What is the management plan for a patient with anisocytosis, microcytosis, and poikilocytosis?

Management of Anisocytosis, Microcytosis, and Poikilocytosis

These peripheral blood findings require immediate evaluation for iron deficiency anemia as the first priority, followed by systematic exclusion of thalassemia, anemia of chronic disease, and hereditary hemolytic disorders if iron studies are inconclusive.

Initial Diagnostic Workup

Order serum ferritin as the single most important first test, as it provides optimal sensitivity and specificity for iron deficiency with a cut-off of <45 μg/L in clinical practice 1, 2, 3. Ferritin <15 μg/L indicates absent iron stores, while <30 μg/L indicates low body iron stores 1, 3.

Complete the Iron Panel

• Measure transferrin saturation (TSAT) alongside ferritin, as TSAT is more sensitive than hemoglobin alone for detecting iron deficiency 4, 1, 3. TSAT <16-20% supports iron deficiency 3.
• Check red cell distribution width (RDW) to differentiate causes: low MCV with RDW >14.0% strongly suggests iron deficiency anemia, while low MCV with RDW ≤14.0% suggests thalassemia minor 4, 1, 3.
• Obtain complete blood count with reticulocyte count to assess bone marrow response and exclude hemolytic processes 4.

Key Diagnostic Algorithm

If ferritin is low (<45 μg/L) and TSAT is low (<20%), diagnose iron deficiency anemia and proceed directly to treatment 3. If ferritin is normal or elevated despite microcytosis, consider the following differential:

• Anemia of chronic disease: Low iron with decreased total iron-binding capacity and elevated ferritin in the presence of inflammation (CRP, ESR) 4, 5
• Thalassemia trait: Order hemoglobin electrophoresis if RDW is normal/low, MCV disproportionately low relative to anemia severity, or appropriate ethnic background 1, 2, 5
• Hereditary hemolytic anemia: These findings (anisocytosis and poikilocytosis) are characteristic of pyruvate kinase deficiency, though morphology is usually unremarkable 4

Treatment Protocol for Iron Deficiency

Initiate oral ferrous sulfate 200 mg (65 mg elemental iron) three times daily for at least 3 months after hemoglobin normalizes to replenish iron stores 1, 2, 3. Alternative formulations include ferrous gluconate or ferrous fumarate if not tolerated 1, 3.

Enhance Absorption and Monitor Response

• Add ascorbic acid (vitamin C) to enhance iron absorption 1, 3
• Expect hemoglobin to rise ≥10 g/L (≥1 g/dL) within 2 weeks if iron deficiency is confirmed 1, 2, 3
• If no response within 2-4 weeks, consider non-compliance, ongoing blood loss, malabsorption, or switch to intravenous iron 1, 2, 3

Investigation of Underlying Cause

In all adults with confirmed iron deficiency, investigate the source of iron loss 2, 3. The most common source is gastrointestinal blood loss, and gastrointestinal malignancy must be excluded 5.

• Men with Hb <110 g/L or non-menstruating women with Hb <100 g/L warrant fast-track GI referral 2
• Consider upper and lower endoscopy based on risk factors and severity 1
• Screen for celiac disease if malabsorption is suspected 2
• Evaluate for menstrual blood loss in premenopausal women 2

Special Considerations for Refractory Cases

If the patient fails oral iron therapy despite adequate supplementation and compliance, consider genetic disorders of iron metabolism or heme synthesis 1, 2.

When to Suspect Hereditary Disorders

• Extreme microcytosis (MCV <70 fL) or family history of refractory anemia warrants genetic testing 2
• Anisocytosis and poikilocytosis without other explanation may indicate pyruvate kinase deficiency, which displays these morphological features 4
• Increased reticulocyte count with hemolysis markers (elevated LDH, reduced haptoglobin, elevated bilirubin) suggests hereditary hemolytic anemia 4

Specific Genetic Disorders to Consider

• IRIDA (TMPRSS6 defects): Requires intravenous iron (iron sucrose or gluconate) as oral iron is ineffective 2
• Pyruvate kinase deficiency: Presents with anisocytosis and poikilocytosis as primary morphological features; confirm with enzyme activity testing or PKLR gene mutation analysis 4
• X-linked sideroblastic anemia (ALAS2 defects): Trial pyridoxine 50-200 mg daily initially 2

Monitoring and Follow-Up

Monitor hemoglobin and red cell indices at 3-month intervals for one year, then after one additional year 1, 2. Provide additional oral iron if hemoglobin or MCV falls below normal 1, 2.

Critical Pitfalls to Avoid

• Do not assume all microcytic anemia is iron deficiency: Anemia of chronic disease, thalassemia, and sideroblastic anemia must be differentiated to avoid unnecessary iron therapy 2
• Do not overlook combined deficiencies: Iron deficiency can coexist with B12 or folate deficiency, which may mask typical findings 1, 2
• In the presence of inflammation, ferritin up to 100 μg/L may still indicate iron deficiency—use TSAT to clarify 4, 3
• Monitor for iron overload in patients receiving multiple transfusions or long-term therapy, particularly in genetic disorders where ineffective erythropoiesis can cause iron accumulation 4, 2