Polycythemia Vera: Diagnosis and Management
Primary Diagnosis
This patient most likely has polycythemia vera (PV), given the constellation of leukocytosis (WBC 14.3), erythrocytosis (RBC 5.91), elevated hemoglobin (16.6 g/dL), and elevated hematocrit (50.9%). 1
The combination of elevated red blood cell parameters with leukocytosis strongly suggests a myeloproliferative neoplasm rather than secondary erythrocytosis, which typically presents with isolated erythrocytosis. 2, 3
Diagnostic Workup
Immediate Laboratory Testing
- JAK2 V617F mutation testing (exon 14) as first-line molecular diagnostic test, present in approximately 95-98% of PV cases 1, 4
- If JAK2 V617F is negative, proceed with JAK2 exon 12 mutation testing, which accounts for most remaining PV cases 1
- Serum erythropoietin level to differentiate primary from secondary causes; a subnormal EPO level supports PV diagnosis 1, 4
- Peripheral blood smear to assess cell morphology and identify abnormalities 5
- Serum ferritin and transferrin saturation to evaluate for concurrent iron deficiency, which can mask the full extent of erythrocytosis 5, 2
Bone Marrow Biopsy Considerations
A bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) and pleomorphic mature megakaryocytes fulfills a major diagnostic criterion. 1 However, this may not be required if hemoglobin exceeds 18.5 g/dL in men or 16.5 g/dL in women with positive JAK2 mutation and subnormal EPO. 1
WHO 2016 Diagnostic Criteria for PV
Diagnosis requires either all 3 major criteria OR the first 2 major criteria plus the minor criterion: 1
Major Criteria:
- Hemoglobin >16.5 g/dL in men, >16.0 g/dL in women OR Hematocrit >49% in men, >48% in women OR increased red cell mass 1
- Bone marrow biopsy showing hypercellularity with trilineage growth including prominent erythroid, granulocytic, and megakaryocytic proliferation with pleomorphic mature megakaryocytes 1
- Presence of JAK2 V617F or JAK2 exon 12 mutation 1
Minor Criterion:
- Subnormal serum erythropoietin level 1
This patient's hematocrit of 50.9% exceeds the threshold for men (>49%), fulfilling the first major criterion. 1
Exclusion of Secondary Causes
Before confirming PV, systematically exclude secondary erythrocytosis: 5, 6
- Hypoxic causes: Obstructive sleep apnea, chronic obstructive pulmonary disease, cyanotic congenital heart disease, high altitude residence 5, 6
- Non-hypoxic causes: Smoking (carbon monoxide-induced), testosterone use, erythropoietin-producing tumors (renal cell carcinoma, hepatocellular carcinoma), exogenous erythropoietin therapy 5, 6
- Relative polycythemia: Dehydration, diuretic use, plasma volume contraction 5, 6
A normal or elevated erythropoietin level suggests secondary erythrocytosis, while a low level supports PV. 5, 6
Risk Stratification
High-risk patients include those with: 1, 7
- Age ≥60 years 1
- Prior history of thrombosis 1
- Poor tolerance of phlebotomy 1
- Symptomatic or progressive splenomegaly 1
- Severe disease-related symptoms (pruritus, night sweats, fatigue) 1
- Platelet count >1,500 × 10⁹/L 1
- Progressive leukocytosis 1
Low-risk patients are those age <60 years with no prior thrombosis. 1
Management Strategy
All Patients (Low and High Risk)
Therapeutic phlebotomy to maintain hematocrit strictly below 45% is the cornerstone of therapy and significantly reduces thrombotic risk. 1, 7, 4 The CYTO-PV study demonstrated that maintaining hematocrit <45% substantially reduces thrombotic events. 5
Low-dose aspirin (81-100 mg daily) should be prescribed for all patients unless contraindicated, as it significantly reduces thrombotic events without substantially increasing bleeding risk. 1, 7, 4
Manage cardiovascular risk factors including smoking cessation, hypertension control, diabetes management, and hyperlipidemia treatment. 1, 4
High-Risk Patients: Cytoreductive Therapy
First-line cytoreductive options: 1, 7
- Hydroxyurea is the most commonly used first-line agent, but should be used with caution in younger patients (<40 years) due to potential leukemogenic risk 1, 7, 3
- Interferon alfa or pegylated interferon is particularly effective for intractable pruritus and may be preferred in younger patients or pregnant women 1, 7
Second-line options for hydroxyurea intolerance/resistance: 1
- Ruxolitinib (JAK2 inhibitor) is FDA-approved for patients with inadequate response to or intolerance of hydroxyurea, with high rates of hematocrit control (88-89% by 3-6 months) 1, 8
- Busulfan as alternative cytoreductive agent 7
Definition of Hydroxyurea Intolerance/Resistance
Patients should be considered for alternative therapy if they experience: 1
- Inadequate response (frequent/persistent need for phlebotomy, symptomatic/progressive splenomegaly, symptomatic thrombocytosis, progressive leukocytosis) 1
- Unacceptable toxicity (leg ulcers, mucocutaneous manifestations, fever, gastrointestinal symptoms, pneumonitis) 1
Monitoring and Response Assessment
Complete response is defined as: 7
- Hematocrit <45% without phlebotomy 7
- Platelet count <400 × 10⁹/L 7
- WBC count <10 × 10⁹/L 7
- No disease-related symptoms 7
- No palpable splenomegaly 7
Symptom assessment using the MPN Symptom Assessment Form (MPN-SAF) should be performed at baseline and during treatment, with symptom response defined as ≥50% reduction in total symptom score. 1
Critical Pitfalls to Avoid
Do not perform aggressive phlebotomy without volume replacement, as this can cause iron depletion, decreased oxygen-carrying capacity, and paradoxically increase stroke risk. 5 When phlebotomy is performed, replace with equal volume of saline or dextrose. 5
Do not use therapeutic phlebotomy unless hematocrit exceeds 65% with hyperviscosity symptoms in secondary erythrocytosis, as repeated phlebotomies are contraindicated due to iron depletion risks. 5
Do not overlook concurrent iron deficiency, which can mask the full extent of erythrocytosis and cause microcytic polycythemia with elevated RBC count but reduced hemoglobin. 5, 2 If iron deficiency is confirmed, cautious oral iron supplementation with close hemoglobin monitoring is necessary. 5, 7
Do not assume normal hematocrit excludes PV in young women or patients with plasma volume expansion, as the hematocrit may be falsely normal despite increased red cell mass. 3 Direct measurement of red cell mass and plasma volume may be required in these cases. 3
Referral Indications
Immediate hematology referral is indicated for: 5