What is the appropriate diagnostic and treatment approach for a patient with erythrocytosis (high red blood cell count), elevated RDW, thrombocytopenia with low MPV, lymphocytosis, hyperferritinemia, and elevated sedimentation rate?

Diagnostic Approach for Erythrocytosis with Elevated RDW, Thrombocytopenia, Lymphocytosis, Hyperferritinemia, and Elevated ESR

This constellation of findings—high RBC with elevated RDW, low MPV with thrombocytopenia, lymphocytosis, high ferritin, and elevated ESR—suggests a myeloproliferative neoplasm (most likely polycythemia vera) complicated by iron deficiency, though the elevated inflammatory markers and lymphocytosis raise concern for concurrent infection, inflammatory disorder, or secondary reactive process that must be systematically excluded.

Initial Diagnostic Evaluation

Confirm Polycythemia Vera as Primary Consideration

The elevated RBC count with high RDW strongly suggests polycythemia vera (PV) with concurrent iron deficiency 1, 2. In PV, iron deficiency is common and causes microcytosis, which elevates the RDW while the RBC count remains high 2, 3. The RBC count may more precisely reflect the true erythrocytosis in PV than hematocrit when microcytosis is present, as HCT = RBC × MCV 2.

• Measure serum erythropoietin (EPO) level as the first diagnostic step: a low EPO has >90% specificity for PV, though sensitivity is only ~70% 1
• If EPO is low or normal, proceed to bone marrow examination with cytogenetic studies to evaluate for characteristic PV histology (hypercellularity, panmyelosis) 1
• Test for JAK2 V617F mutation, which is present in >95% of PV cases and serves as a clonal marker 1
• The elevated ESR is paradoxically useful: ESR <2 mm has 98% specificity for PV diagnosis, though only 37% sensitivity 2

Evaluate the Thrombocytopenia and Low MPV

The thrombocytopenia with low MPV is atypical for untreated PV, which usually presents with thrombocytosis 1. This finding requires additional investigation:

• Review medication history for myelosuppressive agents that could cause thrombocytopenia 4
• Consider if the patient has received prior treatment for PV (phlebotomy, hydroxyurea) that could cause secondary thrombocytopenia 4
• Evaluate peripheral blood smear for platelet clumping (pseudothrombocytopenia) or morphologic abnormalities
• Assess for concurrent essential thrombocythemia (ET) transitioning to spent phase, though this would be unusual 1

Address the Hyperferritinemia and Elevated ESR

The combination of high ferritin with elevated ESR indicates an inflammatory or infectious process that must be identified and treated 1. This is critical because:

• In the presence of inflammation, ferritin up to 100 μg/L may still be consistent with iron deficiency 5, 6, 7
• High ferritin with inflammation does NOT exclude concurrent iron deficiency in PV 5, 7
• Measure C-reactive protein (CRP) to quantify inflammation 6
• Markedly elevated ESR (>70 mm/h) has a positive likelihood ratio of 11 for osteomyelitis if there is a diabetic foot wound 1, though this is context-specific

Investigate the Lymphocytosis

The elevated lymphocyte percentage requires systematic evaluation:

• Obtain absolute lymphocyte count, not just percentage, as relative lymphocytosis can occur with neutropenia 8
• Review for viral infections: EBV, CMV, HIV serology 9
• Consider virus-associated hemophagocytic syndrome if fever, hepatosplenomegaly, or cytopenias are present, as this can cause hyperferritinemia and lymphocytosis 9
• Evaluate for chronic lymphocytic leukemia or lymphoproliferative disorder with flow cytometry if absolute lymphocytosis is confirmed 1
• Assess for reactive lymphocytosis secondary to infection or inflammation

Diagnostic Algorithm

1. Measure serum EPO level immediately 1

   • If low: Proceed to step 2
   • If normal: Still proceed to step 2 (PV remains possible)
   • If high: Consider secondary polycythemia causes

2. Obtain bone marrow biopsy with:

   • Histologic examination for PV features 1
   • Cytogenetic studies 1
   • JAK2 V617F mutation testing 1
   • Iron staining to assess iron stores 1

3. Simultaneously evaluate for inflammation/infection:

   • CRP, comprehensive metabolic panel 6
   • Blood cultures if febrile
   • Viral serologies (EBV, CMV, HIV) 9
   • Chest X-ray to exclude pulmonary infection or malignancy
   • Consider CT imaging if occult infection or malignancy suspected

4. Assess iron status in context of inflammation:

   • Serum iron, TIBC, transferrin saturation 5, 7
   • Interpret ferritin cautiously: values up to 100 μg/L may indicate iron deficiency if inflammation is present 5, 6

5. Evaluate thrombocytopenia:

   • Peripheral smear review 1
   • Exclude medication-induced causes 4
   • Consider bone marrow findings from step 2

Critical Pitfalls to Avoid

• Do not dismiss PV based on normal or high ferritin alone—iron deficiency commonly coexists with PV, and inflammation elevates ferritin 1, 5, 7
• Do not rely on hematocrit alone when microcytosis is present—use RBC count as a more accurate reflection of erythrocytosis 2
• Do not assume reactive thrombocytosis based on inflammation—verify platelet count is actually elevated, not decreased as in this case 1
• Do not ignore the lymphocytosis—this may indicate a separate hematologic process or serious infection requiring urgent treatment 9, 8
• Do not start empiric iron supplementation without confirming deficiency—this may be ineffective and potentially harmful if inflammation is the primary issue 6

Treatment Considerations Pending Diagnosis

• If PV is confirmed and iron deficiency is present, iron supplementation should generally be avoided or used cautiously, as correcting iron deficiency can worsen erythrocytosis and increase thrombotic risk 1
• If infection or inflammatory disorder is identified, treat the underlying condition first—this is the priority for morbidity and mortality 6
• If hemophagocytic syndrome is suspected (fever, hepatosplenomegaly, cytopenias, hyperferritinemia), this is a medical emergency requiring immediate corticosteroids and possibly IVIG 9
• Avoid live vaccines during evaluation and treatment of suspected myeloproliferative disorder 4