What causes polycythemia with low reticulocyte count?

Causes of Polycythemia with Low Reticulocyte Count

Polycythemia with low reticulocytes indicates either polycythemia vera (a primary bone marrow disorder) or post-renal transplant erythrocytosis, as these conditions suppress reticulocyte production despite elevated red cell mass. 1

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is the most common cause of polycythemia with low reticulocytes and suppressed erythropoietin levels. 1, 2

Key Diagnostic Features:

• JAK2 V617F mutation is present in >95% of cases, making it the cornerstone of diagnosis 2, 3, 4
• Serum erythropoietin levels are characteristically low (typically <2.9 mU/mL), distinguishing it from secondary causes 1, 4
• Bone marrow biopsy shows hypercellularity with increased megakaryocytes, cluster formation, giant megakaryocytes, and decreased iron stores 1
• Reticulocyte count is typically low or inappropriately normal because the bone marrow is producing mature red cells directly rather than releasing reticulocytes 1

Clinical Presentation:

• Hemoglobin >16.5 g/dL in men or >16.0 g/dL in women is required for diagnosis 2
• Associated thrombocytosis (53% of cases) and leukocytosis (49% of cases) 2
• Pruritus (33%), erythromelalgia (5.3%), splenomegaly (36%), and transient visual changes (14%) 2
• Thrombotic events occur in 16% (arterial) and 7% (venous) at or before diagnosis 2

Secondary Polycythemia with Low Reticulocytes

Post-Renal Transplant Erythrocytosis:

• This condition presents with polycythemia and low reticulocytes through unclear mechanisms, possibly involving EPO hypersensitivity or increased IGF-1 1
• Serum EPO levels may be elevated or normal, unlike polycythemia vera 1

Congenital Polycythemia with EPOR Mutations:

• Activating mutations of the erythropoietin receptor (EPOR) gene cause autosomal-dominant congenital polycythemia with characteristically low serum EPO levels 1
• The truncated receptor is more efficient in signal transduction, leading to autonomous red cell production 1
• Reticulocytes remain low because mature red cells are produced directly 1

Critical Distinction: Why Reticulocytes Are Low

The key pathophysiologic difference is that primary polycythemia and EPOR-mediated conditions produce mature red blood cells directly from the bone marrow without releasing immature reticulocytes into circulation. 1 In contrast, secondary polycythemia from hypoxia (chronic lung disease, sleep apnea, high altitude) typically shows elevated or normal reticulocytes as the bone marrow responds to elevated EPO by releasing reticulocytes. 1, 5

Diagnostic Algorithm

Step 1: Measure Serum Erythropoietin

• Low EPO (<2.9 mU/mL) → Probable polycythemia vera 1
• Normal EPO (2.9-15.1 mU/mL) → Possible polycythemia vera, proceed to bone marrow biopsy 1
• High EPO (>15.1 mU/mL) → Evaluate for secondary polycythemia (but this typically shows normal/high reticulocytes, not low) 1

Step 2: Test for JAK2 V617F Mutation

• Positive JAK2 mutation confirms polycythemia vera in >95% of cases 2, 3, 4
• Negative result does not exclude polycythemia vera; proceed to bone marrow biopsy 1

Step 3: Bone Marrow Biopsy

• Characteristic findings include hypercellularity, increased megakaryocytes with clustering, pleomorphism, and decreased iron stores 1
• If histology is consistent with polycythemia vera, diagnosis is confirmed 1
• If equivocal, specialized testing (c-mpl immunohistochemistry, PRV-1 expression) may be needed 1

Common Pitfalls to Avoid

Do not assume low reticulocytes rule out a hematologic disorder - this finding actually points toward primary polycythemia rather than secondary causes. 1

Do not confuse relative polycythemia (dehydration, diuretics) with true polycythemia - relative polycythemia has normal red cell mass and normal reticulocytes. 1, 6

Do not overlook post-renal transplant erythrocytosis in transplant patients - this unique condition presents with polycythemia and low reticulocytes but through different mechanisms than polycythemia vera. 1