What is the appropriate evaluation and initial management for a patient with an elevated hemoglobin on laboratory testing?

Approach to Elevated Hemoglobin

When evaluating elevated hemoglobin, first distinguish between true erythrocytosis (increased red cell mass) and relative/apparent erythrocytosis (decreased plasma volume), as this fundamentally changes management—measurement of total hemoglobin mass and plasma volume should be considered when the clinical picture suggests volume contraction rather than true polycythemia. 1

Initial Diagnostic Evaluation

Confirm the Elevation and Assess Severity

• Verify elevated hemoglobin with repeat testing using age- and sex-specific criteria: hemoglobin >185 g/L (or hematocrit >0.52) in men; hemoglobin >165 g/L (or hematocrit >0.48) in women warrants investigation 2
• Review the complete blood count parameters, particularly mean corpuscular hemoglobin concentration (MCHC)—values significantly above reference range are not physiologically possible and suggest hemolytic anemia requiring urgent peripheral smear examination 3

Distinguish True vs. Relative Erythrocytosis

Critical clinical assessment should focus on:

• Volume status indicators: dehydration, diuretic use, gastrointestinal losses, third-spacing conditions 1, 4
• Conditions causing plasma volume contraction: heart failure, chronic liver disease, severe burns, or capillary leak syndromes 1
• Hemoconcentration triggers: acute stress, sympathetic activation, or recent physical exertion 4

In patients with heart failure or chronic liver disease, plasma volume excess (not hemoglobin deficiency) explains most variance in hemoglobin concentration—total hemoglobin mass may be normal or even elevated despite "anemic" hemoglobin levels, and conversely, normal hemoglobin concentration may mask significant plasma volume expansion 1

Systematic Workup for True Erythrocytosis

Primary Laboratory Studies

• JAK2 V617F mutation testing to evaluate for polycythemia vera (though this was performed in only 17.9% of cases in clinical practice, representing a significant gap in guideline adherence) 2
• Serum erythropoietin (EPO) level: low/normal suggests primary polycythemia; elevated suggests secondary causes 2
• Oxygen saturation measurement (pulse oximetry and arterial blood gas if indicated) to identify hypoxia-driven erythrocytosis 2

Identify Secondary Causes

Hypoxia-related (most common secondary cause): 2

• Chronic lung disease (COPD, sleep apnea)
• Cyanotic heart disease
• High-altitude exposure (note: initial hemoglobin/hematocrit peaks at altitude are primarily due to dehydration, with true erythropoiesis contributing later) 5
• Carbon monoxide exposure (smoking—59% of young adults with erythrocytosis were smokers) 2

Other secondary causes to evaluate:

• Renal pathology: renal artery stenosis, polycystic kidney disease, renal tumors
• Hepatocellular carcinoma or other EPO-secreting tumors
• Exogenous testosterone or anabolic steroid use
• Obesity (43% of young adults with erythrocytosis were obese) 2
• Alcohol or recreational drug use (38% prevalence in one cohort) 2

Additional Targeted Testing

• Thyroid function (TSH) if signs of thyroid dysfunction present 6
• Hemoglobin A1c in patients with diabetes risk factors 6
• Liver function tests if hepatic dysfunction suspected 6
• Sleep study if obstructive sleep apnea suspected based on obesity, snoring, daytime somnolence

Management Approach

When No Cause Identified

• Approximately 43% of young adults with elevated hemoglobin have no identifiable cause after initial workup 2
• Ensure adequate follow-up: less than half of patients in clinical practice receive long-term monitoring, representing a critical gap in care 2
• Recheck hemoglobin/hematocrit in 3-6 months to assess for progression or resolution

Therapeutic Interventions

Phlebotomy considerations:

• Reserved for symptomatic patients or those with very high hematocrit (>54%) at risk for thrombotic complications
• Only 5 patients in a cohort of 56 required phlebotomy 2

Aspirin therapy:

• Consider in confirmed polycythemia vera or when thrombotic risk is elevated
• Used in only 7 of 56 patients in clinical practice 2

Address modifiable factors:

• Smoking cessation (critical given high prevalence)
• Weight reduction in obese patients
• Discontinue causative medications or substances
• Optimize treatment of underlying conditions (COPD, sleep apnea, heart failure)

Critical Pitfalls to Avoid

• Do not assume all elevated hemoglobin represents true erythrocytosis—plasma volume contraction is frequently overlooked but may be the primary mechanism, particularly in heart failure and liver disease 1
• Do not order extensive laboratory panels reflexively—target testing based on clinical suspicion 6
• Do not neglect follow-up—current clinical practice shows poor adherence to monitoring recommendations 2
• Do not miss medication-induced causes—specifically inquire about testosterone, anabolic steroids, and erythropoiesis-stimulating agents
• Recognize that altitude-related hemoglobin elevation initially reflects dehydration rather than true erythropoiesis, which develops over weeks 5