What is the condition called when Red Blood Cell (RBC) count, Hemoglobin (HGB) level, and Hematocrit (HCT) level are all elevated?

Erythrocytosis

When RBC count, hemoglobin, and hematocrit are all elevated, this condition is called erythrocytosis (or polycythemia). 1

Defining Erythrocytosis

Erythrocytosis is diagnosed when hemoglobin exceeds 18.5 g/dL in men or 16.5 g/dL in women, or when hematocrit exceeds 55% in men or 49.5% in women. 1 This represents an absolute increase in red blood cell mass, distinguishing it from relative polycythemia where plasma volume is decreased but RBC mass is normal. 1

Classification Framework

Erythrocytosis can be classified into two major categories based on the underlying mechanism:

Primary Erythrocytosis

• Polycythemia vera (PV) is the most common primary cause, characterized by a JAK2 mutation present in over 95% of cases. 2
• The World Health Organization diagnostic criteria require either both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria. 1
• JAK2 mutation testing (both exon 14 and exon 12) should be performed when evaluating for PV. 1

Secondary Erythrocytosis

• Secondary causes are driven by increased erythropoietin production, either appropriate (hypoxia-driven) or inappropriate (tumor-related). 1
• Hypoxia-driven causes include chronic obstructive pulmonary disease, obstructive sleep apnea, cyanotic congenital heart disease, smoking ("smoker's polycythemia"), and high-altitude adaptation. 1
• Non-hypoxic causes include renal cell carcinoma, hepatocellular carcinoma, testosterone therapy, and erythropoietin-producing tumors. 1

Diagnostic Approach

Initial Laboratory Evaluation

• Complete blood count with red cell indices, reticulocyte count, differential, serum ferritin, transferrin saturation, and C-reactive protein should be obtained. 1
• Hemoglobin is more reliable than hematocrit for diagnosis because hematocrit can falsely increase by 2-4% with prolonged sample storage (>8 hours) or hyperglycemia, while hemoglobin remains stable. 3, 1
• The coefficient of variation for hemoglobin measurement is one-half to one-third that of hematocrit in automated analyzers. 3

Distinguishing True from Relative Polycythemia

• Assess hydration status, recent fluid losses, diuretic use, and conditions causing plasma volume contraction (burns, third-spacing). 4
• Relative polycythemia (Gaisböck syndrome) is typically seen in obese, hypertensive males who smoke. 4

Erythropoietin Level

• A low erythropoietin level indicates primary erythrocytosis (pursue JAK2 testing), while normal or elevated levels suggest secondary causes. 5, 6

Secondary Cause Evaluation

• Obtain smoking history and assess carbon monoxide exposure. 1
• Consider sleep study if nocturnal hypoxemia is suspected. 1
• Evaluate for chronic lung disease, testosterone use (prescribed or unprescribed), and renal pathology. 1, 4
• In young patients or those with family history, consider congenital causes including high-oxygen-affinity hemoglobin variants, erythropoietin receptor mutations, and Chuvash polycythemia. 1

Management Principles

Polycythemia Vera

• All patients with PV should receive therapeutic phlebotomy to maintain hematocrit strictly below 45% and low-dose aspirin (if no contraindications). 2
• Patients at high risk for thrombosis (age ≥60 years or prior thrombosis) or with persistent symptoms may benefit from cytoreductive therapy with hydroxyurea or interferon. 2
• Ruxolitinib can alleviate pruritus and decrease splenomegaly in patients intolerant of or resistant to hydroxyurea. 2

Secondary Erythrocytosis

• Treatment focuses on addressing the underlying condition: smoking cessation for smoker's polycythemia, CPAP for obstructive sleep apnea, management of chronic lung disease, and dose adjustment or discontinuation of testosterone if causative. 1

Phlebotomy Indications

• Therapeutic phlebotomy is indicated ONLY when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with associated symptoms of hyperviscosity, after excluding dehydration. 1, 4
• When performed, phlebotomy should be replaced with equal volume of dextrose or saline to prevent further hemoconcentration. 1
• Repeated routine phlebotomies are contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and stroke. 1, 4

Critical Pitfalls to Avoid

• Do not assume elevated hematocrit alone drives thrombotic risk—other cellular changes independent of hematocrit contribute significantly. 7
• Iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia with elevated RBC count but paradoxically reduced hemoglobin; mean corpuscular volume is unreliable for screening iron deficiency in this context. 1
• If iron deficiency is confirmed despite erythrocytosis, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur. 1, 4
• In patients with cyanotic congenital heart disease, erythrocytosis is a compensatory response to optimize oxygen transport; evaluate for intercurrent issues (dehydration, iron deficiency, infection) rather than performing phlebotomy. 1
• Avoid rapid increases in hematocrit (>8 percentage points per month) in patients on erythropoietin therapy. 1