What are the causes of elevated hemoglobin (Hb) and hematocrit (Hct) levels?

Causes of High Hemoglobin and Hematocrit

Elevated hemoglobin and hematocrit levels are primarily caused by either true polycythemia or relative polycythemia, each with specific underlying etiologies that must be identified for proper management and prevention of adverse outcomes related to hyperviscosity. 1, 2

Classification of Elevated Hemoglobin/Hematocrit

1. True Polycythemia

True polycythemia refers to an actual increase in red blood cell mass and can be divided into:

A. Primary Polycythemia (Polycythemia Vera)

• Clonal myeloproliferative disorder characterized by:
  • JAK2 mutation (present in >97% of cases) 1
  • Low serum erythropoietin levels (in most cases) 1
  • Characteristic bone marrow findings (hypercellularity, increased megakaryocytes) 1
  • May present with splenomegaly, pruritus, erythromelalgia, and thrombotic events 3

B. Secondary Polycythemia

Secondary polycythemia may be:

Hypoxia-driven:

• Cardiopulmonary disorders:
  • Chronic obstructive pulmonary disease
  • Congenital heart disease
  • Sleep apnea 1
• High altitude exposure: Causes predictable hemoglobin increases:
  • +0.2 g/dL at 1000m
  • +0.5 g/dL at 1500m
  • +0.8 g/dL at 2000m
  • +1.9 g/dL at 3000m
  • +3.5 g/dL at 4000m 2, 4
• Smoking: Carbon monoxide exposure leads to "smoker's polycythemia" that resolves with smoking cessation 1, 2

Hypoxia-independent:

• Tumor-related EPO production:
  • Renal cell carcinoma
  • Hepatocellular carcinoma
  • Uterine leiomyoma
  • Pheochromocytoma
  • Meningioma 2
• Medication-induced:
  • Testosterone/androgen therapy (43.8% risk of erythrocytosis with injectable testosterone) 1, 2
  • Erythropoietin therapy 2
• Genetic causes:
  • Chuvash polycythemia
  • Congenital polycythemia with activating EPOR mutations 1, 2

2. Relative Polycythemia (Apparent Polycythemia)

Relative polycythemia results from reduced plasma volume rather than increased red cell mass:

• Dehydration:
  • Severe dehydration
  • Diarrhea
  • Vomiting
  • Excessive diuretic use 1, 2
• Other causes:
  • Capillary leak syndrome
  • Severe burns 1
  • Gaisböck syndrome (controversial) - relative polycythemia associated with hypertension and nephropathy 1
  • Stress polycythemia (controversial) - relative polycythemia associated with emotional stress 1

Clinical Significance and Complications

Elevated hemoglobin/hematocrit levels can lead to:

• Increased thrombotic risk - both arterial and venous thromboses 5
• Hyperviscosity syndrome - headaches, dizziness, visual disturbances 2, 6
• Cardiovascular complications - particularly with hematocrit >54% 1, 2
• Impaired tissue oxygenation - paradoxically, extreme polycythemia can worsen tissue oxygenation due to increased blood viscosity 6

Diagnostic Approach

When elevated hemoglobin/hematocrit is detected:

1. Confirm true elevation: Repeat measurement and consider if values exceed sex- and race-adjusted normal values 1
2. Assess for dehydration: Most causes of relative polycythemia are clinically obvious 1
3. Check serum erythropoietin level: Low in PV, normal/high in secondary causes 1
4. JAK2 mutation testing: Positive in >97% of PV cases 1, 3
5. Evaluate for hypoxemia: Pulse oximetry, arterial blood gases if indicated
6. Review medication history: Particularly androgens/testosterone 1
7. Consider bone marrow examination: In equivocal cases to assess for PV 1

Management Considerations

Management depends on the underlying cause:

• Polycythemia vera: Phlebotomy to maintain hematocrit <45%, cytoreductive therapy in high-risk patients 5
• Testosterone-induced erythrocytosis: Intervention required if hematocrit exceeds 54% - options include temporarily withholding therapy, dose reduction, or therapeutic phlebotomy 1, 2
• Altitude-related polycythemia: Usually no treatment required; consider descent to lower altitude if symptoms develop 2
• Smoking-related polycythemia: Smoking cessation is the definitive treatment 1, 2
• Dehydration-related polycythemia: Fluid repletion 1

It's important to note that extreme elevations in hematocrit can lead to hyperviscosity and increased thrombotic risk, requiring prompt intervention regardless of the underlying cause.