Workup for High Hemoglobin (Polycythemia)
When evaluating elevated hemoglobin, first confirm the elevation is real by accounting for altitude and sex-specific thresholds, then systematically rule out secondary causes before considering primary polycythemia vera.
Initial Confirmation and Context
Define True Elevation
- For males at sea level: Hemoglobin >16.5 g/dL warrants investigation 1
- For females at sea level: Hemoglobin >16.0 g/dL (using adjusted thresholds) 2
- Altitude adjustment is critical: Hemoglobin increases approximately 0.9 g/dL per 1000 meters above sea level 2
Repeat Measurement
- Confirm elevation with repeat complete blood count (CBC) using automated cell counter 3
- Hemoglobin is preferred over hematocrit as it remains stable at room temperature, whereas hematocrit can increase 2-4% with prolonged storage 2
Systematic Diagnostic Approach
Step 1: Obtain Complete Blood Count with Indices
- Full CBC with differential to evaluate all cell lines 4
- Examine peripheral blood smear for morphologic abnormalities 4
- Look for isolated erythrocytosis versus pancytosis (suggests polycythemia vera) 3
Step 2: Rule Out Secondary Causes
Hypoxia-Related:
- Pulse oximetry and arterial blood gas to assess oxygenation 2
- Consider chronic lung disease, sleep apnea, right-to-left cardiac shunts 5
- High-altitude residence (already addressed above) 2
Renal Causes:
- Renal function tests (creatinine, GFR) 3
- Renal ultrasound to evaluate for masses, cysts, or hydronephrosis (can cause inappropriate erythropoietin production) 5
Other Secondary Causes:
- Smoking history: Causes upward shift in hemoglobin requiring separate adjustment 2
- Testosterone or anabolic steroid use 5
- Erythropoietin-secreting tumors (hepatocellular carcinoma, renal cell carcinoma, cerebellar hemangioblastoma) 5
Step 3: Laboratory Workup for Polycythemia Vera
Essential Tests:
- Serum erythropoietin level: Low or inappropriately normal suggests polycythemia vera; elevated suggests secondary polycythemia 3
- JAK2 V617F mutation testing: Present in >95% of polycythemia vera cases 3
- Iron studies (ferritin, transferrin saturation): Iron deficiency must be corrected before accurate interpretation, as it blunts expected responses 2
Additional Considerations:
- Vitamin B12 level: Often elevated in polycythemia vera 5
- Leukocyte alkaline phosphatase: May be elevated in polycythemia vera 5
Step 4: Apply WHO Diagnostic Criteria for Polycythemia Vera
- Hemoglobin >99th percentile for age, sex, and altitude (generally >18.5 g/dL in men, adjusted for altitude) 2
- Presence of JAK2 mutation or other clonal marker 3
- Bone marrow biopsy may be needed if diagnosis remains unclear 3
Critical Pitfalls to Avoid
- Never assume altitude-adjusted values are abnormal without proper calculation—this leads to unnecessary workups 2
- Always correct iron deficiency first before interpreting hemoglobin in polycythemia evaluation, as deficiency masks true elevation 2
- Do not overlook smoking status—requires separate adjustment beyond altitude alone 2
- Consider relative polycythemia (Gaisböck syndrome) from dehydration or diuretic use—check volume status 5
- In patients with thrombocytosis and elevated hemoglobin, strongly consider polycythemia vera and obtain JAK2 mutation testing 3
Special Populations
Chronic Kidney Disease Patients
- Elevated hemoglobin is unusual in CKD; most have anemia 3
- If elevated, investigate for polycystic kidney disease (can cause increased erythropoietin) 5