Does a patient with erythrocytosis, low Erythropoietin (EPO) level, functional iron deficiency, and low iron saturation have polycythemia vera?

Does This Patient Have Polycythemia Vera?

Yes, this patient's presentation of erythrocytosis with low EPO, functional iron deficiency, and low iron saturation is highly suggestive of polycythemia vera (PV), and the next step should be JAK2 mutation testing followed by bone marrow examination to confirm the diagnosis. 1, 2

Why This Clinical Picture Points to PV

The combination of findings in this patient creates a classic diagnostic pattern for PV:

• Low EPO level is highly specific for PV (>90% specificity) and is the single most important discriminating feature between primary and secondary polycythemia 1, 2. In secondary polycythemia, EPO levels are typically elevated or normal, not low 3, 4.

• Functional iron deficiency with low iron saturation is characteristic of PV, as virtually all PV patients are iron deficient at presentation or during disease course 5. This occurs because the pathologic baseline red cell mass can be lowered by superimposed iron deficiency, and iron deficiency is an intrinsic component of PV pathobiology 6.

• The presence of erythrocytosis despite iron deficiency represents a physiological disconnect that strongly suggests a primary clonal process rather than appropriate EPO-driven erythropoiesis 5.

Diagnostic Algorithm to Follow

Immediate Next Steps:

1. Order JAK2 mutation testing (JAK2V617F and exon 12 mutations) - Present in >95% of PV patients 2, 3

2. Proceed with bone marrow examination since EPO is low 1, 2:

   • Look for hypercellularity 2
   • Assess for increased megakaryocytes with cluster formation and pleomorphic giant megakaryocytes 2
   • Evaluate bone marrow iron stores (typically decreased in PV) 1
   • Include cytogenetic studies 2

3. Assess for additional PV-related features 1:

   • Thrombocytosis or leukocytosis
   • Splenomegaly (physical exam or imaging)
   • Symptoms: aquagenic pruritus, erythromelalgia, unusual thrombosis (Budd-Chiari syndrome)

Important Caveats and Pitfalls

Do not rely on red cell mass (RCM) measurement - This is a costly redundancy that doesn't rule out PV even if normal, as some PV patients fall at the extreme left tail of the distribution, and iron deficiency can lower RCM into the normal range 6, 1.

Normal EPO does not exclude PV - The sensitivity of low EPO for PV is <70%, meaning up to 30% of PV patients may have normal EPO levels 1, 2. However, this patient has LOW EPO, which is much more diagnostically useful.

Beware of the rare exception: While extremely uncommon, case reports document PV patients with elevated EPO levels who still meet WHO diagnostic criteria through JAK2 mutation positivity and bone marrow findings 7. However, elevated EPO should prompt investigation for secondary causes first 2.

Iron deficiency can mask the full extent of erythrocytosis - The hemoglobin/hematocrit may be lower than it would be if iron replete, and microcytosis may be present 1, 8. This patient's functional iron deficiency fits this pattern.

Why Secondary Polycythemia is Unlikely

Secondary polycythemia causes would present with:

• Elevated or normal EPO levels (not low) 9, 3
• Identifiable causes: hypoxia-driven (lung disease, sleep apnea, smoking), EPO-producing tumors (renal cell cancer, hepatocellular carcinoma), or drug-associated (testosterone, EPO doping) 6, 1, 9

The low EPO effectively excludes these secondary causes 1, 2.

Clinical Implications

If PV is confirmed, management priorities include:

• Target hematocrit <45% to reduce thrombotic risk 9
• Therapeutic phlebotomy as primary treatment 9
• Low-dose aspirin (81 mg daily) unless contraindicated 9
• Risk stratification based on age >60 years and prior thrombosis history 9

The iron deficiency should NOT be repleted until hematocrit is controlled, as iron repletion would worsen the erythrocytosis 5.