What is the most likely cause and appropriate management for a female smoker with elevated red blood cell count, hemoglobin, and hematocrit?

Smoking-Induced Secondary Polycythemia

The most likely cause in this female smoker with elevated RBC count, hemoglobin, and hematocrit is smoking-induced secondary polycythemia, and the primary management is smoking cessation—not phlebotomy. 1

Pathophysiologic Mechanism

• Carbon monoxide from cigarette smoke binds to hemoglobin with 200-250 times greater affinity than oxygen, forming carboxyhemoglobin and creating a relative hypoxic state that triggers compensatory erythropoiesis 1
• Smokers typically maintain carboxyhemoglobin levels of 3-5%, with approximately 2.5% increase per pack smoked daily; heavy smokers can exceed 10% 1
• This chronic tissue hypoxia stimulates erythropoietin production, resulting in increased hematocrit, hemoglobin, and red blood cell count 2, 1
• The "left-shifted" oxygen-hemoglobin dissociation curve further impairs oxygen delivery to tissues, perpetuating the erythropoietic drive 3

Diagnostic Approach

Initial laboratory evaluation should include:

• Complete blood count with red cell indices, reticulocyte count, and differential to confirm true erythrocytosis 2
• Serum ferritin and transferrin saturation to exclude coexisting iron deficiency 2, 4
• JAK2 mutation testing (exon 14 and exon 12) to exclude polycythemia vera if hemoglobin >16.5 g/dL or hematocrit >48-49% in women 2
• Carboxyhemoglobin level measurement, which should be routine in all polycythemic smokers 3

Key diagnostic thresholds:

• True erythrocytosis in women is defined as hemoglobin >16.5 g/dL or hematocrit >49.5% 2
• Male patients with hematocrit >60% and female patients with hematocrit >55% always have absolute polycythemia 5

Primary Management: Smoking Cessation

Smoking cessation is the definitive first-line treatment and typically leads to complete resolution of polycythemia. 2, 1

• Cardiovascular risk reduction begins within 1 year of cessation, with return to baseline risk after 5 years 1
• Erythrocytosis improves markedly in all patients who successfully reduce or eliminate smoking 3, 6
• Combining behavioral counseling with first-line pharmacologic aids (nicotine-replacement therapy, bupropion, or varenicline) yields the highest cessation success rates 1

Important caveat: E-cigarettes should not be recommended as a cessation tool because they are not risk-free and have been associated with development of polycythemia 1

When Phlebotomy is NOT Indicated

Routine phlebotomy is explicitly contraindicated in secondary polycythemia and causes harm. 2, 4

• Phlebotomy is indicated ONLY when ALL of the following criteria are met: hemoglobin >20 g/dL AND hematocrit >65% AND documented hyperviscosity symptoms (headache, blurred vision, confusion, bleeding) AND adequate hydration confirmed AND iron deficiency excluded 2, 4
• Repeated phlebotomies cause iron depletion, decreased oxygen-carrying capacity, reduced red cell deformability, and paradoxically increase stroke risk 2, 4
• When phlebotomy is performed (rarely), it must be replaced with equal volume of dextrose or saline to prevent hemoconcentration 2

Monitoring and Follow-Up

• Reassess smoking status at 2-4 week follow-up visit by directly asking about current cigarette consumption 1
• Monitor hematological parameters (CBC) to confirm resolution of polycythemia after smoking cessation 1, 4
• Periodic assessment of iron status to avoid iatrogenic iron deficiency 4
• Screen for obstructive sleep apnea (witnessed apneas, loud snoring, morning headaches, daytime somnolence), which can coexist and contribute to erythrocytosis 2, 1

Common Clinical Pitfalls to Avoid

• Do not perform phlebotomy in smoker's polycythemia unless the strict criteria above are met (Hgb >20 g/dL, Hct >65%, symptoms, adequate hydration, no iron deficiency) 2, 4
• Do not rely on pulse oximetry to assess oxygenation in smokers, as standard pulse oximeters cannot differentiate carboxyhemoglobin from oxyhemoglobin and will give falsely reassuring readings 1
• Do not overlook coexisting iron deficiency, which can mimic hyperviscosity symptoms but requires iron supplementation rather than phlebotomy 2, 4
• Do not assume the classic "cherry red" skin appearance will be present; this is rare and requires lethal carboxyhemoglobin levels 1
• Do not create iron deficiency through excessive phlebotomy, as iron-deficient red cells have reduced oxygen-carrying capacity and deformability, paradoxically increasing stroke risk 2, 4

Special Considerations

• If JAK2 mutation is positive, immediate hematology referral is required to evaluate for polycythemia vera 2
• Smoking-induced polycythemia increases blood viscosity and raises thrombotic risk approximately 1.8-fold 1
• Symptoms such as fatigue, headache, and poor concentration typically resolve with smoking cessation 4, 3
• In patients unable to quit completely, switching to heat-not-burn tobacco may reduce erythrocytosis, though complete cessation remains the goal 7