What is the diagnosis and management for a patient with erythrocytosis and microcytic hypochromic anemia?

Diagnosis: Polycythemia Vera with Concurrent Iron Deficiency (Microcytic Erythrocytosis)

This patient has polycythemia vera (PV) with iron deficiency, evidenced by persistently elevated RBC count (6.36-7.23 million/uL) with severe microcytosis (MCV 70.1-71.7 fL) and hypochromia (MCH 21.2-22.5 pg, MCHC 30.2-31.5 g/dL). The combination of erythrocytosis with microcytic indices is pathognomonic for iron-deficient PV, where ongoing phlebotomy or iron depletion masks the typical elevated hemoglobin/hematocrit seen in classic PV 1, 2.

Immediate Diagnostic Workup

Order JAK2 V617F mutation testing immediately, as >95% of PV patients harbor this mutation, which definitively distinguishes PV from secondary erythrocytosis 1, 2.

• Measure serum ferritin and transferrin saturation (TSAT) to confirm iron deficiency—expect ferritin <30 μg/L and TSAT <20% 3, 4.
• Check serum erythropoietin level, which will be low or inappropriately normal in PV (unlike secondary causes where it's elevated) 1.
• Obtain baseline platelet count and white blood cell differential, as 53% have thrombocytosis and 49% have leukocytosis 1.
• Screen for splenomegaly via physical exam or ultrasound (present in 36% of PV patients) 1.
• Assess thrombosis risk factors: age >60 years, prior thrombotic events, cardiovascular risk factors, and JAK2 mutation status 2.

Critical Distinction: Why This is NOT Simple Iron Deficiency

The persistently elevated RBC count (>6.0 million/uL across multiple measurements) despite severe microcytosis distinguishes this from isolated iron deficiency anemia, where RBC count would be low or normal 1, 5. In PV with iron deficiency, the bone marrow's autonomous erythroid proliferation continues producing excessive RBCs despite inadequate iron, resulting in numerous small, pale cells 2.

Management Algorithm

Phase 1: Thrombosis Prevention (Highest Priority for Mortality)

All PV patients require therapeutic phlebotomy to maintain hematocrit <45% to reduce thrombosis risk, which is the leading cause of morbidity and mortality 1, 2.

• However, in this iron-deficient patient, phlebotomy is contraindicated until iron stores are assessed, as further iron depletion will worsen microcytosis without adequately controlling the erythrocytosis 1.
• Start low-dose aspirin 81 mg daily immediately (unless contraindications exist) to reduce arterial thrombosis risk by 16% 1, 2.
• If platelet count >1000 × 10⁹/L, screen for acquired von Willebrand syndrome before starting aspirin due to bleeding risk 2.

Phase 2: Cytoreductive Therapy

Initiate hydroxyurea as first-line cytoreductive therapy for patients with high thrombosis risk (age >60 years or prior thrombosis) or symptomatic disease 1, 2.

• Hydroxyurea reduces thrombosis risk and controls blood counts without requiring phlebotomy, making it ideal for iron-deficient PV 1.
• Alternative: Interferon-α for younger patients or those intolerant to hydroxyurea 2.
• Ruxolitinib (JAK inhibitor) reserved for hydroxyurea-resistant/intolerant patients with persistent symptoms (pruritus, splenomegaly) 1.

Phase 3: Iron Management (After Cytoreduction)

Do NOT supplement iron in PV patients, as iron repletion will unmask the full erythrocytosis and dramatically increase thrombosis risk 1, 2.

• The microcytosis in PV serves as a protective mechanism, limiting hemoglobin/hematocrit elevation 2.
• Once cytoreductive therapy achieves adequate RBC control (hematocrit <45%), the microcytosis may persist but is clinically appropriate 1.
• Only consider iron supplementation if symptomatic anemia develops (hemoglobin <10 g/dL) after achieving disease control, and only under close hematologic monitoring 3.

Monitoring Protocol

• Complete blood count every 2-4 weeks initially until stable, then every 3 months 1, 2.
• Maintain hematocrit <45% (target demonstrated to reduce cardiovascular death and major thrombosis) 1.
• Monitor for thrombotic events (arterial 16%, venous 7%, including unusual sites like splanchnic veins) 1.
• Screen for disease progression: myelofibrosis (12.7% at 20 years) or acute myeloid leukemia (6.8% at 20 years) 1.
• Assess for symptoms: pruritus (33%), erythromelalgia (5.3%), visual changes (14%), abdominal discomfort from splenomegaly 1.

Common Pitfalls to Avoid

The most dangerous error is treating this as simple iron deficiency anemia and administering iron supplementation, which will cause explosive erythrocytosis and potentially fatal thrombosis 1, 2.

• Do not delay JAK2 testing—this is the definitive diagnostic test and should be ordered immediately 1.
• Do not perform phlebotomy in severely iron-deficient PV patients, as it's ineffective and worsens microcytosis 2.
• Do not assume normal hemoglobin/hematocrit excludes PV—iron deficiency can mask the erythrocytosis 1, 2.
• Do not overlook cardiovascular risk stratification, as thrombosis is the primary cause of morbidity and mortality 1, 2.

Prognosis and Long-term Considerations

Median survival is 14-27 years from diagnosis, with younger patients achieving 24-year median survival 1, 2. Life expectancy is reduced compared to age-matched controls 2. Risk factors for worse survival include advanced age, leukocytosis, and thrombotic events 2. The combination of aspirin, hematocrit control <45%, and cytoreductive therapy in high-risk patients significantly reduces thrombotic complications and improves outcomes 1, 2.