunosuppression in in erythrocytes transplant patients cause macrocytic and sometimes megaloblastic changes in erythrocytes. History should be revealing. See
Web enhancement for list of drugs that commonly cause macrocytosis (www.acponline.org/essentials/hematology-section.html). Erythroleukemia Erythroleukemia is a morphologic diagnosis based on marrow study. Characterized by normal or high serum vitamin B12.
blood smear is central to identifying red cell morphologies that implicate certain hemolysis mechanisms (see Table 1).
In oxidant hemolysis, a by-product is methemoglobin (con- taining ferric ions), which has altered spectrophotometric prop- erties from hemoglobin (containing ferrous ions). As a conse- quence, patients with methemoglobinemia have PaO2 values
(reflecting the total concentration of oxygen in blood) that appear higher than expected in relation to the percent oxygen saturation (which specifically reflects the percent of oxygen bound to hemo- globin containing ferrous ions).