In a male patient with an elevated red blood cell count (5.94 ×10⁶/µL), hemoglobin (17.9 g/dL) and hematocrit (54 %), what is the appropriate diagnostic work‑up and initial management for suspected polycythemia?

Diagnostic Work-Up and Management of Elevated Red Blood Cell Parameters

Initial Assessment and Confirmation

In a male patient with RBC 5.94 ×10⁶/µL, hemoglobin 17.9 g/dL, and hematocrit 54.1%, the first priority is to confirm true polycythemia by repeating the complete blood count and immediately ordering JAK2 mutation testing plus serum erythropoietin level to distinguish polycythemia vera from secondary causes. 1, 2

• These values exceed the WHO diagnostic thresholds for polycythemia (hemoglobin >18.5 g/dL in men OR hematocrit >52% in men), though the hemoglobin is just below the major criterion cutoff while hematocrit is elevated. 3, 1
• Repeat CBC with red cell indices (MCV, MCH, MCHC, RDW) to confirm sustained elevation and assess for iron deficiency, which can mask higher hemoglobin levels in polycythemia vera. 1, 2
• A low MCV (<80 fL) suggests iron deficiency that may be suppressing hemoglobin despite underlying polycythemia vera, creating a diagnostic pitfall. 1

Essential Laboratory Testing

Order JAK2 V617F mutation testing immediately, as this mutation is present in >95% of polycythemia vera cases and provides definitive differentiation between primary and secondary erythrocytosis. 1, 2

• Serum erythropoietin (EPO) level is critical: low or inappropriately normal EPO has >90% specificity for polycythemia vera, while elevated EPO points toward secondary polycythemia. 1, 2
• Complete iron studies (serum ferritin, iron, transferrin saturation) are mandatory because iron deficiency frequently coexists with erythrocytosis and can obscure the diagnosis. 1, 2
• Obtain white blood cell count with differential and platelet count, as thrombocytosis or leukocytosis in ~50% of polycythemia vera patients supports the diagnosis. 1

Systematic Evaluation for Secondary Causes

If EPO is elevated or JAK2 is negative, systematically exclude secondary causes before concluding the work-up. 1, 2

Hypoxia-Driven Causes (Most Common)

• Smoking history and carboxyhemoglobin measurement – chronic carbon monoxide exposure from smoking is the most common cause of secondary polycythemia and resolves with cessation. 1, 2
• Sleep study (polysomnography) – obstructive sleep apnea causes nocturnal hypoxemia driving compensatory erythrocytosis. 1, 4
• Arterial oxygen saturation and chest imaging – chronic lung disease (COPD, pulmonary fibrosis) or right-to-left cardiopulmonary shunts cause hypoxia-mediated erythrocytosis. 1, 2

Hypoxia-Independent Causes

• Abdominal ultrasound or CT – screen for EPO-producing tumors: renal cell carcinoma, hepatocellular carcinoma, uterine leiomyoma, pheochromocytoma, meningioma. 1, 2
• Medication review – exogenous testosterone, anabolic steroids, or erythropoietin therapy can cause secondary erythrocytosis. 1, 2
• Renal function testing – evaluate for post-renal-transplant erythrocytosis. 1, 2

Diagnostic Algorithm Based on Test Results

If JAK2 Positive + Low/Normal EPO

• Bone marrow biopsy is required to confirm polycythemia vera diagnosis and assess for trilineage myeloproliferation (hypercellularity with panmyelosis). 3, 1, 2
• WHO 2016 criteria require either: (1) all three major criteria (elevated Hb/Hct, JAK2 mutation, characteristic bone marrow), OR (2) first two major criteria plus subnormal EPO. 3, 1
• Immediate hematology referral for risk stratification and treatment planning. 1, 2

If JAK2 Negative + Elevated EPO

• Focus diagnostic efforts on identifying the specific secondary cause using the systematic evaluation outlined above. 1, 2
• Consider JAK2 exon 12 mutation testing, as this accounts for another 2-4% of polycythemia vera cases lacking V617F mutation. 1

Initial Management Principles

Do NOT perform therapeutic phlebotomy at these hemoglobin/hematocrit levels unless the diagnosis of polycythemia vera is confirmed and the patient is symptomatic. 1, 2

• For confirmed polycythemia vera: maintain hematocrit strictly <45% through phlebotomy to reduce thrombotic risk (CYTO-PV trial: 2.7% vs 9.8% event rate, P=0.007). 1, 2
• For secondary polycythemia: treat the underlying condition (smoking cessation, CPAP for sleep apnea, oxygen therapy for hypoxemia). 1, 2, 4
• Phlebotomy in secondary polycythemia is contraindicated except when hemoglobin >20 g/dL AND hematocrit >65% with documented hyperviscosity symptoms after excluding dehydration. 1, 2

Critical Pitfalls to Avoid

• Never assume normal EPO excludes polycythemia vera – EPO sensitivity is only 64-70%, so normal EPO with elevated hemoglobin still requires JAK2 testing. 1
• Do not overlook iron deficiency – microcytosis with elevated RBC count suggests iron-deficient polycythemia vera, where hemoglobin may appear deceptively normal. 1
• Avoid aggressive phlebotomy in secondary polycythemia – this causes iron depletion, decreased oxygen-carrying capacity, and paradoxically increases stroke risk. 1, 2
• Do not attribute polycythemia to incidental findings (e.g., spinal lesions) without first ruling out established secondary causes and polycythemia vera. 1
• In chronic hypoxic states, EPO may normalize after hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera. 1