Causes of Erythrocytosis
Erythrocytosis results from either primary bone marrow disorders (most commonly polycythemia vera with JAK2 mutations in 95% of cases), secondary causes driven by hypoxia or erythropoietin overproduction, congenital/hereditary defects in oxygen-sensing pathways or hemoglobin variants, or relative polycythemia from plasma volume contraction 1, 2.
Primary Causes
Acquired
- Polycythemia Vera (PV): The most frequent primary acquired cause, characterized by clonal myeloproliferation with JAK2V617F mutation in ~95% of cases and JAK2 exon 12 mutations in most remaining cases 1, 3. This is a myeloproliferative neoplasm requiring specific diagnostic criteria and carries thrombotic risk.
Congenital
- Other myeloproliferative neoplasms (primary myelofibrosis, essential thrombocythemia) with JAK2 mutations at ~50% frequency 1
Secondary Causes
Acquired Secondary Erythrocytosis
Hypoxia-driven (most common secondary cause):
- Chronic lung disease (COPD, pulmonary fibrosis)
- Chronic heart disease with right-to-left shunting
- Sleep apnea
- Smoking/nicotine abuse 3
- High altitude residence
- Central hypoxia from cardiopulmonary disease or peripheral hypoxia from renal artery stenosis 2
Erythropoietin overproduction:
- Renal cell carcinoma (EPO-secreting tumor) 2
- Other EPO-producing tumors (hepatocellular carcinoma, hemangioblastoma, uterine fibroids)
- Renal diseases (polycystic kidney disease, post-renal transplant)
Drug-induced:
- Testosterone therapy (increasingly recognized in gender-affirming care, affecting 9.5% of adolescents, typically in second year of treatment) 2, 4
- SGLT2 inhibitors (sodium-glucose co-transporter-2 inhibitors) - increasingly recognized cause 2
- Erythropoiesis-stimulating agents (ESAs)
- Anabolic steroids/androgens 5
- EPO doping 3
Congenital Secondary Erythrocytosis (Hereditary/Familial Erythrocytosis)
Oxygen-sensing pathway defects (elevated EPO):
- VHL gene mutations (von Hippel-Lindau, familial erythrocytosis type 2) 6
- EGLN1/PHD2 mutations (familial erythrocytosis type 3) 6
- EPAS1/HIF2A mutations (familial erythrocytosis type 4) 6
- EPO gene mutations (familial erythrocytosis type 5, producing hyperactive hepatic-like EPO) 2, 6
Erythropoietin receptor hypersensitivity (low/normal EPO):
Increased oxygen affinity hemoglobins (elevated EPO):
- HBB, HBA1, HBA2 mutations (familial erythrocytosis types 6-7) 6
- High oxygen-affinity hemoglobin variants 2, 7
Other congenital causes:
- BPGM mutations (2,3-bisphosphoglycerate deficiency, familial erythrocytosis type 8) 2, 6
- PIEZO1 mutations 2
- Methemoglobinemia 2
Apparent/Relative Polycythemia
- Plasma volume contraction (dehydration, diuretic use, burns, capillary leak) - not true erythrocytosis 2, 5
- Physiological outliers - individuals at extreme of normal distribution 2
Idiopathic Erythrocytosis
- Diagnosis of exclusion when increased hemoglobin/hematocrit has no identifiable etiology after comprehensive workup 2, 7
- Represents >70% of cases in some series where genetic causes remain unidentified 6
- Advances in next-generation sequencing panels are expected to reclassify many of these cases 2
Key Diagnostic Pitfall
The critical first step is excluding PV through JAK2 mutation screening (exons 12-15) 2. Missing PV has significant implications for thrombotic risk and management. After excluding PV, serum erythropoietin levels guide the diagnostic pathway: low EPO suggests primary causes (PV, EPOR mutations), while normal/high EPO points toward secondary causes including hypoxia, tumors, or oxygen-sensing pathway defects 2, 7, 8.