Polycythemia Vera

Overview

Definition

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs (erythrocytosis), WBCs, and platelets. This triad differentiates PV from erythrocytosis seen with chronic hypoxia and other conditions.

Classification

• Primary PV is due to a myeloproliferative disorder.
• Secondary polycythemia is due to an increase in EPO caused by environmental circumstances or other conditions:
  • Lung disease/chronic hypoxia
  • Sleep apnea
  • Smoking
  • High altitude
  • EPO-secreting tumors, such as renal cell carcinoma

Epidemiology

• Affects an estimated 44–57 of 100,000 individuals in the US
• Incidence is slightly higher in men than women for unclear reasons
• Seen in all ages, but the incidence increases with age and peaks between 50 and 70 years
• Affects all ethnic groups

Etiology and Pathophysiology

Etiology

• Not fully understood
• Most patients have a mutation of the Janus kinase-2 gene (JAK2) on chromosome 9, which encodes for a protein essential for RBC production.

Pathophysiology

• The JAK2 gene is involved in signal transduction for EPO, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF).
• A JAK2 mutation, found in 98% of patients with PV, results in enhanced cytokine signaling that results in the increased production of all hematopoietic stem cells.
• Other mutations lead to sustained activation of JAK2 kinase, which causes excess blood cell production independent of EPO:
  • Calreticulin (CALR) mutations have been found in patients with PV without a JAK2 mutation.
  • Lymphocytic adaptor protein (LNK) mutations have been found in patients with isolated erythrocytosis.

Clinical Presentation

Polycythemia vera is often diagnosed incidentally when a CBC obtained for other reasons reveals increased hemoglobin and hematocrit. Patients also present with disease-related symptoms or complications.

• Neurologic:
  • Headache
  • Dizziness
  • Visual disturbances
  • Erythromelalgia, a burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis, in the presence of palpable pulses (29% of cases)
• Dermatologic and musculoskeletal:
  • Plethora (ruddy complexion)
  • Pruritus, especially after a hot bath or shower (36%)
  • Gouty tophi
• GI: 
  • Splenomegaly (36%)
  • Hepatomegaly
  • Epigastric pain
  • Peptic ulcer disease
• Cardiovascular: 
  • Hypertension (46%)
  • Venous thrombosis (7%)
  • Arterial thrombosis
  • Hemorrhagic symptoms such as petechiae, epistaxis, and bleeding gums
  • Angina pectoris
  • Stroke
  • Intermittent claudication
• Hematologic (due to platelet dysfunction):
  • Epistaxis
  • Ecchymosis
  • Gingival bleeding
  • Major hemorrhage (4%)

Diagnosis

Polycythemia vera is suspected in patients with characteristic physical findings and/or increased levels of hemoglobin and hematocrit on a CBC.

Rule out secondary causes of polycythemia (high EPO levels):

•  High altitude
•  Chronic hypoxia
•  Paraneoplastic syndrome (renal cell carcinoma)

Other laboratory findings for primary PV:

• CBC and chemistry:
  • Increased:
    • Hemoglobin and hematocrit
    • Leukocytes
    • Platelets
    • Uric acid and B12 (not needed for diagnosis)
    • LDH
  • Decreased:
    • MCV
    • Iron
    • EPO
• Peripheral smear: Findings depend on the stage at the time of diagnosis.
  • Erythrocytosis (excess RBCs)
  • Dacryocytes (teardrop-shaped RBCs)
  • Poikilocytosis (abnormally shaped RBCs)
  • Circulating nucleated RBCs
  • Hypochromia and microcytosis in the case of iron deficiency
  • Thrombocytosis
  • Leukocytosis in the absence of fever or infection
• Testing for JAK2, CALR, and LNK mutations (done sequentially)
• Bone marrow biopsy:
  • No bone marrow findings absolutely differentiate PV from other disorders of erythrocytosis.
  • Increased cellularity (versus fibrosis)
  • Typically shows panmyelosis
  • Large and clumped megakaryocytes
  • Occasional increase in reticulin fibers

Management and Prognosis

Management

• The therapeutic goal is to reduce the hematocrit to < 45%.
• Phlebotomy is the mainstay of therapy.
• Myelosuppressive therapies:
  • Hydroxyurea 
  • Ruxolitinib (JAK2 inhibitor)
  • Interferon
• Low-dose aspirin is used to reduce the symptoms of microvascular events.
• Allopurinol is used for hyperuricemia.
• Antihistamines are used to relieve the sensation of pruritus.
• In rare cases, stem cell transplantation can be performed.

Prognosis and complications

• Thrombosis is the most common cause of morbidity and death, followed by the complications of myelofibrosis and the development of leukemia.
• About 10%–30% of patients progress to a syndrome compatible with primary myelofibrosis but with better survival.
• The development of PV into acute leukemia occurs infrequently in about 1%–2% of patients and may take many years to develop.

Differential Diagnosis

• Secondary polycythemia: an increase in RBCs due to chronic hypoxemia, familial erythrocythemia, paraneoplastic syndromes, or relative polycythemia due to contraction of plasma volume as seen with dehydration.
• Essential thrombocytosis (primary thrombocythemia): a nonreactive, chronic myeloproliferative disorder in which excessive proliferation of megakaryocytes and platelets is seen. Patients are largely asymptomatic but may develop thrombosis and bleeding.
• Chronic myeloid leukemia: a myeloproliferative disorder characterized by an increase in WBCs, including an increased number of granulocytes and their immature precursors. Blast cells are also seen occasionally. 
• Primary myelofibrosis: a clonal disorder arising from the neoplastic transformation of early hematopoietic stem cells. Primary myelofibrosis is characterized by anemia, bone marrow fibrosis, extramedullary hematopoiesis, leukoerythroblastosis, teardrop-shaped RBCs, and hepatosplenomegaly.
• EPO receptor mutations: a rare familial disorder that can mimic the basic findings of PV (elevated hemoglobin and hematocrit with low serum EPO). A positive family history, early age at disease onset, and the lack of PV-associated clinical findings can help distinguish EPO receptor mutations from primary PV.