What is the most likely cause of mildly elevated red blood cell, hemoglobin, and hematocrit levels in a female patient?

Most Likely Cause of Mildly Elevated RBC, Hemoglobin, and Hematocrit in a Female Patient

The most likely cause in a female patient with mildly elevated red blood cell parameters is either polycythemia vera (if values meet diagnostic thresholds) or secondary polycythemia from hypoxic conditions, medication use, or relative polycythemia from plasma volume depletion. 1, 2

Diagnostic Thresholds and Initial Considerations

For women, hemoglobin ≥16.5 g/dL or hematocrit >49.5% constitutes the first major criterion for polycythemia vera diagnosis and warrants immediate JAK2 mutation testing. 2, 3 Normal post-menopausal females typically have hemoglobin 14.0 ± 2.0 g/dL and hematocrit 41 ± 5%, while menstruating females have slightly lower values. 1

Primary vs Secondary vs Relative Polycythemia

The differential diagnosis follows this hierarchy:

Primary Polycythemia (Polycythemia Vera):

• Polycythemia vera must be ruled out first as it carries significant thrombotic risk and requires specific management to prevent morbidity and mortality. 2
• JAK2 V617F mutation is present in >90-97% of PV cases. 2, 3, 4
• Even a documented sustained increase of ≥2 g/dL from baseline hemoglobin should raise suspicion for early PV, even without reaching absolute diagnostic thresholds. 2
• Low or inappropriately normal serum erythropoietin levels suggest PV. 2, 3

Secondary Polycythemia (Hypoxia-Driven):

• Obstructive sleep apnea produces nocturnal hypoxemia that drives erythropoietin production. 1, 2
• Chronic obstructive pulmonary disease and other chronic lung conditions causing hypoxemia. 1, 2
• Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure, which stimulates erythropoietin production. 1, 2
• Cyanotic congenital heart disease with right-to-left shunting results in compensatory erythrocytosis. 1

Secondary Polycythemia (Non-Hypoxia-Driven):

• Testosterone therapy (prescribed or unprescribed) can cause erythrocytosis and should be considered in the differential diagnosis. 1, 2
• Erythropoietin-producing tumors including renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma. 1, 2
• Elevated serum erythropoietin levels suggest secondary polycythemia. 2, 3

Relative Polycythemia (Plasma Volume Depletion):

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause relative polycythemia. 1
• Confirm true polycythemia by repeating measurements after adequate hydration. 1

Recommended Diagnostic Algorithm

Immediate Laboratory Workup:

• Complete blood count with red cell indices, reticulocyte count, and manual differential to assess for leukocytosis or thrombocytosis suggesting myeloproliferative disorder. 1, 3
• JAK2 V617F mutation testing as first-line diagnostic test. 2, 3
• Serum ferritin and transferrin saturation to evaluate iron status, as iron deficiency can coexist with erythrocytosis. 1, 3
• Serum erythropoietin level to differentiate primary from secondary causes. 2, 3
• Peripheral blood smear review by qualified hematologist. 1, 3

If JAK2 Positive:

• Bone marrow biopsy required to confirm PV diagnosis and assess for trilineage myeloproliferation. 1
• WHO criteria require both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR first major criterion plus two minor criteria. 1, 3

If JAK2 Negative:

• Sleep study (polysomnography) if obstructive sleep apnea suspected. 2, 3
• Pulmonary function tests and chest imaging for COPD or chronic lung disease. 2, 3
• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or polycystic kidney disease. 1, 3
• Medication review for testosterone use or other causative agents. 1, 3
• Smoking history assessment. 2, 3

Management Based on Etiology

For Confirmed Polycythemia Vera:

• Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk. 1, 2, 3
• Initiate low-dose aspirin (81-100 mg daily) as second cornerstone of therapy for thrombosis prevention. 1, 2, 3
• Cytoreductive therapy with hydroxyurea for high-risk patients (age >60 years or prior thrombosis). 3, 4

For Secondary Erythrocytosis:

• Treatment of underlying condition is necessary: smoking cessation for smoker's polycythemia, CPAP therapy for obstructive sleep apnea, management of chronic lung disease. 1, 2, 3
• Therapeutic phlebotomy is indicated ONLY when hemoglobin >20 g/dL and hematocrit >65% with symptoms of hyperviscosity, after excluding dehydration. 1
• Dose adjustment or discontinuation of testosterone if causative. 1

Critical Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement, as this increases hemoconcentration and stroke risk. 1
• Repeated routine phlebotomies are contraindicated in secondary polycythemia due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1
• Don't overlook coexisting iron deficiency—mean corpuscular volume (MCV) is unreliable for screening iron deficiency in erythrocytosis. 1
• If iron deficiency confirmed in context of erythrocytosis, cautious oral iron supplementation with close hemoglobin monitoring is necessary. 1

Red Flags Requiring Immediate Hematology Referral

• Positive JAK2 mutation. 3
• Hemoglobin >20 g/dL with symptoms of hyperviscosity. 3
• Unexplained splenomegaly with elevated blood counts. 3
• Diagnosis remains unclear after initial workup. 3