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How do I work up my patient with anemia?

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Key concept

Anemia is defined in clinical practice as a hemoglobin level <13.5 g/dL in men and <12 g/dL in women. Symptoms of anemia correlate with the degree and rate of development. An underlying abnormality should always be explored in an anemic patient.

Clinical scenario

A 69-year-old man with a history of an Escherichia coli urinary tract infection treated 8 days ago with ceftriaxone presents to the emergency room with symptoms of fatigue and jaundice. Physical examination reveals pallor and icteric sclerae. Laboratory evaluation reveals a hemoglobin level of 7.9 g/dL, elevated lactate dehydrogenase (LDH), low haptoglobin, indirect hyperbilirubinemia, and reticulocytosis. Review of the peripheral smear shows increased reticulocytes, anisocytosis, and spherocytic red blood cells (RBCs). A direct antiglobulin test (DAT) is positive for IgG. The patient is managed with supportive measures and recovers spontaneously after 7 days.

Action items

Production of RBCs requires the interaction of several elements and catalysts, including functional bone marrow, erythropoietin, iron, vitamins, and cytokines; deficiency in any of these can lead to anemia.

A systematic approach in narrowing down the cause of anemia should be taken to ensure an accurate diagnosis and avoid unnecessary testing.


In approaching a patient with anemia, the initial work-up should delineate whether the cause is a result of marrow underproduction or peripheral destruction or sequestration. This should be followed by a focused work-up of the suspected cause. Apparent or occult blood loss should be excluded, after which the pathogenesis can be categorized as follows.

Underproduction anemias

  • Anemia plus corrected reticulocyte count <2%

    • Corrected reticulocyte count = reticulocyte % × patient’s hematocrit/normal hematocrit1

Select examples1:

  • Microcytic RBCs: disorders in heme or globin synthesis (eg, iron deficiency, congenital sideroblastic anemia, thalassemia)

  • Normocytic RBCs: anemia of chronic disease (can be microcytic), chronic kidney disease, or compound deficiencies (eg, iron and folate deficiency)

  • Macrocytic RBCs: deficiency of vitamin B12 or folate, or liver disease

Anemia secondary to increased RBC destruction (hemolytic anemia)

  • Intravascular hemolysis: hemoglobinemia, hemoglobinuria, hemosiderinuria, decreased haptoglobin, or elevated LDH2

  • Extravascular hemolysis (spleen, liver): no release of hemoglobin in the blood; no hemoglobinemia, no hemoglobinuria, no or minimal consumption of haptoglobin, and LDH can be normal

    • Recycled hemoglobin in the spleen or liver can result in indirect hyperbilirubinemia and bilirubinate gallstones2

Select examples1,2

See Table below

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