Why is erythropoietin (EPO) low in idiopathic erythrocytosis?

Why EPO is Low in Idiopathic Erythrocytosis

In idiopathic erythrocytosis with low EPO levels, the underlying mechanism is an intrinsic defect in erythroid precursor cells that causes autonomous, EPO-independent red blood cell production, leading to suppression of endogenous erythropoietin through normal negative feedback from the elevated red cell mass.

Pathophysiologic Mechanism

The low EPO levels in certain cases of idiopathic erythrocytosis reflect a primary erythrocytosis where the defect lies within the erythroid cells themselves, not in the oxygen-sensing pathway 1, 2. This creates a fundamentally different disease process:

• Primary erythrocytoses are characterized by intrinsic defects in erythroid precursor cells and consistently show low erythropoietin levels 1
• The erythroid cells proliferate autonomously without requiring normal EPO stimulation 2
• As red cell mass increases, the kidneys appropriately sense adequate oxygen delivery and suppress EPO production through normal physiologic feedback 2

Molecular Basis: JAK2 Mutations

The most important molecular defect identified in idiopathic erythrocytosis with low EPO is JAK2 mutations, particularly in exon 12:

• JAK2 exon 12 mutations occur in 27% of idiopathic erythrocytosis patients presenting with low serum EPO levels 3
• These mutations cause EPO-independent erythroid progenitor growth, meaning the cells proliferate without requiring EPO stimulation 3
• All patients with JAK2 exon 12 mutations demonstrate EPO-hypersensitive erythroid progenitors (p=0.0002) 3
• The bone marrow shows moderate hypercellularity due to erythroid hyperplasia with mild megakaryocyte atypia 3

Diagnostic Algorithm for Low EPO in Idiopathic Erythrocytosis

When encountering idiopathic erythrocytosis with low EPO, follow this approach:

Step 1: Confirm Low EPO Pattern

• EPO levels below 2 U/L strongly favor a primary erythrocytosis 4
• Low serum EPO has over 90% specificity for primary polycythemic disorders 4

Step 2: Test for JAK2 Mutations

• Screen for JAK2 exon 12 mutations in all patients with idiopathic erythrocytosis and low EPO levels 3
• This is essential because 27% will have identifiable mutations 3
• JAK2 V617F should also be tested, though exon 12 mutations are more common in isolated erythrocytosis 3

Step 3: Assess Erythroid Progenitor Behavior

• Test for EPO-hypersensitive or EPO-independent erythroid colony formation if available 3
• This finding occurs exclusively in patients with JAK2 exon 12 mutations 3

Step 4: Bone Marrow Examination

• Look for erythroid hyperplasia without significant megakaryocytic or granulocytic proliferation 3, 2
• Assess for mild megakaryocyte atypia which may be present 3

Contrast with Secondary Erythrocytosis

Understanding why EPO is low requires distinguishing from secondary causes:

• Secondary erythrocytoses are extrinsic to erythroid progenitors and characterized by either high or inappropriately normal EPO levels 1
• In secondary polycythemia, EPO levels above 12 U/L favor a secondary cause 4
• The 2-12 U/L range shows significant overlap and requires additional investigation 4

Critical Pitfall to Avoid

Do not assume normal EPO levels rule out primary erythrocytosis, as the sensitivity of low EPO for polycythemia vera is less than 70% 4. However, in true idiopathic erythrocytosis with documented low EPO, the mechanism is autonomous erythroid proliferation with appropriate physiologic EPO suppression.

Clinical Implications

• Low-dose aspirin and venesection to target hematocrit are the main therapeutic options for managing idiopathic erythrocytosis 2
• The presence of JAK2 exon 12 mutations may indicate these patients represent a forme fruste of myeloproliferative neoplasm 3
• Specific venesection targets should be individualized based on the underlying molecular defect 2