Causes of Polycythemia
Classification Framework
Polycythemia is categorized into three distinct types: apparent (relative) polycythemia from plasma volume depletion, primary polycythemia from clonal hematopoietic disorders, and secondary polycythemia driven by either hypoxia-dependent or hypoxia-independent mechanisms. 1, 2
Apparent (Relative) Polycythemia
This represents false elevation without true increase in red cell mass:
Plasma volume depletion from severe dehydration, diarrhea, vomiting, diuretic use, capillary leak syndrome, or severe burns causes hemoconcentration that is clinically obvious 1, 2
Smoker's polycythemia is a real condition caused by chronic carbon monoxide exposure, which binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia; this resolves with smoking cessation 1, 2, 3
Primary Polycythemia
These are clonal disorders with autonomous red cell production:
Polycythemia vera (PV) is a JAK2-mutated myeloproliferative neoplasm characterized by low or inappropriately normal serum EPO levels, with JAK2 V617F mutation present in up to 97% of cases 1, 2
Familial polycythemia is an autosomal-dominant condition with activating mutations of the EPO receptor (EPOR), causing truncated receptors lacking negative regulatory domains 2, 4
Primary familial and congenital polycythemias result from inborn mutations affecting hematopoietic and erythroid cells, with molecular mechanisms varying between families 5, 6
Secondary Polycythemia: Hypoxia-Driven Causes
These represent physiologic compensation for tissue hypoxia:
Chronic lung disease (COPD, pulmonary fibrosis) triggers compensatory erythropoiesis through tissue hypoxia 1, 2, 3
Right-to-left cardiopulmonary vascular shunts and cyanotic congenital heart disease cause hypoxemia with compensatory erythrocytosis 1, 2, 3
High-altitude habitation leads to physiologic polycythemia as an adaptive response to reduced atmospheric oxygen 1, 2, 3
Hypoventilation syndromes including obstructive sleep apnea cause chronic intermittent hypoxia leading to compensatory erythrocytosis 1, 2, 3
High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) causes functional tissue hypoxia despite normal oxygen saturation 3, 4
2,3-bisphosphoglycerate (BPG) mutase deficiency results in impaired oxygen release to tissues 1, 4, 7
Methemoglobinemia causes functional hypoxia 4
Secondary Polycythemia: Hypoxia-Independent Causes
These produce EPO autonomously without hypoxic stimulus:
Malignant Tumors
- Renal cell carcinoma produces EPO independently of hypoxia 1, 2, 3
- Hepatocellular carcinoma produces EPO independently of hypoxia 1, 2, 3
- Parathyroid carcinoma produces EPO autonomously 3
Benign Tumors
- Cerebellar hemangioblastoma produces EPO independently of hypoxia 1, 2, 3
- Uterine leiomyomas can produce EPO 1, 3
- Pheochromocytoma can produce EPO 1, 3
- Meningioma can produce EPO 1, 3
Congenital Disorders of Oxygen Sensing
- Chuvash polycythemia results from homozygous germline mutations in the von Hippel-Lindau (VHL) gene, causing increased hypoxia-inducible factor-1 (HIF-1) expression in normoxic conditions with inappropriately elevated EPO levels 3, 6, 4
Other Causes
- Post-renal transplant erythrocytosis (PRTE) 3, 6
- Exogenous administration of erythropoietic drugs (EPO, androgen preparations, testosterone) 3
Key Diagnostic Discriminators
Serum EPO level is the critical discriminator between primary and secondary polycythemia:
Low or inappropriately normal EPO (present in 64-94% of PV cases) strongly suggests polycythemia vera with >90% specificity 1, 2, 3
Elevated EPO suggests secondary polycythemia, though EPO may normalize after hemoglobin stabilizes at a compensatory higher level in chronic hypoxic states 1, 3
Critical Pitfalls to Avoid
Do not assume normal EPO excludes PV - EPO sensitivity for PV is only 64-70%; normal EPO with elevated hemoglobin still requires JAK2 testing 3
Do not overlook smoking as a cause - smoker's polycythemia is real and resolves with cessation, with risk reduction beginning within 1 year 1, 2, 3
Do not misinterpret normal EPO in chronic hypoxic states - levels may normalize after hemoglobin stabilizes at a higher compensatory level, potentially mimicking polycythemia vera 1, 3
Do not perform aggressive routine phlebotomies in secondary polycythemia - this risks iron depletion, decreased oxygen-carrying capacity, and paradoxically increased stroke risk 3