What is the appropriate diagnosis and treatment for a patient with elevated red blood cell count, hemoglobin, and hematocrit, specifically polycythemia?

Diagnosis and Management of Polycythemia

Initial Diagnostic Assessment

This patient's laboratory values (RBC 5.91, hemoglobin 16.6 g/dL, hematocrit 50.9%) meet WHO 2016 criteria for erythrocytosis and require immediate evaluation to distinguish polycythemia vera from secondary causes before initiating treatment. 1

Confirm True Polycythemia

• Hemoglobin of 16.6 g/dL exceeds the WHO 2016 major diagnostic criterion threshold of >16.5 g/dL in men or >16.0 g/dL in women, establishing erythrocytosis. 1, 2
• Hematocrit of 50.9% significantly exceeds the diagnostic threshold of >49% in men or >48% in women per WHO criteria. 1
• Red blood cell mass measurement is no longer required for diagnosis when hemoglobin/hematocrit thresholds are met. 1

Distinguish Polycythemia Vera from Secondary Polycythemia

The diagnostic algorithm must prioritize JAK2 mutation testing and serum erythropoietin level as the critical discriminators:

Essential First-Line Testing

• JAK2 V617F mutation testing is mandatory, as >95% of polycythemia vera patients harbor this mutation. 1, 2, 3
• JAK2 exon 12 mutations should be tested if JAK2 V617F is negative, as these account for most remaining PV cases. 1
• Serum erythropoietin (EPO) level is the key discriminator: subnormal/low EPO strongly suggests PV, while elevated or high-normal EPO indicates secondary polycythemia. 1, 4

Clinical Evaluation for Secondary Causes

Before diagnosing polycythemia vera, systematically exclude secondary causes:

• Assess for chronic hypoxemia: obtain pulse oximetry, consider polysomnography if obstructive sleep apnea suspected (especially with obesity, fatigue, or BMI >30). 4
• Smoking history must be documented, as carbon monoxide exposure causes reversible secondary polycythemia. 1
• Evaluate for chronic lung disease (COPD), cyanotic heart disease, or high-altitude residence causing hypoxia-driven erythrocytosis. 1
• Screen for renal pathology (renal cell carcinoma, cysts, post-transplant erythrocytosis) and other EPO-secreting tumors (uterine leiomyoma, pheochromocytoma, meningioma). 1

Bone Marrow Evaluation

• Bone marrow biopsy is required if JAK2 mutations are absent or to confirm diagnosis when criteria are equivocal. 1
• PV bone marrow shows age-adjusted hypercellularity with trilineage myeloproliferation and pleomorphic, mature megakaryocytes. 1, 2
• Absence of significant reticulin fibrosis (grade 0-1) distinguishes PV from primary myelofibrosis. 1

WHO 2016 Diagnostic Criteria for Polycythemia Vera

Diagnosis requires meeting either all three major criteria OR the first two major criteria plus one minor criterion: 1

Major Criteria

1. Hemoglobin >16.5 g/dL (men) or >16.0 g/dL (women), OR hematocrit >49% (men) or >48% (women), OR increased red cell mass >25% above predicted. 1
2. Bone marrow biopsy showing age-adjusted hypercellularity with trilineage myeloproliferation and pleomorphic, mature megakaryocytes. 1
3. Presence of JAK2 V617F or JAK2 exon 12 mutation. 1

Minor Criterion

• Subnormal serum erythropoietin level. 1

Risk Stratification

All patients must be stratified into low-risk versus high-risk categories to guide cytoreductive therapy decisions: 2

High-Risk Criteria (requires cytoreductive therapy)

• Age ≥60 years, OR 2
• Prior history of thrombosis (arterial or venous). 2

Low-Risk Criteria

• Age <60 years AND no prior thrombosis. 2

Treatment Algorithm

Universal Treatment for All Patients

Every patient with confirmed polycythemia vera requires these interventions regardless of risk category:

Therapeutic Phlebotomy

• Target hematocrit <45% through regular phlebotomy to reduce thrombotic risk. 2, 5
• Phlebotomy remains the cornerstone of PV management and must be maintained throughout disease course. 1, 2
• Remove 250-500 mL of blood per session, with frequency determined by hematocrit response. 1

Antiplatelet Therapy

• Low-dose aspirin 81-100 mg daily is indicated for all patients unless contraindications exist (active bleeding, acquired von Willebrand disease with extreme thrombocytosis >1000 × 10⁹/L). 6, 2
• Aspirin effectively prevents microvascular symptoms including erythromelalgia and reduces thrombotic risk. 1, 2

Additional Treatment for High-Risk Patients

Patients aged ≥60 years or with prior thrombosis require cytoreductive therapy in addition to phlebotomy and aspirin:

First-Line Cytoreductive Therapy

• Hydroxyurea is the preferred first-line cytoreductive agent for high-risk patients. 2, 3
• Typical starting dose: 15-20 mg/kg/day, adjusted to maintain target blood counts. 2
• Monitor complete blood count every 2-4 weeks during dose titration. 2

Second-Line Options

• Interferon-alpha (including pegylated formulations) is an alternative first-line option, particularly in younger patients or those planning pregnancy. 1, 2
• Ruxolitinib (JAK1/JAK2 inhibitor) is indicated for patients intolerant of or resistant to hydroxyurea. 2, 5
• Ruxolitinib achieves hematocrit control in 88-89% of patients by 3-6 months and effectively reduces splenomegaly and pruritus. 5

Symptom-Directed Management

• For refractory pruritus: selective serotonin receptor antagonists or ruxolitinib if hydroxyurea-resistant. 1, 2
• For symptomatic splenomegaly: ruxolitinib is most effective; consider splenectomy or splenic irradiation only if drug-refractory. 1

Critical Pitfalls to Avoid

• Never assume elevated hemoglobin/hematocrit represents polycythemia vera without excluding secondary causes, especially in patients with obesity, smoking history, or symptoms suggesting sleep apnea. 1, 4
• Do not use excessive aspirin doses (>100 mg daily), as this increases bleeding risk without additional thrombotic benefit. 1
• Avoid cytoreductive therapy in low-risk patients, as this exposes them to leukemogenic risk without proven benefit. 2
• Monitor for acquired von Willebrand disease in patients with extreme thrombocytosis (platelets >1000 × 10⁹/L), as this creates paradoxical bleeding risk. 1, 6
• Recognize that 12.7% of PV patients develop myelofibrosis and 6.8% develop acute myeloid leukemia during disease course, requiring ongoing surveillance. 2
• Do not overlook masked polycythemia vera: a subset of patients may have normal hemoglobin/hematocrit due to blood dilution or coincidental blood loss but still harbor JAK2 mutations and thrombotic risk. 7

Monitoring and Follow-Up

• Complete blood count every 3-6 months once stable on therapy. 2
• Maintain hematocrit <45% through phlebotomy adjustments. 2, 5
• Annual assessment for disease progression to myelofibrosis (increasing splenomegaly, leukoerythroblastosis, worsening anemia). 1
• Monitor for transformation to acute myeloid leukemia (increasing blast percentage, worsening cytopenias). 1, 2