Causes of Polycythemia
Polycythemia results from three major categories: apparent (relative) polycythemia due to plasma volume depletion, primary clonal disorders (polycythemia vera), or secondary polycythemia driven by either hypoxia-dependent or hypoxia-independent mechanisms. 1
Apparent (Relative) Polycythemia
This represents a false elevation in hematocrit without true increase in red cell mass:
Plasma volume depletion from severe dehydration, diarrhea, vomiting, diuretic use, capillary leak syndrome, or severe burns causes relative polycythemia that is clinically obvious and does not require specialized testing. 1
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
Primary Polycythemia (Polycythemia Vera)
This is a JAK2-mutated myeloproliferative neoplasm representing clonal stem cell disease:
Polycythemia vera (PV) is characterized by clonal erythrocytosis with low or inappropriately normal serum erythropoietin (EPO) levels, distinguishing it from secondary causes. 1
JAK2 V617F mutation is present in up to 97% of PV cases and should be tested when EPO is low or normal. 1, 2
PV is classified as a chronic myeloproliferative disorder along with essential thrombocythemia and myelofibrosis with myeloid metaplasia, representing clonal stem cell disorders. 3
The disease often presents with leukocytosis, thrombocytosis, and panmyeloid hyperplasia of the bone marrow, with risks of progression to myelofibrosis or acute leukemia. 3, 4
Secondary Polycythemia: Hypoxia-Driven Causes
These conditions trigger compensatory erythropoiesis through tissue hypoxia:
Chronic lung disease (COPD, pulmonary fibrosis) triggers compensatory erythropoiesis through tissue hypoxia. 1, 2
Right-to-left cardiopulmonary vascular shunts cause secondary polycythemia due to hypoxia. 1, 2
High-altitude habitation leads to physiologic polycythemia as an adaptive response to reduced atmospheric oxygen. 1, 5
Carbon monoxide poisoning and chronic exposure in smokers creates functional hypoxia by binding hemoglobin with 200-250 times greater affinity than oxygen. 1, 2
Hypoventilation syndromes including obstructive sleep apnea cause chronic intermittent hypoxia leading to compensatory erythrocytosis. 1, 6
Secondary Polycythemia: Hypoxia-Independent Causes
These conditions produce EPO independently of tissue oxygen status:
Renal cell carcinoma produces EPO independently of hypoxia and is a major cause of tumor-associated polycythemia. 1, 2
Hepatocellular carcinoma produces EPO independently of hypoxia. 1, 2
Cerebellar hemangioblastoma produces EPO independently of hypoxia. 1
Uterine leiomyomas (benign tumors) can produce EPO. 1
Pheochromocytoma can produce EPO. 1
Meningioma can produce EPO. 1
Post-renal transplant erythrocytosis (PRTE) is a potential cause of secondary polycythemia. 2
Exogenous administration of erythropoietic drugs (EPO, androgen preparations) can cause secondary polycythemia. 2
Congenital Causes
These are rare genetic disorders affecting oxygen sensing or hemoglobin function:
High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) can lead to secondary polycythemia. 2, 5
EPOR mutations (some cases of autosomal-dominant congenital polycythemia) can lead to secondary polycythemia. 2, 5
Abnormally elevated set point for EPO production and abnormal oxygen homeostasis (Chuvash polycythemia) represent congenital causes. 2, 5
2,3-bisphosphoglycerate mutase deficiency causes congenital polycythemia. 5
Von Hippel-Lindau gene mutations can cause disturbances of renal oxygen sensing leading to polycythemia. 5