Polycythemia Vera

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm characterized by the overproduction of RBCs. In addition, the WBC and platelet counts are also increased, which differentiate PV from erythrocytosis seen with chronic hypoxia and other chronic conditions. Polycythemia vera is presumed to have a genetic basis due to mutations in the Janus kinase-2 gene. The clinical presentation includes disease-related symptoms that can affect various organ systems. Sometimes, the disease can be an incidental finding during laboratory testing. Diagnosis is based on peripheral blood analysis and bone marrow biopsy findings. Management is with phlebotomy or drug therapy. The prognosis is generally good and patient survival is anticipated to improve further with the wide use of new therapies.

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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%)
Erythromelalgia

Erythromelalgia:
A sensation of burning pain in the feet or hands accompanied by erythema, pallor, or cyanosis, in the presence of palpable pulses

Image: “Erythromelalgia” by Herbert L. Fred, MD and Hendrik A. van Dijk. License: CC BY 2.0

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.

References

  1. Tefferi, A. (2019). Clinical manifestations and diagnosis of polycythemia vera. UpToDate. Retrieved April 9, 2021, from https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polycythemia-vera
  2. Liesveld, J. (2020). Polycythemia vera. Merck Manual Professional Version. Retrieved April 9, 2021, from https://www.merckmanuals.com/professional/hematology-and-oncology/myeloproliferative-disorders/polycythemia-vera
  3. Tefferi, A., et al. (2013). Survival and prognosis among 1545 patients with contemporary polycythemia vera: An international study. Leukemia. 27(9),1874–1881. https://pubmed.ncbi.nlm.nih.gov/23739289/
  4. Nagala, S. (2020). Polycythemia vera. Medscape. Retrieved April 9, 2021, from https://emedicine.medscape.com/article/205114-differential

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