What is polycythemia vera?

What is Polycythemia Vera

Polycythemia vera (PV) is a clonal stem cell disease characterized by uncontrolled overproduction of red blood cells, driven in more than 95% of cases by the acquired JAK2V617F mutation, and classified as a chronic myeloproliferative disorder. 1, 2

Disease Classification and Pathophysiology

PV belongs to the chronic myeloproliferative disorders (CMPDs), a category that includes essential thrombocythemia and myelofibrosis with myeloid metaplasia, distinguished from chronic myeloid leukemia by the absence of the Philadelphia chromosome. 1

Clonal Nature and Molecular Basis

• PV originates from a clonal hematopoietic stem cell disorder with trilineage myeloid involvement (red cells, white cells, and platelets), though normal stem cells coexist alongside the malignant clone. 1
• The JAK2V617F mutation is present in >95% of PV patients, serving as the principal driver that constitutively activates the JAK-STAT signaling pathway. 2, 3
• JAK2 exon 12 mutations account for 2-4% of cases in patients who test negative for JAK2V617F, producing functionally equivalent pathway activation. 2
• The mutation is acquired (somatic), not inherited, occurring during a person's lifetime in bone marrow cells rather than being passed from parent to child. 3

Clinical Features and Diagnosis

Defining Characteristic

The clinical distinction of PV from other myeloproliferative disorders is made by demonstrating clonal erythrocytosis (increased red blood cell mass), which differentiates it from essential thrombocythemia (clonal thrombocytosis without erythrocytosis) and myelofibrosis (substantial bone marrow fibrosis). 1

Bone Marrow Findings

• Bone marrow shows hypercellularity with atypical megakaryocytic hyperplasia and clustering. 1
• JAK2 exon 12-mutated PV typically displays isolated erythroid hyperplasia without the panmyelosis (megakaryocytic and granulocytic proliferation) seen in JAK2V617F-positive disease. 2

Associated Features

• Variable splenomegaly, leukocytosis, and thrombocytosis may occur, though these are not required for diagnosis. 1
• Clonal cytogenetic abnormalities are infrequent (13-18% in treatment-naïve patients) and nonspecific, including trisomies of chromosomes 9 and 8. 1

Epidemiology

• The incidence is approximately 2.3 per 100,000 population with stable trends over time. 1
• Median age at diagnosis is 60 years with a slight male predominance (1.2:1). 1
• Only 7% of patients are diagnosed before age 40, and pediatric cases are rare. 1, 3
• Higher incidence occurs in persons of Jewish ancestry and among parent-offspring pairs, suggesting genetic predisposition to acquiring the JAK2 mutation rather than direct inheritance. 1, 3

Natural History and Complications

Disease Course

PV is a relatively indolent neoplasm with median survival exceeding 35 years in young patients, but the natural history can be interrupted by serious complications. 4

Major Complications

• Thrombotic events occur at a 20-year rate of 26%, including stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis. 4, 5
• Progression to myelofibrosis occurs in 16% at 20 years. 4
• Leukemic transformation occurs in 4% at 20 years. 4

Microvascular and Hemorrhagic Issues

• Platelet-mediated microvascular disturbances include erythromelalgia (painful burning in extremities), headaches, and visual disturbances. 1
• Acquired von Willebrand disease occurs in more than one-third of patients, associated with extreme thrombocytosis and bleeding diathesis, though this is less common in JAK2 exon 12-mutated PV. 1, 2

Diagnostic Approach

Working diagnosis is made based on the constellation of clinical and bone marrow histological findings, as there is no single specific disease marker. 1

Key Diagnostic Steps

• Initial testing should target JAK2V617F using whole-blood or granulocyte DNA, as this is the most common mutation. 2
• If JAK2V617F is negative but clinical suspicion remains high (elevated hemoglobin/hematocrit, low serum erythropoietin, splenomegaly), order JAK2 exon 12 mutation analysis on purified granulocyte DNA to improve sensitivity for low-burden mutations. 2
• Bone marrow histology should be performed to assess for characteristic hypercellularity and megakaryocytic changes. 2

Diagnostic Pitfalls

• Co-existing iron deficiency can mask polycythemia by lowering hemoglobin below diagnostic thresholds while red cell mass remains elevated; look for elevated red cell count with microcytosis. 2
• Apparent polycythemia may result from plasma volume depletion (dehydration, diuretics, severe burns) rather than true increase in red cell mass. 1