What are the classifications of polycythemia?

Classification of Polycythemia

Primary Classification Framework

Polycythemia is classified into three major categories: apparent (relative) polycythemia, primary polycythemia (polycythemia vera), and secondary polycythemia, which is further subdivided into hypoxia-driven and hypoxia-independent causes. 1, 2

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Apparent (Relative) Polycythemia

This represents a spurious elevation in hemoglobin/hematocrit without true increase in red blood cell mass, caused by plasma volume depletion. 1, 2

Common Causes:

• Severe dehydration, diarrhea, vomiting, diuretic use, capillary leak syndrome, and severe burns are clinically obvious causes that do not require specialized testing such as red cell mass measurements 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 2, 3, 4

Key Diagnostic Point:

• Gaisböck syndrome (relative polycythemia associated with hypertension) and stress polycythemia have little foundation, and in a series of 109 consecutive red cell mass measurements, no patients with relative polycythemia were identified 1

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Primary Polycythemia (Polycythemia Vera)

Polycythemia vera is a JAK2-mutated myeloproliferative neoplasm characterized by clonal erythrocytosis with low or inappropriately normal serum erythropoietin (EPO) levels. 2, 5

Diagnostic Features:

• JAK2V617F mutation is present in approximately 95-97% of PV cases 1, 2, 6, 7
• Exon 12 JAK2 mutations account for most remaining cases 1
• Bone marrow examination showing panmyelosis with prominent erythroid and megakaryocytic proliferation remains the cornerstone for confirming diagnosis 1, 2
• Serum EPO levels are characteristically low or inappropriately normal 1, 2

Additional Genetic Considerations:

• Familial polycythemia is an autosomal-dominant condition with activating mutations of the EPO receptor (EPOR) 2

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Secondary Polycythemia: Hypoxia-Driven

This category includes conditions where tissue hypoxia triggers compensatory erythropoiesis through elevated EPO production. 1, 2

Major Causes:

Pulmonary Causes:

• Chronic lung disease (COPD, pulmonary fibrosis) triggers compensatory erythropoiesis through tissue hypoxia 2, 4
• Hypoventilation syndromes, including obstructive sleep apnea, cause chronic intermittent hypoxia leading to compensatory erythrocytosis 2, 4

Cardiovascular Causes:

• Right-to-left cardiopulmonary shunts cause secondary polycythemia due to hypoxia 2, 4

Environmental Causes:

• High-altitude habitation leads to physiologic polycythemia as an adaptive response to reduced atmospheric oxygen 2, 4

Hemoglobin Abnormalities:

• High oxygen-affinity hemoglobinopathy (congenital, autosomal-dominant) prevents adequate oxygen release to tissues 3, 4

Diagnostic Consideration:

• Serum EPO levels may be initially elevated but can return to normal range once hemoglobin stabilizes at a higher level, which can lead to misinterpretation 3, 4

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Secondary Polycythemia: Hypoxia-Independent

This category includes conditions where EPO is produced independently of tissue hypoxia, typically by tumors or through congenital mechanisms. 1, 2

Malignant Tumors:

• Renal cell carcinoma produces EPO independently of hypoxia 2, 3, 4
• Hepatocellular carcinoma produces EPO independently of hypoxia 2, 3, 4
• Cerebellar hemangioblastoma produces EPO independently of hypoxia 2, 3, 4

Benign Tumors:

• Uterine leiomyomas, pheochromocytoma, and meningioma can produce EPO 3, 4

Congenital Causes:

• Abnormally elevated set point for EPO production and abnormal oxygen homeostasis (Chuvash polycythemia) 3
• EPOR-mediated causes in some cases of autosomal-dominant congenital polycythemia 3

Iatrogenic Causes:

• Exogenous administration of erythropoietic drugs (EPO, androgen preparations) 3
• Post-renal transplant erythrocytosis (PRTE) 3

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Diagnostic Algorithm

Step 1: Distinguish Apparent from True Polycythemia

• Assess for clinically obvious plasma volume depletion (dehydration, diarrhea, vomiting, diuretic use, burns) and verify hemoglobin/hematocrit values are truly elevated beyond sex- and race-adjusted normal values 1, 2, 4
• Familiarity with sex- and race-adjusted normal values prevents unnecessary testing, including red cell mass measurements 1

Step 2: Measure Serum EPO Level

• Serum EPO is the key discriminator: low or inappropriately normal EPO suggests polycythemia vera, while elevated EPO suggests secondary polycythemia 2, 4

Step 3: If EPO is Low or Normal

• Test for JAK2V617F mutation, which is present in up to 97% of PV cases 1, 2, 4
• Consider bone marrow examination to confirm PV diagnosis with characteristic morphologic features 2, 4

Step 4: If EPO is Elevated

• Evaluate for hypoxia using arterial blood gas analysis or pulse oximetry 3, 4
• Perform chest X-ray to evaluate for chronic lung disease 3, 4
• If hypoxia is present, consider pulmonary, cardiovascular, or environmental causes 4

Step 5: If EPO Elevated Without Hypoxia

• Perform abdominal ultrasound or CT to screen for renal cell carcinoma, hepatocellular carcinoma, or other EPO-producing tumors 3, 4
• Consider congenital causes in young patients, including hemoglobin electrophoresis for high oxygen-affinity hemoglobinopathy and genetic testing for EPOR mutations 4

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Critical Pitfalls to Avoid

• Failing to distinguish relative from true polycythemia leads to unnecessary workup and misdiagnosis 2, 4
• Overlooking smoking as a cause—smoker's polycythemia resolves with cessation, with risk reduction beginning within 1 year 2, 4
• Misinterpreting normal EPO levels in chronic hypoxic states where levels may have normalized after compensatory hemoglobin elevation 2, 3, 4
• Performing unnecessary red cell mass measurements when clinical context is obvious (e.g., severe dehydration or hematocrit >60% without hemoconcentration) 1, 2, 4