What are the diagnostic and treatment approaches for polycythemia?

Polycythemia Diagnosis and Evaluation

Initial Diagnostic Approach

Begin the diagnostic workup by measuring serum erythropoietin (EPO) level when hemoglobin/hematocrit exceeds the 95th percentile for sex and race, or when there is a sustained increase of ≥2 g/dL from baseline, followed by JAK2 mutation testing and bone marrow examination in appropriate cases. 1, 2

When to Suspect Polycythemia Vera

Initiate evaluation when any of the following are present:

• Hemoglobin >16.5 g/dL in women or >18.5 g/dL in men (or hematocrit >49% in women, >52% in men) 3, 4
• Sustained hemoglobin increase ≥2 g/dL above baseline, even within normal reference ranges 3, 1
• Associated clinical features: aquagenic pruritus (33% of patients), unusual thrombosis including Budd-Chiari syndrome, erythromelalgia (5.3%), thrombocytosis (53%), leukocytosis (49%), or splenomegaly (36%) 1, 2, 4

Critical Pitfall: Iron Deficiency Masking

Do not miss iron deficiency, which can falsely normalize hemoglobin/hematocrit while true erythrocytosis persists. Check mean corpuscular hemoglobin concentration (MCHC); values <32% suggest iron deficiency requiring serum ferritin, iron studies, and transferrin saturation assessment before proceeding 5, 2. In routine clinical practice, you can make a working diagnosis of PV in the presence of iron deficiency even if WHO hemoglobin/hematocrit thresholds are not met 3.

Diagnostic Algorithm

Step 1: Serum Erythropoietin Level

• Low EPO: Highly suggestive of PV with >90% specificity; proceed to bone marrow examination 3, 1, 2
• Normal EPO: Does not exclude PV (sensitivity of low EPO is <70%); proceed to bone marrow examination 3, 1, 2
• High EPO: Evaluate for secondary polycythemia causes 3, 1, 2

EPO levels remain low in PV even during phlebotomy treatment, making this a reliable marker 3, 5.

Step 2: JAK2 Mutation Testing

More than 95% of PV patients harbor a JAK2 mutation (JAK2V617F or exon 12 mutations), making this the most efficient test to distinguish PV from secondary erythrocytosis. 6, 4 This test can be performed early in the diagnostic workup, particularly when clinical features strongly suggest PV 6, 7.

Step 3: Bone Marrow Examination

Perform bone marrow biopsy with cytogenetic studies when EPO is low or normal 3, 2. Key histologic findings supporting PV diagnosis include:

• Hypercellularity for age with trilineage growth (panmyelosis) 3, 1
• Increased megakaryocytes with cluster formation and giant pleomorphic forms 3, 1, 2
• Decreased bone marrow iron stores 3, 5, 2
• Mild reticulin fibrosis (present in 12% at diagnosis) 3

Cytogenetic abnormalities (trisomies of chromosomes 8 and 9, deletions of 13q and 20q) occur in only 13-18% of patients and have limited diagnostic value 3, 1.

Revised WHO Diagnostic Criteria (2007)

Diagnosis requires either both major criteria plus one minor criterion, OR the first major criterion plus two minor criteria. 3

Major Criteria:

1. Hemoglobin ≥18.5 g/dL in men, ≥16.5 g/dL in women (or hematocrit ≥52% in men, ≥49% in women, or sustained increase >2 g/dL from baseline) 3
2. Presence of JAK2V617F or functionally similar mutation (such as JAK2 exon 12 mutation) 3

Minor Criteria:

1. Bone marrow biopsy showing hypercellularity with trilineage growth 3
2. Serum erythropoietin level below normal range 3
3. Endogenous erythroid colony formation (when available) 3

This combination captures >97% of PV cases when both major criteria are met 3.

Specialized Testing for Equivocal Cases

In the approximately 10% of cases where diagnosis remains unclear after standard workup, consider 3, 1, 2:

• Decreased megakaryocyte expression of TPO receptor (c-mpl) on bone marrow immunohistochemistry 3, 1
• Peripheral blood neutrophil assay for PRV-1 expression (high in PV, not detectable in secondary polycythemia) 3, 1
• Spontaneous (endogenous) erythroid colony assays (limited availability, requires expertise) 3, 1

Important caveat: None of these specialized tests can differentiate PV from other myeloproliferative disorders, and negative results do not exclude PV 3.

Distinguishing Secondary Polycythemia

When EPO is elevated, systematically evaluate for 1, 2, 4:

Hypoxia-Driven Causes:

• Chronic lung disease, sleep apnea, high altitude exposure
• Measure arterial oxygen saturation and carboxyhemoglobin level 2
• Smoker's polycythemia from chronic carbon monoxide exposure (resolves with smoking cessation) 2

Pathologic EPO Production:

• Renal cell carcinoma, hepatocellular carcinoma, cerebellar hemangioblastoma
• Perform imaging of kidneys, liver, and central nervous system 1, 2

Other Causes:

• High oxygen-affinity hemoglobinopathy (congenital) 1
• EPO doping, androgen preparations 1

What NOT to Do

Do not routinely measure red cell mass (RCM), as it is costly, adds no diagnostic value when hematocrit is >60%, and a normal RCM does not rule out PV 1, 5, 2. This represents an outdated approach that has been superseded by JAK2 mutation testing 6.

Do not rely on traditional markers alone: splenomegaly, leukocytosis, thrombocytosis, elevated leukocyte alkaline phosphatase, and increased vitamin B12 levels lack both sensitivity and specificity for PV diagnosis 1, 5.

Do not miss dehydration as the most common cause of falsely elevated hematocrit; exclude this before intensifying diagnostic workup 5.

Prognostic Considerations

Understanding the natural history informs the urgency of diagnosis:

• Median survival: 14.1 to 27.6 years from diagnosis, exceeding 35 years in young patients 8, 4
• 20-year thrombotic event rate: 26% 8
• Transformation risk: 12.7% develop myelofibrosis, 6.8% develop acute myeloid leukemia 4
• Thrombosis at or before diagnosis: 16% arterial, 7% venous (including unusual sites like splanchnic veins) 4

The high thrombotic risk drives the need for prompt diagnosis and treatment initiation 8, 4, 9.