My hemoglobin is elevated while my spleen size, white‑blood‑cell count, and platelet count are normal; what are the next steps in evaluation and management?

Elevated Hemoglobin with Normal Spleen, WBC, and Platelets: Evaluation and Management

You must immediately test for JAK2V617F mutation and measure serum erythropoietin level to distinguish polycythemia vera from secondary causes of erythrocytosis, as these are the critical diagnostic steps when hemoglobin is elevated with normal other parameters. 1, 2

Initial Diagnostic Approach

Confirm True Polycythemia

• Verify adequate hydration status first to exclude relative (spurious) polycythemia from plasma volume depletion, which is the most common cause of isolated hematocrit elevation 3
• Repeat complete blood count after ensuring adequate hydration to confirm persistent elevation 2
• For males, hemoglobin >18.5 g/dL or hematocrit >55% suggests true polycythemia; for females, hemoglobin >16.5 g/dL or hematocrit >48% 1

Exclude Secondary Causes

• Obtain arterial blood gas to assess oxygen saturation - normal oxygen saturation (>92%) helps exclude hypoxic causes 1, 4
• Evaluate for chronic lung disease, sleep apnea, high altitude exposure, and heavy smoking (>20 pack-years) 5, 4
• Order renal ultrasound to exclude renal cysts, renal artery stenosis, or renal tumors producing erythropoietin 5, 4
• Measure carboxyhemoglobin level in smokers to exclude carbon monoxide-induced polycythemia 5

Molecular and Laboratory Testing

JAK2 Mutation Testing (First-Line)

• Order JAK2V617F mutation testing (exon 14) immediately - this is positive in approximately 95% of polycythemia vera cases 1, 2
• If JAK2V617F is negative, proceed with JAK2 exon 12 mutation testing, which accounts for most remaining PV cases 1, 2
• The presence of JAK2 mutation with elevated hemoglobin fulfills major WHO diagnostic criteria for polycythemia vera 1

Serum Erythropoietin Level

• Measure serum erythropoietin - subnormal levels strongly support polycythemia vera, while elevated levels indicate secondary erythrocytosis 1, 5, 6
• Low or inappropriately normal erythropoietin in the setting of elevated hemoglobin is a minor diagnostic criterion for PV 1, 6

Additional Supportive Testing

• Obtain peripheral blood smear to assess for morphologic abnormalities 7
• Check absolute neutrophil count - elevation >10 × 10⁹/L (or >12.5 × 10⁹/L in smokers) is a minor criterion for PV 5, 6
• Verify platelet count - elevation >400 × 10⁹/L supports PV diagnosis as a minor criterion 1, 6

Diagnostic Criteria for Polycythemia Vera

WHO Major Criteria (All Required)

1. Hemoglobin >18.5 g/dL (men) or >16.5 g/dL (women), OR evidence of increased red cell volume 1
2. Presence of JAK2V617F or JAK2 exon 12 mutation 1
3. Bone marrow biopsy showing hypercellularity with trilineage myeloproliferation 1

Minor Criteria (One Required if Major Criteria Met)

• Subnormal serum erythropoietin level 1, 5

Note: The absence of splenomegaly does NOT exclude polycythemia vera - palpable splenomegaly is present in only 30-40% of PV patients at diagnosis 5, 4

Management Based on Diagnosis

If Polycythemia Vera Confirmed

Risk Stratification

• High-risk patients: Age >60 years OR prior history of thrombosis 1
• Low-risk patients: Age ≤60 years AND no prior thrombosis 1

Low-Risk PV Management

• Phlebotomy to maintain hematocrit <45% - this is mandatory for ALL patients regardless of risk category 1
• Remove 250-500 mL of blood every 2-3 days initially until target hematocrit achieved 4
• Low-dose aspirin 81-100 mg daily unless contraindicated by bleeding history or extreme thrombocytosis 1
• Cytoreductive therapy is NOT recommended as initial treatment for low-risk patients 1

High-Risk PV Management

• Phlebotomy to maintain hematocrit <45% plus cytoreductive therapy 1
• Hydroxyurea as first-line cytoreductive agent: Start 15-20 mg/kg/day orally, adjust dose to maintain hematocrit <45%, WBC 3-5 × 10⁹/L, and platelets 100-400 × 10⁹/L 1
• Low-dose aspirin 81-100 mg daily 1
• Consider pegylated interferon alfa-2a as alternative to hydroxyurea in younger patients or those planning pregnancy 1

If Secondary Polycythemia Identified

• Treat the underlying cause (e.g., CPAP for sleep apnea, smoking cessation, treat renal pathology) 4
• Phlebotomy may be considered if hematocrit >54% with hyperviscosity symptoms 4
• Aspirin is NOT routinely indicated for secondary polycythemia 4

Critical Pitfalls to Avoid

• Do not assume normal spleen size excludes PV - many PV patients present without splenomegaly, and this is a recognized variant called "masked PV" 8
• Do not delay JAK2 testing - this is the single most important diagnostic test and should be ordered immediately when PV is suspected 2, 8
• Do not target hematocrit <42% or <40% - the evidence-based target is strictly <45%, and lower targets increase risk of bleeding without additional benefit 1
• Do not overlook thrombosis risk - even with normal platelet and WBC counts, untreated PV carries significant thrombotic risk requiring aspirin therapy 1, 4
• Do not perform bone marrow biopsy before JAK2 testing - molecular testing should precede invasive procedures 2

Monitoring and Follow-Up

Initial Phase

• Check CBC weekly during phlebotomy induction phase until hematocrit <45% achieved 1
• Monitor for iron deficiency (common with repeated phlebotomy) but do NOT supplement iron as this will worsen polycythemia 4

Maintenance Phase

• CBC every 3 months once stable hematocrit achieved 1
• Clinical assessment for thrombotic/hemorrhagic events at each visit 1
• Annual abdominal ultrasound only if clinically indicated (not routine) 1
• Monitor for disease progression to myelofibrosis (development of splenomegaly, leukoerythroblastosis, worsening anemia) 1

Referral Indications

• Refer to hematology immediately if JAK2 mutation is positive or if diagnosis remains uncertain after initial workup 1
• Consider referral for all confirmed PV patients for specialized management and clinical trial opportunities 1