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.
- 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
- High altitude
- EPO-secreting tumors, such as renal cell carcinoma
- 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
- 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.
- 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.
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.
- 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
- Splenomegaly (36%)
- Epigastric pain
- Peptic ulcer disease
- Hypertension (46%)
- Venous thrombosis (7%)
- Arterial thrombosis
- Hemorrhagic symptoms such as petechiae, epistaxis, and bleeding gums
- Angina pectoris
- Intermittent claudication
- Hematologic (due to platelet dysfunction):
- Gingival bleeding
- Major hemorrhage (4%)
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:
- Hemoglobin and hematocrit
- Uric acid and B12 (not needed for diagnosis)
- 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
- 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
- The therapeutic goal is to reduce the hematocrit to < 45%.
- Phlebotomy is the mainstay of therapy.
- Myelosuppressive therapies:
- Ruxolitinib (JAK2 inhibitor)
- 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.
- 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.
- 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
- 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
- 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/
- Nagala, S. (2020). Polycythemia vera. Medscape. Retrieved April 9, 2021, from https://emedicine.medscape.com/article/205114-differential