What do target cells on a peripheral blood smear indicate and how should they be evaluated and managed in a patient with anemia?

Target Cells in Anemia: Diagnostic Significance and Management

Target cells on peripheral blood smear indicate specific underlying conditions—most commonly liver disease, hemoglobinopathies (particularly thalassemia and hemoglobin C disease), iron deficiency anemia, and post-splenectomy states—and should prompt targeted evaluation based on the clinical context and associated red blood cell morphology.

What Target Cells Indicate

Target cells (codocytes) appear as cells with a central area of hemoglobin surrounded by a pale ring and an outer ring of hemoglobin, resembling a "bull's eye" or target. Their presence signals:

Primary Diagnostic Considerations

• Hemoglobinopathies: Target cells are characteristic of beta-thalassemia minor and hemoglobin C disease, where they appear alongside other microcytic changes 1
• Iron deficiency anemia: Target cells are present in most cases of IDA, though they are not specific for this diagnosis and appear in similar numbers to thalassemia 1
• Liver disease: Increased membrane lipid content leads to target cell formation 2
• Post-splenectomy state: Loss of splenic culling function allows persistence of abnormal cells 3

The key distinction is that target cells alone cannot differentiate between iron deficiency and thalassemia—you must evaluate the complete morphologic picture 1.

Systematic Evaluation Approach

Step 1: Assess Complete RBC Morphology

Examine the peripheral blood smear systematically for at least 200 cells 4:

• Prekeratocytes and pencil cells: These strongly favor iron deficiency anemia over thalassemia (prekeratocytes present in 78% of IDA vs 37% of thalassemia, p=0.001) 1
• Basophilic stippling: Contrary to traditional teaching, this appears in only 17% of beta-thalassemia cases and is not diagnostically useful 1
• Microcytosis severity: Evaluate MCV and degree of hypochromia 3, 5
• Other poikilocytes: Look for schistocytes, spherocytes, or sickle cells that suggest alternative diagnoses 6, 3

Step 2: Integrate with RBC Indices

• MCV <83 fL defines microcytic anemia and narrows the differential to iron deficiency, thalassemia, anemia of chronic disease, or sideroblastic anemia 5
• RBC histogram analysis on automated analyzers provides quantifiable morphology data that enhances diagnostic accuracy 7
• RBC distribution width (RDW): Elevated in iron deficiency, typically normal in thalassemia 3

Step 3: Perform Targeted Laboratory Testing

Based on the morphologic pattern:

For suspected iron deficiency:

• Serum ferritin (most definitive non-invasive test) 5
• Iron concentration, transferrin saturation, and total iron-binding capacity 5
• Serum transferrin receptors (newer, may obviate bone marrow evaluation) 5

For suspected hemoglobinopathy:

• Hemoglobin electrophoresis or HPLC 3
• Family history assessment 3

For suspected liver disease:

• Liver function tests, albumin, bilirubin 6
• Clinical assessment for hepatomegaly or splenomegaly 6

Step 4: Consider Advanced Diagnostics When Indicated

• Flow cytometry: Recommended to distinguish clonal from reactive processes and evaluate specific cell markers 4, 8
• Bone marrow examination: Reserve for patients >60 years, those with systemic symptoms, or when diagnosis remains unclear after initial workup 6
• Cytogenetic analysis: Necessary for suspected myelodysplastic syndromes or hematologic malignancies 6, 4

Critical Pitfalls to Avoid

Do not rely on target cells alone for diagnosis—they lack specificity and appear in multiple conditions with similar frequency 1. The diagnostic value comes from the complete morphologic constellation.

Do not assume basophilic stippling confirms thalassemia—this finding is present in only a minority of cases and should not drive diagnostic decisions 1.

Do not skip the peripheral smear review—automated indices alone miss critical morphologic clues that direct appropriate workup 4, 3. A qualified hematologist or pathologist must examine the smear 6, 4.

Process specimens within 24 hours of collection in sodium heparin tubes (20 IU/mL) to ensure accurate morphologic assessment 4.

Management Principles

Management depends entirely on the underlying cause identified through systematic evaluation:

• Iron deficiency: Oral iron supplementation is effective and well-tolerated in the vast majority; parenteral iron dextran reserved for malabsorption or intolerance 5
• Thalassemia minor: Typically requires no treatment; avoid inappropriate iron supplementation 1, 3
• Liver disease: Address underlying hepatic pathology 3
• Hemoglobinopathies: Refer to hematology for specialized management 3

The presence of target cells should trigger a diagnostic algorithm, not empiric treatment—misdiagnosis leads to inappropriate therapy, particularly unnecessary iron supplementation in thalassemia patients 1, 5.