Can polycythemia with elevated hematocrit (hypercalcemia not present, but elevated red blood cell count) be secondary to sleep apnea?

Yes, Polycythemia Can Be Secondary to Sleep Apnea

Obstructive sleep apnea is a well-established cause of secondary polycythemia through chronic intermittent hypoxia, and should be strongly considered in any patient presenting with elevated hematocrit and red blood cell count, particularly when obesity is present. 1, 2

Pathophysiologic Mechanism

Sleep apnea causes secondary polycythemia through a hypoxia-driven compensatory mechanism:

• Chronic intermittent nocturnal hypoxemia from repetitive upper airway obstruction triggers renal erythropoietin (EPO) release, stimulating bone marrow red cell production to improve oxygen-carrying capacity 1, 2
• The hypoxic stimulus persists nightly despite patients being unaware of their sleep fragmentation, creating a chronic compensatory erythrocytosis 1
• Obesity (BMI ≥36) is the strongest risk factor for OSA and represents the primary driver of the upper airway collapse that generates the hypoxic episodes 1

Prevalence and Clinical Significance

The actual prevalence of polycythemia in OSA patients varies by disease severity:

• Overall prevalence is approximately 2% (95% CI 1-4%) across all OSA patients 3
• In mild-to-moderate OSA: 2% (95% CI 1-3%) 3
• In severe OSA: 6% (95% CI 3-12%) - representing a three-fold increase 3
• One contradictory study found only 0.3% prevalence, suggesting polycythemia is "very rarely" caused by OSA 4, but this conflicts with the larger meta-analysis and guideline consensus

The true prevalence is likely underestimated due to the 2016 change in diagnostic criteria for polycythemia, which raised the hemoglobin thresholds 3

Diagnostic Approach

When evaluating polycythemia potentially secondary to sleep apnea, follow this algorithmic sequence:

Step 1: Confirm True Polycythemia

• Exclude spurious erythrocytosis by assessing for dehydration, diuretic use, vomiting, or burns that cause plasma volume contraction 2, 5
• Hemoglobin of 17.4 g/dL represents mild polycythemia more consistent with secondary causes than polycythemia vera, which typically presents with hemoglobin >18.5 g/dL 1

Step 2: Order Polysomnography

• The American College of Physicians recommends polysomnography (sleep study) as the definitive test to confirm OSA as the cause of chronic hypoxemia 1
• Nocturnal oximetry during the sleep study is more diagnostic than daytime arterial blood gas or pulse oximetry 1
• Look for apnea-hypopnea index (AHI) ≥5 events/hour with associated oxygen desaturations

Step 3: Measure Serum Erythropoietin

• Check serum EPO level to distinguish secondary from primary polycythemia 1, 2
• EPO is expected to be elevated or high-normal in hypoxia-driven secondary polycythemia 1, 2
• Critical caveat: EPO levels may normalize after hemoglobin stabilizes at a higher baseline in chronic hypoxic states, potentially creating diagnostic confusion 1, 2

Step 4: Exclude Polycythemia Vera

• If EPO is low or inappropriately normal, order JAK2 V617F mutation testing, as this mutation is present in >95% of polycythemia vera cases 1, 6
• This step is essential because OSA does not exclude polycythemia vera - the two conditions can coexist, and assuming secondary polycythemia based on OSA history alone can lead to missed PV diagnosis 6

Management and Expected Response

Primary Treatment: CPAP Therapy

• The American Academy of Sleep Medicine recommends CPAP therapy as the primary treatment, which should resolve the polycythemia by eliminating nocturnal hypoxemia 1, 2
• CPAP reduces hemoglobin by 3.76 g/L (95% CI -4.73 to -2.80 g/L) in pooled analysis of 434 patients 3
• CPAP reduces hematocrit by 1.1% (95% CI -1.4 to -0.9%) even in patients without baseline polycythemia 3
• Case reports demonstrate complete regression of marked polycythemia with CPAP treatment, eliminating the need for phlebotomy 7

Adjunctive Treatment: Weight Loss

• Weight loss is essential as it directly addresses the underlying pathophysiology of OSA by reducing upper airway soft tissue mass 1

Avoid Inappropriate Phlebotomy

• Do not perform aggressive or repeated routine phlebotomies in secondary polycythemia, as this risks iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 2
• Phlebotomy is indicated only for hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity in the absence of dehydration 2

Critical Pitfalls to Avoid

• Never assume "adequate sleep" rules out sleep apnea - patients with OSA are typically unaware of their sleep fragmentation and nocturnal arousals, presenting with chronic fatigue despite reporting sufficient sleep duration 1
• Do not rush to diagnose polycythemia vera without first excluding secondary causes, especially in an obese patient with fatigue 1
• Do not assume OSA explains the polycythemia without confirming the diagnosis - OSA and polycythemia vera can coexist, and failure to check JAK2 mutation and EPO levels can lead to missed PV diagnosis 6
• Beware of false reassurance from "normal" EPO levels - in chronic hypoxic states, EPO may normalize after hemoglobin stabilizes at a compensatory higher level, potentially mimicking polycythemia vera 2
• If hemoglobin rises significantly despite CPAP treatment, reconsider the diagnosis and perform JAK2 mutation testing to exclude polycythemia vera 2

Monitoring After CPAP Initiation

• Monitor CBC monthly for the first 3 months to assess hematologic stability and response to CPAP therapy 2
• Once stable, monitor every 3-6 months with CBC and nocturnal oximetry to ensure adequate CPAP adherence and efficacy 2
• Perform periodic arterial oxygen saturation or arterial blood gas to assess whether the hypoxic stimulus persists or has worsened 2