Differential Diagnosis

  • Iron deficiency anemia

  • Thalassemia

  • Anemia of chronic disease

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  • Acute blood loss

  • Lead poisoning

  • Anemia from folate or vitamin B12 deficiency

  • Sickle cell anemia

  • Hereditary spherocytosis or elliptocytosis

  • Hemoglobinopathies other than sickle cell disease

  • Autoimmune hemolytic anemia

  • Hemolytic disease of the newborn

  • Microangiopathic hemolytic anemia

  • Glucose-6-phosphate dehydrogenase (GGPD) deficiency

  • Pyruvate kinase deficiency

  • Paroxysmal nocturnal hemoglobinuria (PNH)

  • Sideroblastic anemia

  • Aplastic anemia

Don't Miss – Dangerous Situations

Acute blood loss resulting in a rapid decrease in hemoglobin or hematocrit can be life-threatening. If not promptly treated, many of the listed disorders in the list can result in clinically severe and possibly lethal outcomes.

Commonly Encountered Situations

More commonly encountered anemias

  • Iron deficiency anemia

  • Beta thalassemia minor

  • Anemia of chronic disease

Suggested Additional Lab Testing

Obtain hematocrit or hemoglobin measurement or RBC number to determine RBC mass.

Initial studies to assist in the evaluation of the type of anemia:

  • MCV (indicates cell size)

  • Peripheral blood smear examination

For the individual types of anemia, certain other tests are valuable in the diagnosis. These are listed in conjunction to the type of anemia.

Iron deficiency anemia

  • Microcytic hypochromic RBC with elliptocytes with a low reticulocyte production

  • Bone marrow deficient in iron is not usually needed to establish the diagnosis

  • Low serum ferritin, low serum iron, and elevated total iron binding capacity (TIBC) is typical.

  • Elevated RBC distribution width


  • Microcytic RBCs with a variety of abnormalities on the peripheral smear, depending on the type of thalassemia and the clinical severity of the disease

  • Hemoglobin analysis may be abnormal and indicative of a certain type of thalassemia.

  • Patients with thalassemia often have normal to high serum ferritin, normal to low TIBC, normal to high serum iron, and normal RBC distribution width.

Anemia of chronic disease

  • RBCs are microcytic or normocytic, with an increase in size and shape variation.

  • Typical case: normal to elevated serum ferritin, low serum iron, low TIBC, increased sed rate

Anemia from acute blood loss

  • Reticulocyte production index is high.

  • RBC size and hemoglobin content reflect RBC status prior to the acute blood loss.

Anemia from folate or vitamin B12 deficiency

  • RBCs are macrocytic with macro-ovalocytes and low reticulocyte production.

  • For folate deficiency specifically, there is low or normal serum folate with low RBC folate and hypersegmented PMNs in peripheral blood smear.

  • For vitamin B12 deficiency, along with low serum vitamin B12, there may be elevated homocysteine and methylmalonic acid (MMA) levels indicative of pernicious anemia.

  • Anti-parietal cell antibodies and/or anti-intrinsic factor antibodies may be present in cases with pernicious anemia; hypersegmented PMNs can be found in the peripheral blood smear.

Sickle cell anemia

  • Sickle cells are found in sickle cell disease but not in sickle cell trait (under normal oxygen conditions).

  • Signs of hemolysis are found, including low haptoglobin, elevated unconjugated bilirubin, and increased LDH.

  • Hemoglobin analysis shows hemoglobin SS for sickle cell disease and hemoglobin AS for sickle cell trait.

  • Screening tests for the presence of sickle hemoglobin, usually based on the altered solubility of sickle hemoglobin, are positive in both sickle cell disease and sickle cell trait.

Anemias from hereditary spherocytosis or elliptocytosis

  • Reticulocyte production is high with the presence of spherocytes or elliptocytes and a prominent hemolytic component for hereditary spherocytosis in particular.

  • In hereditary spherocytosis, there is increased osmotic fragility of RBCs in the presence of a negative direct antiglobulin test.

Anemias from hemoglobinopathies other than sickle cell disease

  • There are hundreds of common and uncommon hemoglobin variants.

  • Hemoglobin electrophoresis can identify most of the clinically significant abnormal hemoglobins.

Hemolytic disease of the newborn

  • Reticulocyte production index is high with a prominent hemolytic component: low haptoglobin, elevated unconjugated bilirubin, and elevated LDH.

  • Mother tests Rh negative and baby tests Rh positive, with a positive direct antiglobulin test on the RBCs of the baby and an antibody to offspring RBCs in the mother’s blood.

Microangiopathic hemolytic anemia

  • Peripheral smear shows fragmented RBCs (schistocytes) with prominent signs of hemolysis.

G6PD deficiency

  • Reticulocyte production index is high, with a prominent hemolytic component.

Test for RBC G6PD shows a deficiency.

  • Heinz bodies in the RBCs can be identified on the peripheral smear.

Pyruvate kinase deficiency

  • Reticulocyte production index is high, with a prominent hemolytic component.

  • An assay to quantitate RBC pyruvate kinase reveals the deficiency.


  • Prominent hemolytic component, with low platelet and WBC (especially granulocyte) counts

  • Flow cytometry of granulocytes and RBC showed decreased CD 55 and CD 59.

  • RBC populations in sideroblastic anemia are normochromic and hypochromic.

  • Increase in ringed sideroblasts in a normoblast population on bone marrow biopsy

  • Elevated serum ferritin

Aplastic anemia

  • Reticulocyte production index is low, with a hypocellular bone marrow from a production failure in all blood cell lines