What causes secondary polycythemia?

Secondary Polycythemia Causes

Secondary polycythemia is caused by either hypoxia-driven or hypoxia-independent processes that lead to a true increase in red blood cell mass, distinct from relative polycythemia which results from plasma volume depletion. 1

Hypoxia-Driven Causes

• Chronic lung disease - conditions that impair oxygen exchange in the lungs lead to compensatory erythropoiesis 1
• Right-to-left cardiopulmonary shunts - allowing deoxygenated blood to bypass the lungs 1
• High-altitude habitation - lower atmospheric oxygen pressure triggers increased red cell production 1
• Hypoventilation syndromes including sleep apnea - intermittent hypoxia during sleep stimulates erythropoietin production 1
• Smoking - carbon monoxide from cigarette smoke binds to hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia and triggering compensatory erythropoiesis 1, 2

Hypoxia-Independent Causes

• Malignant tumors - particularly renal cell carcinoma and hepatocellular carcinoma that secrete erythropoietin 1, 3
• Benign tumors - including uterine leiomyomas, pheochromocytoma, and meningioma can produce erythropoietin 1
• Congenital causes:
  • Abnormally elevated set point for EPO production 1
  • Abnormal oxygen homeostasis (Chuvash polycythemia) 1
  • EPOR-mediated causes (some cases of autosomal-dominant congenital polycythemia) 1
  • High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) 1, 4
  • Mutations of the Erythropoietin-receptor gene 4
  • 2,3-bisphosphoglycerate mutase deficiency 4
• Exogenous administration of erythropoietic drugs (EPO, androgen preparations) 1
• Post-renal transplant erythrocytosis (PRTE) 1

Distinguishing Secondary Polycythemia from Other Types

• Secondary polycythemia must be differentiated from:
  • Relative polycythemia - normal red cell mass with decreased plasma volume due to dehydration, diarrhea, vomiting, diuretic use, or burns 5, 1
  • Polycythemia vera - a myeloproliferative neoplasm characterized by JAK2 gene variant (present in >95% of cases) 6

Diagnostic Approach

• Determine if polycythemia is true (increased red cell mass) or apparent (normal red cell mass with decreased plasma volume) 1
• Assess for clinical signs of plasma volume depletion 1
• Evaluate for hypoxemia through arterial blood gas analysis or pulse oximetry 1
• Check serum EPO levels - typically elevated in secondary polycythemia but may normalize once hemoglobin stabilizes at a higher level 1, 7
• Consider JAK2 mutation analysis to rule out polycythemia vera 4, 6, 8
• Perform hemoglobin electrophoresis if high oxygen-affinity hemoglobinopathy is suspected 4
• Consider sleep study for suspected sleep apnea 1
• Imaging studies may be needed to identify potential tumors causing erythropoietin production 3, 7

Clinical Pearls and Pitfalls

• Smoker's polycythemia is a real condition that resolves with smoking cessation, with risk reduction beginning within 1 year 1, 2
• Serum EPO levels may be normal in chronic hypoxic states after hemoglobin stabilizes at a higher level 1
• Unnecessary red cell mass measurements can be avoided when the cause of polycythemia is clinically obvious 5, 1
• Secondary polycythemia due to erythropoietin-secreting tumors (like renal cell carcinoma) may resolve after tumor removal 3
• Secondary polycythemia increases blood viscosity, which can lead to thrombotic events such as ischemic stroke 2, 3