Elevated Red Blood Cell Count: Causes and Diagnostic Approach
An elevated red blood cell count requires systematic evaluation for secondary causes—particularly obstructive sleep apnea, chronic lung disease, smoking, and renal disorders—before considering primary myeloproliferative disorders like polycythemia vera. 1
Initial Diagnostic Confirmation
Confirm true erythrocytosis by repeating hemoglobin and hematocrit measurements, as single values are unreliable for diagnosis. 2 Diagnostic thresholds are:
Hemoglobin is the preferred measurement over hematocrit because it remains stable during sample storage (hematocrit can falsely increase 2-4% with prolonged storage) and is less affected by technical variables like hyperglycemia. 3, 2
Essential Initial Laboratory Workup
Order the following tests immediately to distinguish primary from secondary causes: 2
- Complete blood count with red cell indices (MCV, MCH, MCHC, RDW) 2
- Reticulocyte count to assess bone marrow response 3
- Serum ferritin and transferrin saturation to evaluate iron status 2
- C-reactive protein (CRP) to screen for inflammation 2
- Peripheral blood smear to assess red cell morphology 2
High RDW with normal or low MCV suggests coexisting iron deficiency, which commonly occurs with erythrocytosis and requires specific management. 2
Secondary Causes: The Most Common Culprits
Hypoxia-Driven Erythrocytosis
Obstructive sleep apnea (OSA) is a frequently overlooked cause, particularly in patients with BMI >30 who report chronic fatigue despite "adequate sleep." 1 Nocturnal hypoxemia drives compensatory erythropoietin production. 1 Order polysomnography if obesity, snoring, or daytime somnolence are present. 1
Chronic obstructive pulmonary disease (COPD) causes chronic hypoxemia leading to secondary erythrocytosis. 1, 4 Assess oxygen saturation and consider pulmonary function testing. 1
Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure, which creates tissue hypoxia and stimulates erythropoietin production. 2 This resolves with smoking cessation. 2
High-altitude residence causes physiologic erythrocytosis—hemoglobin increases by 0.2 g/dL at 1,000 meters up to 4.5 g/dL at 4,500 meters. 2 Adjust diagnostic thresholds accordingly. 2
Non-Hypoxic Secondary Causes
Renal disorders including renal cell carcinoma and renal cysts produce inappropriate erythropoietin, causing elevated RBC counts. 1 Consider upper abdominal ultrasonography to evaluate kidneys and spleen. 5
Testosterone therapy or abuse is a common cause in younger adults and should be specifically queried. 2 Dose reduction or temporary discontinuation is necessary if causative. 2
Other erythropoietin-producing tumors include hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma. 2
Relative Polycythemia
Plasma volume depletion from dehydration, diuretic use, or stress polycythemia (Gaisböck syndrome) causes falsely elevated RBC parameters. 2 Assess hydration status before pursuing extensive workup. 2
Distinguishing Primary from Secondary Erythrocytosis
Measure serum erythropoietin level to differentiate causes: 1
- Low or inappropriately normal EPO suggests polycythemia vera 1
- Elevated EPO indicates secondary erythrocytosis from hypoxia or inappropriate production 1
Note that EPO has high specificity (>90%) but reduced sensitivity (<70%) for distinguishing polycythemia vera from secondary causes. 2
Testing for Polycythemia Vera
If secondary causes are excluded and EPO is low, test for JAK2 mutations (both exon 14 and exon 12), which are present in up to 97% of polycythemia vera cases. 2
WHO diagnostic criteria for polycythemia vera require: 2
- Both major criteria (elevated hemoglobin/hematocrit/RBC mass AND JAK2 mutation) plus one minor criterion, OR
- First major criterion plus two minor criteria
Minor criteria include: 2
- Bone marrow hypercellularity with trilineage growth
- Subnormal serum erythropoietin level
- Endogenous erythroid colony formation
Bone marrow biopsy is required if JAK2 is positive to confirm diagnosis and assess for trilineage myeloproliferation. 2
Management Based on Etiology
For Secondary Erythrocytosis
Treat the underlying condition: 2
- Smoking cessation for smoker's polycythemia 2
- CPAP therapy for obstructive sleep apnea 2
- Optimize management of COPD or other pulmonary disease 2
- Dose adjustment or discontinuation of testosterone if causative 2
Therapeutic Phlebotomy Indications
Therapeutic phlebotomy is indicated ONLY when: 6
- Hemoglobin >20 g/dL AND hematocrit >65% 6
- Symptoms of hyperviscosity (headache, fatigue, poor concentration) are present 6
- Dehydration has been excluded 6
When performing phlebotomy, remove one unit (400-500 mL) and replace with equal volume of isotonic saline (750-1000 mL) to prevent further hemoconcentration. 6
Critical Management Cautions
Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and increased stroke risk. 2, 6 This is a common pitfall in management. 2
Iron deficiency should be avoided even with erythrocytosis because iron-deficient red cells have reduced oxygen-carrying capacity and deformability, increasing stroke risk. 2 If iron deficiency is confirmed, provide cautious oral iron supplementation with close hemoglobin monitoring, as rapid increases in red cell mass can occur. 2
For Confirmed Polycythemia Vera
Maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk. 2 The CYTO-PV study demonstrated significantly reduced thrombotic events with this target. 2
Initiate low-dose aspirin (81-100 mg daily) as the second cornerstone of therapy for thrombosis prevention. 2
Refer immediately to hematology if: 2
- JAK2 mutation is positive
- Hemoglobin >20 g/dL with hyperviscosity symptoms
- Unexplained splenomegaly is present
- Diagnosis remains unclear after initial workup
Common Diagnostic Pitfalls to Avoid
Do not use standard polycythemia vera thresholds at high altitude without adjustment—physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation. 2
Do not overlook coexisting iron deficiency in patients with erythrocytosis—MCV is unreliable for screening in this context; use serum ferritin and transferrin saturation instead. 2
Do not perform aggressive phlebotomy without adequate volume replacement, as this worsens hyperviscosity. 2
Do not exclude patients with CRP >10 mg/L automatically—demographic, behavioral, and technical factors can elevate CRP without acute infection, and excluding these patients may eliminate individuals of research or clinical interest. 3