What is the definition of polycythemia?

Definition of Polycythemia

Polycythemia is defined as an abnormal increase in red blood cell concentration, characterized by hemoglobin and/or hematocrit levels exceeding the 95th percentile for normal distribution based on gender and age. 1

Core Classification

Polycythemia is categorized into three main types 2:

• True polycythemia: An actual increase in red cell mass, which can be either primary (polycythemia vera) or secondary (driven by elevated erythropoietin or other mechanisms) 2
• Apparent polycythemia: Normal red cell mass with decreased plasma volume due to dehydration, diarrhea, vomiting, diuretic use, burns, or capillary leak syndrome 2
• Relative polycythemia: Previously termed "stress polycythemia" or "Gaisböck syndrome," though these are poorly understood entities with little scientific foundation 2

Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a clonal myeloproliferative neoplasm characterized by autonomous overproduction of red blood cells, often accompanied by leukocytosis (49% of cases) and thrombocytosis. 3, 1

Key features include 3, 4:

• JAK2 V617F mutation present in >95% of cases, causing constitutive activation of erythropoietin receptor signaling 4
• Low or inappropriately normal serum erythropoietin levels (specificity >90%, sensitivity 64-70%) 1, 2
• Panmyeloid hyperplasia of bone marrow with prominent erythroid and megakaryocytic proliferation 3
• Erythropoietin-independent erythroid colony formation in vitro 4

The disease was first classified as a chronic myeloproliferative disorder by Dameshek in 1951, alongside chronic myeloid leukemia and agnogenic myeloid metaplasia, based on similarities in clinical and laboratory features 3.

Secondary Polycythemia

Secondary polycythemia results from either hypoxia-driven compensatory erythropoiesis or hypoxia-independent pathologic erythropoietin production. 2

Hypoxia-Driven Causes 2:

• Chronic lung disease (COPD, pulmonary fibrosis)
• Right-to-left cardiopulmonary shunts (cyanotic congenital heart disease)
• High-altitude habitation
• Hypoventilation syndromes including obstructive sleep apnea
• Smoker's polycythemia: Carbon monoxide binds hemoglobin with 200-250 times greater affinity than oxygen, creating functional hypoxia that triggers compensatory erythropoiesis and resolves with smoking cessation 2

Hypoxia-Independent Causes 2:

• EPO-producing tumors: Renal cell carcinoma, hepatocellular carcinoma, uterine leiomyomas, pheochromocytoma, meningioma, parathyroid carcinoma 2
• Congenital causes: Abnormal oxygen homeostasis (Chuvash polycythemia), high oxygen-affinity hemoglobinopathy, EPOR mutations 2
• Exogenous erythropoietin or androgen administration 2
• Post-renal transplant erythrocytosis 2

A critical diagnostic nuance: In chronic hypoxic states, serum EPO levels may be initially elevated but can normalize once hemoglobin stabilizes at a higher compensatory level, potentially causing diagnostic confusion. 2

Epidemiology

The incidence of polycythemia vera is approximately 2.3 per 100,000 population, making it more common than chronic myelogenous leukemia 3, 4. The disease shows 3:

• Median age at diagnosis: 60 years
• Slight male preponderance (1.2:1 ratio)
• Higher incidence in persons of Jewish ancestry
• Only 7% diagnosed before age 40 years

Clinical Significance

During the pre-phlebotomy era, thrombosis was the major cause of death with median life expectancy less than 2 years. 1 The disease can progress to myelofibrosis or acute leukemia as part of its natural history, first reported in 1935 and 1938 respectively 3. Modern management with therapeutic phlebotomy to maintain hematocrit <45% significantly reduces thrombosis risk 1.