Approach to Anemia in the Adult and Child

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Chapter 7 Approach to Anemia in the Adult and Child

Table 7-1 Usefulness of the Reticulocyte Count in the Diagnosis of Anemia*

Diagnosis Value
Hypoproliferative Anemias Absolute Reticulocyte Count <75,000/µL
Anemia of chronic disease  
Anemia of renal disease  
Congenital dyserythropoietic anemias  
Effects of drugs or toxins  
Endocrine anemias  
Iron deficiency  
BM replacement  
Maturation Abnormalities Absolute Reticulocyte Count <75,000/µL
Vitamin B12 deficiency  
Folate deficiency  
Sideroblastic anemia  
Appropriate Response to Blood Loss or Nutritional Supplementation Absolute Reticulocyte Count ≥100,000/µL
Hemolytic Anemias Absolute Reticulocyte Count ≥100,000/µL
Hemoglobinopathies  
Immune hemolytic anemias  
Infectious causes of hemolysis  
Membrane abnormalities  
Metabolic abnormalities  
Mechanical hemolysis  

BM, Bone marrow.

*Note that reticulocyte counts in the range of 75,000 to 100,000/µL can sometimes be associated with appropriate response to blood loss or hemolytic anemia.

Table 7-2 Comparison of the More Common Causes of Anemia in Children and Adult

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DIC, Disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; HUS, hemolytic uremic syndrome; MDS, myelodysplastic syndrome; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.

Table 7-4 Combining the Reticulocyte Count and Red Blood Cell Parameters for Diagnosis

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MCV, Mean corpuscular volume; RDW, red blood cell distribution width.

Table 7-5 Features of the Peripheral Blood Smear

Red Blood Cell Morphology Definition Interpretation
Polychromasia Large, bluish RBCs lacking normal central pallor on peripheral blood smear; bluish stain is the result of residual ribonucleic acid Rapid production and release of RBCs from BM; elevated reticulocyte count; most commonly seen in hemolytic anemia
Basophilic stippling Many small bluish dots in portion of erythrocytes; comes from staining of clustered polyribosomes in young circulating RBCs Seen in a variety of erythropoietic disorders, including acquired and congenital hemolytic anemias and occasionally in lead poisoning (lead inhibits pyrimidine 5’-nucleotidase, which normally digests the residual RNA)
Pappenheimer bodies Several grayish, irregularly shaped inclusions in a portion of erythrocytes visible on peripheral smear; composed of aggregates of ribosomes, ferritin, and mitochondria Erythropoietic malfunction in congenital anemias such as hemoglobinopathies, particularly with splenic hypofunction or acquired anemias such as megaloblastic anemia
Heinz bodies Several grayish, round inclusions visible after supravital staining with methyl crystal violet of the peripheral blood smear, often in the context of bite cells; represent aggregates of denatured hemoglobin Indicative of oxidative injury to the erythrocyte, such as occurs in G6PD deficiency, or less commonly of unstable hemoglobins
Howell-Jolly bodies Usually one or at most a few purplish inclusions in the erythrocyte visible on the routine peripheral blood smear; represent residual fragments of nuclei containing chromatin Associated with states of splenic hypofunction or after splenectomy
Schistocytes RBCs that are fragmented into a variety of shapes and sizes, including helmet-shaped cells; indicative of shearing of the erythrocyte within the circulation Associated with microangiopathic hemolytic anemias, including DIC, TTP, or HUS, as well as other mechanical causes of hemolysis, such as prosthetic valves
Spherocytes RBCs that have lost their central pallor and appear spherical; indicative of loss of cytoskeletal integrity from internal or external causes Associated with hereditary spherocytosis, autoimmune hemolytic anemia; may also be observed in addition to schistocytes in the presence of microangiopathic hemolytic anemia
Teardrop cells Pear-shaped erythrocytes visible on peripheral blood smear; indicative of mechanical stress on the RBC during release from the BM or passage through the spleen Seen in a variety of conditions, including congenital anemias such as thalassemia and acquired disorders such as megaloblastic anemia; may also suggest a more ominous process such as myelophthisis (BM replacement)
Burr cells (echinocytes) RBCs that have smooth undulations present on the surface circumferentially; pathogenesis unknown Indicative of uremia when present on a properly made peripheral blood smear
Spur cells (acanthocytes) RBCs that have spiny points present on the surface circumferentially; reflective of abnormal lipid composition of RBC membrane Most commonly indicative of liver disease when present in significant numbers; also seen in abetalipoproteinemia and in RBCs lacking the Kell blood group antigen

BM, Bone marrow; DIC, disseminated intravascular coagulation; G6PD, glucose-6-phosphate dehydrogenase; HUS, hemolytic uremic syndrome; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.

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Figure 7-2 USEFUL PERIPHERAL BLOOD AND RED BLOOD CELL FEATURES IN THE EVALUATION OF ANEMIA.

A, Normal red blood cells (RBCs). Note the central pallor is one-third the diameter of the entire cell. B, Rouleaux formation is indicative of increased plasma protein. C, Agglutination indicates an antibody-mediated process such as cold agglutinin disease. D, Polychromatophilic cell. The gray-blue color is attributable to RNA and the cell is equivalent to a reticulocyte, which must be identified with a reticulocyte stain. E, Basophilic stippling. This also is attributable to increased RNA caused either by a left shift in erythroid cells or lead toxicity. F, Hypochromic microcytic cells typical of iron-deficiency anemia. Note the widened central pallor and the “pencil” cell in the lower left. G, Macroovalocyte as can be seen in either megaloblastic anemia or myelodysplastic syndrome. H, Microspherocytes typical of hereditary spherocytosis. I, Elliptocytes (ovalocytes) from a patient with hereditary elliptocytosis. J, RBC fragments from thermal injury (burn patient). K, Nucleated RBC. L, Howell-Jolly bodies indicative of splenic dysfunction or absence. M, Pappenheimer bodies from a patient with sideroblastic anemia. N, Cabot ring, as can be seen in megaloblastic anemia or MDS. O, Malarial parasites (Plasmodium falciparum). P, Schistocyte typical of a microangiopathic hemolytic anemia. Q, Tear-drop form indicates marrow fibrosis and extramedullary hematopoiesis. R, Echinocyte (Burr cell) with rounded edges. S, Acanthocyte (spur cell) with more irregular pointed ends. This was from a patient with neuroacanthocytosis. They can also be seen in patients with liver disease and lipid abnormalities. T, “Bite” cell from a patient with glucose-6-phosphate dehydrogenase (G6PD) deficiency. U, Sickle cell, from a patient with homozygous sickle cell disease. V, Hemoglobin C crystal. W, Target cells. X, Hemoglobin C disease. Note that the RBC in center has condensed hemoglobin at each pole. Y, Heinz body preparation (supravital stain) from a patient with G6PD deficiency. Note that the cells to the right have increased precipitated hemoglobin.

Systematic Approach to the Diagnosis of Anemia

Integration of historic features and physical findings with thoughtful review of the results of the automated complete blood cell count and of the peripheral smear often serves to narrow down the differential diagnosis of anemia significantly. For example, a patient who has had a gastric bypass eating a normal diet who presents with gradual onset of fatigue accompanied by the more recent onset of distal paresthesias and a finding of decreased vibration sense in the setting of anemia with significantly elevated mean corpuscular volume and red blood cell distribution width values and numerous six-lobed polymorphonuclear leukocytes on peripheral blood smear almost certainly has vitamin B12 deficiency. This is suggested even before the return of specific laboratory testing because of the relatively narrow differential diagnosis for megaloblastic anemia and the fact that neurologic abnormalities are not associated with folate deficiency. For the purposes of diagnostic efficiency, the rewards of correlation of historic features and physical findings with a careful review of the peripheral blood smear cannot be overstated.

Special stains of the peripheral blood smear can be helpful in elucidating the cause of anemia. If there is significant nuclear debris present, the reticulocyte count obtained by automated methods can be inaccurate. In such cases, manual counting after staining with new methylene blue, which stains residual RNA in reticulocytes, permits accurate enumeration. If bite cells are detected on peripheral smear, supravital staining with methyl crystal violet can reveal Heinz bodies. These are aggregates of denatured hemoglobin reflecting an oxidative insult, most commonly caused by glucose-6-phosphate dehydrogenase deficiency or, less frequently, by the presence of an unstable hemoglobin (see Fig. 7-2, H).