Approach to the Patient with Anemia

Anemia

DEFINITION
  • Anemia can be defined as a reduction to below normal limits in the amount of hemoglobin (Hb) or in the volume of red blood cells (RBCs) (hematocrit [Hct]) in a sample of peripheral venous blood.

ETIOLOGY
  • Decreased RBC production
    • Deficiency of hematinic agents
    • Bone marrow failure
    • Decreased erythropoietin (renal disease)
  • Increased RBC destruction or loss\
    • Hemolysis
    • Hemorrhage

DIAGNOSIS
  • History: 
    • Family and ethnic history: inquire about thalassemia, sickle cell anemia, splenectomy, and cholelithiasis at an early age.
    • Drug and toxic exposures (e.g., NSAIDs, “blood thinners”, chloramphenicol, methyldopa, quinidine, benzene, alkylating agents)
    • Obstetric and menstrual history: “excessive” menstrual bleeding is a frequent cause of iron-deficiency anemia in menstruating women.
    • External blood loss: gastrointestinal, genitourinary (inquire about melena, hematochezia, gross hematuria), frequent phlebotomy  
    • Dietary habits: poor dietary habits and excessive alcohol intake may result in folic acid deficiency.
    • Rapidity of onset: gradual onset is suggestive of bone marrow failure or chronic blood loss, whereas sudden onset of symptoms suggests hemolysis or acute hemorrhage.
    • History of infection (sepsis, AIDS, malaria)
    • History of cancer, renal disease, or endocrine disease
    • History of diarrhea, abdominal pain, bulky stools (malabsorption, celiac disease)
  • Physical examination: 
    • General appearance: evaluate nutritional status.
    • Vital signs: hypotension, tachycardia (acute blood loss)
    • Skin: pallor of the conjunctivae, lips, oral mucosa, nail beds, and palmar creases; jaundice (hemolysis); petechiae; purpura (thrombocytopenia)
    • Mouth: glossitis (pernicious anemia, iron-deficiency anemia)
    • Heart: listen for flow murmurs, prosthetic valves (increased RBC destruction).
    • Abdomen: splenomegaly (hemolysis, neoplasms, infiltrative disorders)
    • Rectum: examine stool for occult (or gross) blood.
    • Lymph nodes: infiltrative lesions, infections
  • Laboratory results: 
    • Hb and Hct: provide a guide to diagnosis and severity of anemia; the RBC distribution width (RDW) measures variability of RBC size and is useful in the diagnostic work-up of anemia.  
    • Reticulocyte count: 
      • Should be performed before any therapeutic maneuvers and is useful in any diagnostic algorithm (Fig. 7-1).

Figure 7-1 Algorithm for diagnosis of anemias. DIC, disseminated intravascular coagulation; HELLP, hepatomegaly-elevated liver (function tests)-low platelets; HUS, hemolytic-uremic syndrome; MCV, mean corpuscular volume; RBC, red blood cell; TTP, thrombotic thrombocytopenic purpura.


      • Reticulocyte counts below 1% indicate inadequate marrow production; counts above 4% indicate RBC destruction or acute blood loss; however, the reticulocyte count should be considered in light of the degree of anemia and the shift of reticulocytes to the peripheral blood. The reticulocyte production index (RPI) can be used as a correction method.
  • Mean corpuscular volume (MCV): classifies anemia as normocytic, microcytic, or macrocytic. 
    • Normocytic anemia: the reticulocyte count is used to distinguish excess destruction or blood loss (high reticulocyte count) from decreased production (low reticulocyte count); a bone marrow examination is of value in distinguishing the following causes of normocytic anemia and reticulocytopenia: 
      • Marrow hypoplasia (toxic drugs, radiation, infection)
      • RBC aplasia
      • Marrow infiltration (myeloma, lymphoma, leukemia)
      • Myelofibrosis
      • Renal insufficiency
    • Microcytic anemia: 
      • Iron deficiency is the most common cause. 
      • Thalassemia, lead poisoning, anemia of chronic disease, and sex-linked sideroblastic anemia are other causes.
      • The peripheral smear and RBC count may help to distinguish iron deficiency from thalassemia minor (relatively high RBC count and basophilic stippling in the latter).
      • Assess iron stores by determining the serum ferritin (or marrow iron stain if bone marrow exam is performed); if ferritin is low, iron deficiency is proved, but if it is normal or elevated, appropriate work-up for thalassemia (Hb electrophoresis), sideroblastic anemia, and anemia of chronic disease (low serum iron, low total iron-binding capacity, increased ferritin, decreased reticulocytes) should be obtained. RDW above 15 suggests iron deficiency.
      • Serum erythropoietin level can be useful in defining and treating anemia of chronic disease. 
    • Macrocytic anemia: 
      • Because reticulocytes have a large diameter, an elevated reticulocyte count will read out as an elevated MCV; if the reticulocyte count is elevated, hemolytic studies (haptoglobin, lactate dehydrogenase [LDH], indirect bilirubin) are indicated.
      • If hemolysis is confirmed, determine the cause with Coombs' test; other studies (as suggested by RBC morphology) may be indicated. 
      • If the reticulocyte count is normal and RBCs are macrocytic, vitamin B12 or folate deficiency is possible; therefore, RBC folate, serum vitamin B12, and serum folate levels should be obtained.
      • The presence of a megaloblastic bone marrow would favor the diagnosis of vitamin B12 or folate deficiency; if the bone marrow exhibits dyserythropoiesis or white blood cell (WBC) abnormalities, a myelodysplastic anemia is the cause of the macrocytic anemia.
      • A systematic and logical search with avoidance of a “shotgun” diagnostic or therapeutic approach will yield the correct diagnosis.
  • Review peripheral blood smear ( Fig. 7-2; see color insert in this chapter). RBC morphology should be evaluated for the following: 
    • Size 
      • Normal RBCs (see Fig. 7-2A ) have a diameter equal to that of the nucleus of a mature lymphocyte.
      • Microcytosis (see Fig. 7-2B ) is seen with iron deficiency, hemoglobinopathies, and sideroblastic anemia.
      • Macrocytosis (see Fig. 7-2C ) indicates megaloblastic anemia, liver disease, or myelodysplasia.
    • Shape 
      • Spherocytes: hereditary spherocytosis, immune, or other hemolytic states
      • Sickle cell: HbSS (see Fig. 7-2H )
      • Helmet cells: microangiopathic hemolysis, severe iron deficiency 
      • Teardrop cells (see Fig. 7-2I ): myeloproliferative diseases, pernicious anemia, and thalassemia
    • Color 
      • Hypochromasia (iron deficiency, sideroblastic anemias) 
      • Hyperchromasia (megaloblastic anemia, spherocytosis)
  • Morphology of WBCs and platelets should be noted and any abnormal cells identified; additional abnormalities of diagnostic value that may be present on peripheral smears are noted as follows: 
    • Howell-Jolly bodies (nuclear fragments) (see Fig. 7-2K ): hemolytic and megaloblastic anemias, splenectomy
    • Basophilic stippling (see Fig. 7-2L ): lead poisoning, thalassemia, and hemolytic states
    • Heinz bodies (denatured Hb) (see Fig. 7-2P ): unstable hemoglobinopathies, some hemolytic anemias; identification of Heinz bodies requires supravital stain
    • Cabot ring (nuclear remnants): megaloblastic anemias
    • Pappenheimer bodies (see Fig. 7-2Q ): postsplenectomy, hemolytic, sideroblastic, and megaloblastic anemias
    • Rouleaux formation (see Fig. 7-2F ): multiple myeloma, Waldenström's macroglobulinemia
    • Presence of parasites (e.g., Plasmodium in malaria, Babesia in babesiosis)
    • Nucleated RBCs: extramedullary hematopoiesis, hypoxia, and hemolysis
    • Target cells (see Fig. 7-2D ): hemoglobinopathies, iron deficiency, liver disease
    • Hypersegmented PMNs: folate/vitamin B12 deficiency

Figure 7-2
Erythrocyte morphology in peripheral blood. Wright's stain, ×1000. A, Normal red cells. B, Microcytic hypochromic cells typical of iron deficiency. C, Macrocytosis typically seen in megaloblastic anemia. D, Target cells. E, Schistocytes and nucleated red cells. F, Rouleaux formation. G, Normal red cells and microspherocytes in hereditary spherocytosis. H, Sickle cell anemia, showing sickled cells, a Howell-Jolly body, and polychromatophilia. I, Teardrop poikilocytes.
Figure 7-2
J, Reticulocytes (special stain). K, Howell-Jolly body (nuclear remnant). L, Homozygous β-thalassemia, showing microcytic and hypochromic erythrocytes, anisocytosis and poikilocytosis, basophilic stippling, a Howell-Jolly body, target cells, and polychromatophilia. M, Heterozygous β-thalassemia, showing hypochromia and microcytosis. N, Hemoglobin sickle cell disease, showing an HbC crystal, target cells, a folded taco-shaped cell, polychromatophilia, and Pappenheimer bodies. O, Eccentrocytes (blister cells) with a lopsided distribution of hemoglobin. Typically seen during a hemolytic episode in glucose-6-phosphate dehydrogenase (G6PD) deficiency. P, Heinz bodies (supravital stain). Q, HbS-β0-thalassemia, showing a nucleated erythrocyte, Howell-Jolly and Pappenheimer bodies, a sickle cell, target cells, polychromatophilia, and microcytosis.

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