What is polycythemia vera?

What is Polycythemia Vera?

Polycythemia vera (PV) is a clonal myeloproliferative neoplasm characterized by the overproduction of red blood cells, white blood cells, and platelets due to a JAK2 mutation (present in >95% of cases), leading to increased thrombosis risk, reduced life expectancy, and potential transformation to myelofibrosis or acute leukemia. 1, 2

Disease Pathophysiology

• PV is a clonal disorder involving a multipotent hematopoietic progenitor cell that produces phenotypically normal blood cells in the absence of a definable external cause 1
• The JAK2 V617F mutation (found in exon 14) drives constitutive STAT5-mediated signaling, resulting in erythropoietin-independent red blood cell production 1
• This autonomous proliferation occurs without the normal regulatory feedback mechanisms, leading to characteristic suppression of serum erythropoietin levels (typically <2.9 mU/mL) 3

Clinical Presentation and Complications

Thrombotic Risk

• Before the phlebotomy era, thrombosis was the major cause of death with median life expectancy less than 2 years; aggressive phlebotomy has improved median survival to ≥10 years 4
• Increased hematocrit enhances thrombosis through multiple mechanisms: increased whole blood viscosity at low shear rates, endothelial displacement of platelets and leukocytes, and platelet-mediated endothelial injury 4
• Patients experience shortened overall survival due to stroke, myocardial infarction, pulmonary embolism, and deep vein thrombosis 5

Constitutional Symptoms

• Patients commonly experience fatigue, pruritus (itching), bone pain, erythromelalgia (painful burning sensation of extremities with erythema), and splenomegaly 5
• Erythromelalgia occurs in approximately 3% of PV patients and results from platelet-mediated endothelial cell injury causing transient thrombotic occlusion 4

Disease Transformation

• In the first decade, transformation to myelofibrosis occurs in 10% and acute leukemia in 5%, with risk increasing progressively beyond the first decade 4
• Extramedullary hematopoiesis and marrow fibrosis can develop over time 1

Diagnostic Features

Laboratory Findings

• Hematocrit exceeding the 95th percentile for normal distribution meets criteria for suspected PV 6
• Low serum erythropoietin level has >90% specificity for PV (though sensitivity is only 70%) 6
• Elevated neutrophils (leukocytosis) occur in 49% of cases and strengthen diagnostic suspicion 6
• Reticulocyte count is typically low or inappropriately normal because bone marrow produces mature red cells directly rather than releasing reticulocytes 3

Bone Marrow Findings

• Bone marrow biopsy shows hypercellularity with increased megakaryocytes, cluster formation, giant megakaryocytes, pleomorphism, and decreased iron stores 3
• Panmyelosis with prominent erythroid and megakaryocytic proliferation is characteristic 7

Epidemiology

• PV has a minimum incidence of 2.6 per 100,000, making it more common than chronic myelogenous leukemia 1
• The disease is particularly prevalent in persons of Ashkenazi Jewish ancestry 1

Pathogenic Mechanisms Beyond Hematocrit

• Qualitative platelet defects include diminished response to prostaglandin D2, increased baseline thromboxane A2 production, and abnormal activation of leukocytes, endothelial cells, and platelets 4
• Widespread activation of coagulation proteins, reduced levels of anticoagulants (antithrombin III, proteins C and S), and decreased fibrinolytic activity create a baseline pro-thrombotic state 4
• The PIA2 allele of platelet glycoprotein IIIa is associated with increased arterial thrombosis risk in PV patients 4