What does it mean to have high hemoglobin (Hgb) and hematocrit (Hct) levels?

Understanding Elevated Hemoglobin and Hematocrit

High hemoglobin (Hgb) and hematocrit (Hct) levels indicate erythrocytosis—an abnormally elevated red blood cell mass that requires systematic evaluation to distinguish between primary causes (like polycythemia vera), secondary causes (such as chronic hypoxia or tumors), and relative polycythemia (from plasma volume depletion). 1

Defining Elevated Values

Erythrocytosis is confirmed 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 For context, normal adult male/post-menopausal female values are hemoglobin 15.5 ± 2.0 g/dL and hematocrit 47 ± 6%, while menstruating females typically have hemoglobin 14.0 ± 2.0 g/dL and hematocrit 41 ± 5%. 2

Primary Causes: Polycythemia Vera

• Polycythemia vera (PV) results from constitutive activation of the JAK-STAT signaling pathway, causing erythropoietin-independent red cell overproduction. 1
• The JAK2 mutation is present in up to 97% of PV cases and should be tested immediately when erythrocytosis is confirmed. 1
• PV diagnosis requires both major criteria (elevated hemoglobin/hematocrit AND JAK2 mutation) plus one minor criterion, OR the first major criterion plus two minor criteria. 1
• Minor criteria include bone marrow hypercellularity with trilineage growth, subnormal serum erythropoietin level, and endogenous erythroid colony formation. 1

Secondary Causes: Hypoxia-Driven

• Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea produce nocturnal hypoxemia that stimulates erythropoietin production, driving compensatory erythrocytosis. 1
• Smoking causes "smoker's polycythemia" through chronic carbon monoxide exposure, which creates tissue hypoxia and stimulates erythropoietin production; this resolves with smoking cessation. 1
• Cyanotic congenital heart disease with right-to-left shunting results in arterial hypoxemia, triggering compensatory erythrocytosis to optimize oxygen transport. 1
• High-altitude residence physiologically increases hemoglobin by 0.2-4.5 g/dL depending on elevation (1000-4500 meters), and diagnostic thresholds must be adjusted accordingly. 1

Secondary Causes: Hypoxia-Independent

• Certain malignancies produce erythropoietin independently, including renal cell carcinoma, hepatocellular carcinoma, pheochromocytoma, uterine leiomyoma, and meningioma. 1
• Testosterone therapy (prescribed or unprescribed) commonly causes erythrocytosis and should be considered in the differential diagnosis, particularly in young adults. 1
• Erythropoietin therapy itself can cause elevated hemoglobin levels and is expected to increase hemoglobin by 0.3 g/dL per week (hematocrit rise of 1% per week). 1

Relative Polycythemia

• Dehydration, diuretic use, burns, and stress polycythemia (Gaisböck syndrome) cause relative polycythemia through plasma volume depletion rather than true red cell mass increase. 1
• Hydration status must be assessed before initiating any workup or treatment, as rehydration with oral or intravenous normal saline may normalize values. 1

Diagnostic Algorithm

When erythrocytosis is identified, order the following tests immediately: 1

• Complete blood count with red cell indices, reticulocyte count, and peripheral blood smear review 1
• Serum ferritin and transferrin saturation to evaluate iron status 1
• C-reactive protein (CRP) to assess for inflammation 1
• JAK2 mutation testing (both exon 14 and exon 12) 1

If JAK2 mutation is absent, systematically evaluate secondary causes: 1

• Sleep study if nocturnal hypoxemia is suspected 1
• Pulmonary function tests and chest imaging for COPD 1
• Renal imaging (ultrasound or CT) to exclude renal cell carcinoma, hydronephrosis, or cystic disease 1
• Medication review, particularly for testosterone use 1
• Serum erythropoietin level measurement (low or normal suggests primary cause; elevated suggests secondary cause) 1

Critical Management Principles

For confirmed polycythemia vera, maintain hematocrit strictly below 45% through therapeutic phlebotomy to reduce thrombotic risk, as demonstrated by the CYTO-PV trial showing significantly reduced thrombotic events (2.7% vs 9.8%, P=0.007). 1 Low-dose aspirin (81-100 mg daily) is the second cornerstone of therapy for thrombosis prevention. 1

For secondary erythrocytosis, treatment of the underlying condition is necessary: 1

• Smoking cessation for smoker's polycythemia 1
• CPAP therapy for obstructive sleep apnea 1
• Management of COPD or other pulmonary disease 1
• Dose adjustment or discontinuation of testosterone if causative 1

Therapeutic phlebotomy in secondary erythrocytosis is indicated ONLY when hemoglobin exceeds 20 g/dL and hematocrit exceeds 65% with documented symptoms of hyperviscosity, after excluding dehydration. 1 Repeated routine phlebotomies are explicitly contraindicated due to risk of iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk. 1

Common Pitfalls to Avoid

• Never perform aggressive phlebotomy without adequate volume replacement, as this increases hemoconcentration and stroke risk. 1
• Do not use standard PV diagnostic thresholds at high altitude without adjustment, as physiologic adaptation can increase hemoglobin by 0.2-4.5 g/dL depending on elevation. 1
• Iron deficiency can coexist with erythrocytosis, causing microcytic polycythemia with elevated RBC count but reduced hemoglobin; serum ferritin, transferrin saturation, and iron levels are required for accurate diagnosis. 1
• If iron deficiency is confirmed in the context of erythrocytosis, cautious oral iron supplementation with close hemoglobin monitoring is necessary, as rapid increases in red cell mass can occur. 1
• Hemoglobin is more accurate than hematocrit for monitoring because hematocrit can falsely increase by 2-4% with prolonged sample storage, while hemoglobin remains stable. 2 Additionally, hyperglycemia falsely elevates mean corpuscular volume (MCV) and calculated hematocrit but does not affect hemoglobin measurement. 2

When to Refer to Hematology

Immediate hematology referral is indicated if: 1

• JAK2 mutation is positive 1
• Hemoglobin exceeds 20 g/dL with symptoms of hyperviscosity 1
• Unexplained splenomegaly is present 1
• Diagnosis remains unclear after initial workup 1