What are the diagnostic tests and treatment options for polyglobulia?

Diagnosis of Polycythemia (Polyglobulia)

Initial Diagnostic Approach

Begin diagnostic evaluation when hemoglobin exceeds 16.5 g/dL (hematocrit >49%) in men or 16.0 g/dL (hematocrit >48%) in women, or when there is a documented increase above an individual's baseline regardless of absolute values. 1, 2

Step 1: Confirm True Erythrocytosis

• Measure hemoglobin/hematocrit levels adjusted for sex, race, and age (must exceed 95th percentile) 3
• Look for associated features suggesting polycythemia vera (PV): thrombocytosis (present in 53%), leukocytosis (49%), splenomegaly (36%), pruritus (33%), erythromelalgia (5.3%), or unusual thrombosis including splanchnic vein thrombosis 1, 3
• If hematocrit is >60% without obvious hemoconcentration, red cell mass (RCM) measurement is unnecessary as it is almost always elevated 3

Step 2: JAK2 Mutation Testing

Order JAK2 mutation testing immediately as it is present in >95% of PV cases and distinguishes primary from secondary polycythemia. 1, 4

• JAK2V617F mutation is the most common variant 2
• A positive JAK2 mutation strongly suggests PV but can also occur in other myeloproliferative neoplasms 4

Step 3: Serum Erythropoietin (EPO) Level

Measure serum EPO level to differentiate between primary and secondary causes. 3, 5

• Low serum EPO (sensitivity ~70%, specificity >90%) is highly suggestive of PV 3
• Normal EPO does not exclude PV, as it can occur in definite cases 3
• Elevated EPO suggests secondary polycythemia from conditions like tobacco smoking, sleep apnea, or other hypoxic states 1, 5

Step 4: Bone Marrow Examination

Perform bone marrow aspirate and biopsy with cytogenetic studies when JAK2 is positive or clinical suspicion remains high despite negative molecular testing. 3, 4

• Bone marrow morphology remains the cornerstone of diagnosis and shows hypercellularity, increased megakaryocytes with cluster formation, and giant megakaryocytes in PV 3, 4
• Cytogenetic analysis identifies abnormal karyotype in 15%-20% of PV patients, most commonly +9 (5%), loss of Y chromosome (4%), +8 (3%), and 20q- (3%) 2
• Additional molecular testing may reveal prognostically adverse mutations including SRSF2, IDH2, RUNX1, and U2AF1 (combined incidence 5%-10%) 2

Diagnostic Criteria Summary

A working diagnosis of PV requires: 1, 2

• Hemoglobin >16.5 g/dL (men) or >16.0 g/dL (women) OR hematocrit >49% (men) or >48% (women)
• JAK2 mutation present (>95% of cases)
• Bone marrow morphology consistent with PV (advised but not mandated in all guidelines)

Excluding Secondary Causes

Evaluate for secondary polycythemia by assessing: 5

• Smoking history and tobacco use
• Sleep apnea symptoms
• Chronic lung disease
• Renal pathology (tumors, cysts)
• High altitude exposure
• Testosterone or erythropoietin use

Additional Baseline Testing

Complete the following at diagnosis: 1, 2

• Complete blood count with differential (assess for leukocytosis, thrombocytosis)
• Comprehensive metabolic panel
• Lactate dehydrogenase (LDH)
• Serum uric acid
• Abdominal imaging to assess spleen size
• Cardiovascular risk factor assessment (for thrombosis risk stratification)

Common Pitfalls

• Do not rely solely on hematocrit <60% to exclude PV, as some patients fall at the left extreme of the Gaussian distribution and can still have the disease 3
• Do not skip bone marrow examination when diagnosis is uncertain, as morphology provides critical diagnostic information even with positive JAK2 mutation 3, 4
• Do not assume normal EPO excludes PV, as sensitivity is only ~70% 3
• Avoid measuring RCM routinely when hematocrit is >60% without clinical hemoconcentration, as it adds cost without diagnostic benefit 3