Causes of Polycythemia
Polycythemia results from either primary clonal stem cell disorders (polycythemia vera) or secondary causes driven by increased erythropoietin production in response to hypoxia or inappropriate EPO secretion. 1
Primary Polycythemia
Polycythemia Vera (PV)
- PV is a clonal stem cell disorder where a single abnormal hematopoietic stem cell gains growth advantage, resulting in overproduction of red cells, granulocytes, and platelets 2
- More than 95% of PV cases harbor the JAK2 V617F mutation, which constitutively activates the JAK-STAT signaling pathway 3, 4
- A small subset of JAK2 V617F-negative PV patients have JAK2 exon 12 mutations or LNK mutations 4
- PV affects approximately 65,000 people in the US with an annual incidence of 0.5 to 4.0 cases per 100,000 persons, making it more common than chronic myelogenous leukemia 3, 5
- Leukocytosis occurs in 49% of PV cases and thrombocytosis in 53% 1, 3
Secondary Polycythemia
Hypoxia-Driven Causes
- Obstructive sleep apnea produces chronic intermittent hypoxia leading to compensatory erythrocytosis, particularly in obese patients 6, 7
- Chronic obstructive pulmonary disease (COPD) and other chronic lung diseases cause persistent hypoxemia 1
- High altitude exposure triggers physiologic EPO production in response to reduced oxygen tension 8
- Smoking causes carbon monoxide exposure that induces real polycythemia, which resolves with cessation 1
- Cyanotic congenital heart disease creates chronic tissue hypoxia 8
Inappropriate EPO Production
- Renal cell carcinoma and other EPO-secreting tumors (hepatocellular carcinoma, cerebellar hemangioblastoma, uterine leiomyoma) produce EPO autonomously 8
- Post-renal transplant erythrocytosis (PRTE) occurs from inappropriate EPO production 9
- Renal artery stenosis causes local renal hypoxia with increased EPO secretion 8
Congenital Polycythemias
- Mutations of the erythropoietin receptor gene cause EPO hypersensitivity 8
- Hemoglobin variants with increased oxygen affinity prevent normal oxygen delivery to tissues 8
- 2,3-bisphosphoglycerate mutase deficiency impairs oxygen release from hemoglobin 8
- Disturbances of renal oxygen sensing (VHL gene mutations, PHD2 mutations) lead to constitutive EPO production 8
Other Acquired Causes
- Post-splenectomy or functional hyposplenism can elevate red cell parameters 7
- Exogenous erythropoietin administration (doping in athletes) creates artificial erythrocytosis 8
- Testosterone and anabolic steroid use stimulates erythropoiesis 8
Critical Diagnostic Distinctions
Serum erythropoietin level is the key discriminator: suppressed (below normal) in PV versus elevated or high-normal in secondary polycythemia 1, 7
- JAK2 V617F mutation is present in >95% of PV cases but absent in secondary causes 7, 3
- Mild hemoglobin elevations (<18.5 g/dL in men) are more typical of secondary causes than PV, which usually presents with higher values 6, 7
- Hematocrit exceeding the 95th percentile for normal distribution meets criteria for suspected polycythemia 1
Common Pitfalls
- Do not assume "adequate sleep" rules out sleep apnea—patients with OSA are unaware of their sleep fragmentation and nocturnal hypoxemia 6, 7
- Do not rush to diagnose PV without excluding secondary causes, especially in obese patients with fatigue or smokers with lung disease 6, 7
- Spurious polycythemia (Gaisböck syndrome) presents with high hematocrit but normal red cell mass due to decreased plasma volume and must be excluded 2