What could cause a steadily rising red blood cell (RBC) count, elevated hematocrit, and elevated hemoglobin in a middle-aged female?

Differential Diagnosis of Steadily Rising RBC Count, Elevated Hematocrit, and Elevated Hemoglobin in a 53-Year-Old Female

The most critical diagnosis to exclude in this 53-year-old female with steadily rising red blood cell parameters is polycythemia vera, followed by secondary causes including obstructive sleep apnea, chronic hypoxemia, and smoking-related erythrocytosis.

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a myeloproliferative neoplasm that must be ruled out first, as it carries significant thrombotic risk and requires specific management to prevent morbidity and mortality. 1

Diagnostic Criteria for Polycythemia Vera

• Hemoglobin ≥16.5 g/dL in women (or hematocrit >49.5%) constitutes the first major criterion for PV diagnosis 1
• A documented sustained increase of at least 2 g/dL from baseline hemoglobin, even without reaching absolute diagnostic thresholds, should raise suspicion for early PV 1
• The presence of JAK2 V617F mutation (found in >90-95% of PV cases) or JAK2 exon 12 mutation is the second major criterion required for diagnosis 1, 2
• Diagnosis requires both major criteria plus one minor criterion, OR the first major criterion plus two minor criteria 1

Minor Criteria Include:

• Bone marrow biopsy showing hypercellularity with trilineage growth (panmyelosis) 1
• Serum erythropoietin level below the reference range for normal 1
• Endogenous erythroid colony formation in vitro 1

Clinical Features Suggestive of PV:

• Splenomegaly, aquagenic pruritus, and erythromelalgia are highly suggestive of PV 3, 4
• Elevated white blood cell count or thrombocytosis in conjunction with elevated hematocrit strongly indicates PV 3

Secondary Polycythemia (Hypoxia-Driven)

Secondary causes are actually more common than polycythemia vera and must be systematically excluded before pursuing extensive hematologic workup. 4, 5

Obstructive Sleep Apnea

• Obesity (BMI >30) is the strongest risk factor for OSA, which causes chronic intermittent hypoxia leading to compensatory erythrocytosis 6
• Chronic fatigue despite "adequate sleep" is a classic presentation, as patients are unaware of their sleep fragmentation and nocturnal hypoxemia 6
• Polysomnography (sleep study) should be ordered to confirm OSA as the cause of chronic hypoxemia 6
• Serum erythropoietin levels are expected to be elevated or high-normal in hypoxia-driven secondary polycythemia 6
• CPAP therapy is the primary treatment and should resolve the polycythemia by eliminating nocturnal hypoxemia 6

Chronic Pulmonary Disease

• Chronic obstructive pulmonary disease (COPD), chronic bronchitis, and other pulmonary conditions causing chronic hypoxemia drive erythropoietin production 7, 4
• Chest X-ray and pulmonary function tests are essential to identify underlying lung disease 8
• Treatment of the underlying pulmonary condition is necessary to manage secondary erythrocytosis 7

Smoking-Related Erythrocytosis

• Smoking is the most frequent cause of an increased hematocrit in the general population 3
• "Smoker's polycythemia" results from chronic carbon monoxide exposure, which causes tissue hypoxia and stimulates erythropoietin production 7
• Smoking cessation should be implemented before ordering extensive blood volume studies 3
• The erythrocytosis typically resolves with smoking cessation 7

Other Hypoxia-Related Causes

• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis 7
• High-altitude residence causes physiological increases in hemoglobin levels as an adaptive response 7

Secondary Polycythemia (Non-Hypoxia-Driven)

Erythropoietin-Producing Tumors

• Renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma can produce erythropoietin independently 7
• Serum erythropoietin levels will be elevated in these conditions 7

Medication-Induced

• Testosterone therapy (prescribed or unprescribed) can cause erythrocytosis and should be considered in the differential diagnosis 7
• Erythropoietin therapy itself can cause elevated hemoglobin levels 7

Relative Polycythemia (Plasma Volume Depletion)

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause relative polycythemia due to plasma volume depletion 7
• Hydration status must be verified to exclude relative polycythemia before pursuing extensive workup 2
• Repeat CBC after ensuring adequate hydration to confirm persistent elevation 2

Critical Diagnostic Algorithm

Initial Laboratory Workup

• Complete blood count with red cell indices, reticulocyte count, and differential blood cell count 7
• Serum ferritin and transferrin saturation to evaluate for concurrent iron deficiency 7
• C-reactive protein (CRP) to assess for inflammatory conditions 7
• Peripheral blood smear review to assess red cell morphology 7

Second-Tier Testing

• JAK2 V617F mutation testing (exon 14) as first-line molecular testing 2
• If JAK2 V617F is negative, order JAK2 exon 12 mutation testing 2
• Serum erythropoietin level: low or low-normal suggests PV, elevated suggests secondary polycythemia 1
• Arterial blood gas or pulse oximetry to document hypoxemia 6
• Polysomnography if OSA is suspected based on obesity, fatigue, or witnessed apneas 6

When to Refer to Hematology

• Positive JAK2 mutation with elevated hemoglobin/hematocrit 2
• Hemoglobin >20 g/dL with symptoms of hyperviscosity 7
• Unexplained splenomegaly 7
• Diagnosis remains unclear after initial workup 7

Critical Pitfalls to Avoid

• Do not assume "adequate sleep" rules out sleep apnea—patients with OSA are typically unaware of their sleep fragmentation and nocturnal arousals 6
• Do not rush to diagnose polycythemia vera without first excluding secondary causes, especially in an obese patient with fatigue 6
• Iron deficiency can coexist with erythrocytosis, particularly in PV, causing microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin 7
• In routine clinical practice, do not be prevented from making a working diagnosis of PV in the presence of iron deficiency, even if WHO criteria are not met; however, formal diagnosis for research purposes requires meeting criteria after iron replacement 1
• Hemoglobin is more accurate than hematocrit for monitoring, as hematocrit can falsely increase by 2-4% with prolonged sample storage, while hemoglobin remains stable 7
• Do not perform aggressive phlebotomy unless hematocrit exceeds 65% with symptoms of hyperviscosity, as repeated routine phlebotomies risk iron depletion, decreased oxygen-carrying capacity, and stroke 7

Management Implications Based on Etiology

If Polycythemia Vera is Confirmed:

• Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk 7, 2
• Low-dose aspirin (81-100 mg daily) is the second cornerstone of therapy for thrombosis prevention 7, 2
• Cytoreductive therapy (hydroxyurea or interferon-alpha) is recommended for high-risk patients (age >60 or prior thrombosis) 2

If Secondary Polycythemia is Identified:

• Treatment of the underlying condition is necessary: CPAP for OSA, smoking cessation for smoker's polycythemia, management of COPD or other pulmonary disease 6, 7
• Therapeutic phlebotomy is indicated only when hemoglobin >20 g/dL and hematocrit >65% with associated symptoms of hyperviscosity 7
• If iron deficiency is confirmed in the context of erythrocytosis, cautious oral iron supplementation with close hemoglobin monitoring is necessary 7