What is the significance of a normal complete blood count with moderate anisocytosis, slight microcytosis and macrocytosis, moderate poikilocytosis, and marked ovalocytes?

Interpretation of Normal CBC with Marked Red Cell Morphologic Abnormalities

This peripheral blood smear pattern—normal CBC parameters with moderate anisocytosis, slight microcytosis and macrocytosis, moderate poikilocytosis, and marked ovalocytes—suggests a compensated hemolytic process or early myelodysplastic syndrome that requires bone marrow evaluation and reticulocyte count to distinguish between these diagnoses.

Understanding the Paradox of Normal Counts with Abnormal Morphology

The presence of normal hemoglobin, white blood cell, and platelet counts does not exclude significant hematologic pathology when red cell morphology is markedly abnormal. 1 This discordance indicates:

• Compensated bone marrow response: The bone marrow may be producing sufficient numbers of red cells to maintain normal hemoglobin levels despite ongoing hemolysis or ineffective erythropoiesis
• Early disease stage: Morphologic changes often precede quantitative abnormalities in progressive hematologic disorders
• Mixed cell populations: The combination of microcytes and macrocytes can result in a falsely "normal" mean corpuscular volume (MCV), masking underlying pathology 2

Significance of Marked Ovalocytes

Marked ovalocytosis (elliptocytosis) is a critical finding that narrows the differential diagnosis considerably. 3, 4

Primary Considerations:

• Hereditary elliptocytosis/ovalocytosis: A red cell membrane disorder that can present with compensated hemolysis and normal CBC parameters 4
• Myelodysplastic syndrome (MDS): Ovalocytes can be a manifestation of dyserythropoiesis, though MDS typically requires ≥10% dysplasia in bone marrow for diagnosis 5
• Megaloblastic processes: Early vitamin B12 or folate deficiency can produce ovalocytes before macrocytosis becomes pronounced 3

Interpreting the Mixed Size Abnormalities

The combination of slight microcytosis AND slight macrocytosis with moderate anisocytosis creates a diagnostic challenge: 2, 3

• The opposing size populations may neutralize each other, producing a deceptively normal MCV
• Red cell distribution width (RDW) should be elevated in this scenario and helps confirm the mixed population 2
• This pattern can occur in:
  • Combined deficiency states (iron + B12/folate)
  • Hemolytic anemia with reticulocytosis (reticulocytes are larger cells) 6
  • Early MDS with multilineage dysplasia 5

Essential Diagnostic Workup

Immediate Next Steps:

1. Reticulocyte count and reticulocyte index calculation 2, 6

• If elevated (RI >2-3): Suggests hemolysis or blood loss with appropriate bone marrow response; all nutritional deficiency states are excluded 6
• If low/normal (RI ≤2): Indicates inadequate bone marrow response, raising concern for MDS, combined deficiencies, or bone marrow failure 2

2. Hemolysis workup if reticulocytes are elevated: 6

• Haptoglobin (decreased in hemolysis)
• Lactate dehydrogenase (LDH) (elevated in hemolysis)
• Indirect bilirubin (elevated in hemolysis)
• Direct antiglobulin test (Coombs) to evaluate immune-mediated hemolysis

3. Nutritional assessment: 2

• Serum ferritin and transferrin saturation (iron status)
• Vitamin B12 and folate levels
• These should be checked even with normal hemoglobin, as deficiencies can cause morphologic changes before anemia develops

4. Bone marrow examination if: 5

• Reticulocyte count is inappropriately low for the degree of morphologic abnormality
• Cytopenias develop over time
• Dysplastic features persist without alternative explanation
• MDS diagnostic criteria require ≥10% dysplasia in one or more myeloid lineages on bone marrow examination 5

Critical Pitfalls to Avoid

• Do not dismiss morphologic abnormalities because the CBC is "normal": Morphology changes often precede quantitative abnormalities and provide early diagnostic clues 3, 7

• Do not assume a "normal" MCV excludes both microcytic and macrocytic processes: Calculate RDW and examine the peripheral smear directly, as opposing populations can mask each other 2

• Do not diagnose MDS based on peripheral blood morphology alone: MDS requires bone marrow evaluation showing ≥10% dysplasia in one or more lineages, <5% blasts (for most subtypes), and exclusion of other causes 5

• Do not overlook hereditary hemolytic anemias: Marked ovalocytes strongly suggest hereditary elliptocytosis, which can present with compensated hemolysis and minimal or no anemia 4

Monitoring Strategy

If initial workup is unrevealing but morphologic abnormalities persist: 5

• Serial CBC monitoring every 2-3 months to detect emerging cytopenias
• Repeat peripheral smear review to assess for progression of dysplastic features
• Consider the term "idiopathic cytopenia of undetermined significance" (ICUS) if cytopenias develop without meeting MDS criteria, though this patient currently has normal counts 5
• Bone marrow examination should be performed if cytopenias develop or morphologic abnormalities worsen 5

Clinical Context Integration

The absence of cytopenias makes several diagnoses less likely but does not exclude them: 5

• MDS typically presents with cytopenias, but early disease or MDS-unclassified (MDS-U) can have borderline counts 5
• Hereditary hemolytic anemias with good compensation may maintain normal hemoglobin through increased reticulocyte production 4
• Combined nutritional deficiencies may not yet have progressed to overt anemia

The key discriminator is the reticulocyte count: An elevated count points toward hemolysis (likely hereditary elliptocytosis given the marked ovalocytes), while a low/normal count raises concern for bone marrow pathology including early MDS or nutritional deficiencies. 2, 6