What is polycythemia?

What is Polycythemia?

Polycythemia is a condition characterized by an abnormally increased red blood cell mass, which can be either primary (polycythemia vera, a clonal stem cell disorder) or secondary (caused by physiologic or pathologic stimulation of red blood cell production). 1, 2

Primary Polycythemia: Polycythemia Vera (PV)

PV is a chronic myeloproliferative neoplasm—a clonal stem cell disease with trilineage myeloid involvement that results in excessive red blood cell production independent of normal regulatory mechanisms. 1

Key Disease Characteristics

• PV is characterized by increased red blood cell mass, with diagnostic criteria requiring hemoglobin >16.5 g/dL in men or >16.0 g/dL in women. 2, 3
• More than 95% of patients harbor a JAK2 gene mutation (JAK2V617F or exon 12 mutations), which distinguishes PV from secondary causes. 4, 2
• The disease affects approximately 65,000 people in the US with an annual incidence of 0.5 to 4.0 cases per 100,000 persons. 2
• Median age at diagnosis is approximately 60 years with a slight male preponderance (1.2:1). 1

Clinical Manifestations

• Patients commonly present with erythrocytosis (100%), thrombocytosis (53%), and leukocytosis (49%). 2
• Characteristic symptoms include aquagenic pruritus (33%), erythromelalgia (5.3%), transient visual changes (14%), and splenomegaly (36%). 4, 2
• The resultant hyperviscosity predisposes patients to thrombosis—arterial thrombosis occurs in 16% and venous thrombosis in 7% at or before diagnosis, including unusual sites like splanchnic veins. 5, 2
• Patients may also experience microvascular disturbances, plethora, and engorged veins. 1, 5

Diagnostic Approach

Begin with serum erythropoietin (EPO) measurement—a low EPO level has >90% specificity for PV, though normal levels do not exclude the diagnosis (sensitivity <70%). 4, 6

• Bone marrow examination should follow, looking for hypercellularity, increased megakaryocytes with cluster formation, giant megakaryocytes with pleomorphic morphology, and decreased iron stores. 1, 4
• JAK2 mutation testing confirms the diagnosis in >95% of cases and helps distinguish PV from secondary polycythemia. 4, 2
• In equivocal cases (≤10% of patients), specialized testing including decreased megakaryocyte c-mpl expression, PRV-1 expression, or spontaneous erythroid colony assays may be used. 1, 4

Prognosis and Complications

• Median survival ranges from 14.1 to 27.6 years from diagnosis, with patients aged ≤40 years having median survival of approximately 37 years. 2, 7
• Untreated patients may survive only 6 to 18 months, whereas adequate treatment extends life expectancy to more than 10 years. 5
• Life-threatening complications include thrombosis, transformation to myelofibrosis (12.7% of patients), and acute leukemia (6.8% of patients). 1, 2
• Leukemic transformation rates at 10 years are estimated at 3% for PV. 7

Secondary Polycythemia (SP)

Secondary polycythemia results from either physiologic compensation for tissue hypoxia or pathologic overproduction of erythropoietin, with serum EPO levels typically elevated or normal (unlike the low levels in PV). 1, 4

Common Causes

• Hypoxia-driven conditions include chronic lung disease (COPD), high altitude exposure, heavy smoking, and sleep apnea. 4, 2
• Pathologic EPO production occurs with renal cell carcinoma, hepatocellular carcinoma, renal artery stenosis, and ureteropelvic junction obstruction. 1, 4, 8
• Congenital causes include high oxygen-affinity hemoglobinopathy and 2,3-diphosphoglycerate mutase deficiency. 1, 4
• Drug-associated causes include EPO doping and androgen preparations (oral, transdermal, or intramuscular). 1, 4
• Post-renal transplant erythrocytosis (PRTE) is distinctly associated with increased thrombosis risk. 1

Diagnostic Differentiation

• High or normal serum EPO levels suggest secondary polycythemia and warrant evaluation for underlying causes. 1, 4
• Initial workup should include arterial hemoglobin-oxygen saturation, carboxyhemoglobin level (especially in smokers), and P50 measurement if family history suggests congenital causes. 1
• Imaging studies of kidney, liver, and central nervous system should be performed when initial studies are unrevealing or EPO remains persistently elevated. 1

Management Principles for Secondary Polycythemia

• Treatment depends on the underlying cause and must balance the physiological benefit of increased hematocrit against impaired oxygen delivery from hyperviscosity. 1
• In cyanotic congenital heart disease and high oxygen-affinity hemoglobinopathy, aggressive phlebotomy should be avoided due to stroke risk; judicious phlebotomy to hematocrit 60% is reasonable. 1
• In COPD, graded phlebotomy to hematocrit 55-60% may improve exercise tolerance and cardiac function. 1
• For PRTE, ACE inhibitors and angiotensin II receptor blockers effectively lower hematocrit levels and reduce thrombosis risk. 1