Polycythemia vera

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm that is characterized by an erythropoietin-independent, irreversible increase in erythrocyte, granulocyte, and platelet counts. The elevated blood cell mass results in hyperviscosity, which is associated with slow blood flow and an increased risk of thrombosis. The disorder typically initially has a long asymptomatic period, then assumes a chronic, insidious course. Clinical features include facial flushing, pruritus, erythromelalgia, headaches, and dizziness. Severe complications such as thrombotic events (e.g., stroke, Budd-Chiari syndrome) may occur. Since PV is an incurable disorder, the primary goals of management involve controlling RBC mass and reducing the risk of thrombotic complications. Periodic phlebotomy reduces the amount of circulating cells and is therefore the treatment of choice.

• The JAK2 (Janus kinase 2) oncogene codes for a non-receptor tyrosine kinase in hematopoietic progenitor cells. JAK2 is essential for the regulation of erythropoiesis, thrombopoiesis (megakaryopoiesis), and granulopoiesis.
• 95% of primary PV patients have a mutation in the JAK2 gene (gain of function)→ ↑ tyrosine kinase activity → erythropoietin-independent proliferation of the myeloid cell lines → ↑ blood cell mass (erythrocytosis, thrombocytosis, and granulocytosis) → hyperviscosity + slow blood flow → ↑ risk of thrombosis and poor oxygenation.

References:^[1][2][3]

• Often asymptomatic (incidental finding on routine blood tests)
• Constitutional symptoms: weight loss, fatigue, sweating
• Hyperviscosity syndrome (triad of mucosal bleeding, neurological symptoms, and visual changes)
• Plethora
  • Facial flushing
  • Cyanotic lips
• Pruritus: Itching typically worsens when the skin comes into contact with warm water (aquagenic pruritus).
• Erythromelalgia ^[4]
• Nonspecific neurological symptoms : dizziness, headache, visual disturbances, tinnitus
• Hypertension
• Splenomegaly : associated with early satiety and abdominal discomfort; less commonly hepatomegaly
• Peptic ulcer disease
• Symptoms of thrombotic and hemorrhagic complications (see “Complications” below)

Patients with PV are at increased risk of thrombosis and bleeding.
References:^{[2][5][6][7][8][9]}

Laboratory findings

• ↑ Hb/Hct, ↑ RBCs
• ↑ Platelets (> 450,000/μL)
• ↑ Leukocytes (> 12,000/μL)
• ↑ Uric acid, ↑ LDH
• ↑ Leukocyte alkaline phosphatase
• ↓ Serum iron levels
• ↓ ESR
• ↓ EPO
• Arterial O₂ saturation: normal

Diagnostic criteria (WHO 2016) ^[10][11]

A diagnosis of polycythemia vera requires:

• All three major criteria
  OR
• The first two major criteria AND the minor criterion

References:^[2][12][13]

Secondary erythrocytosis

• Other causes may present with normal or even decreased endogenous EPO levels.
  • EPO doping
  • Androgen abuse

References:^[14]

The differential diagnoses listed here are not exhaustive.

• Phlebotomy: periodic removal of blood via venapuncture temporarily reduces cell counts and hyperviscosity.
  • 250–500 mL in intervals of 2–3 days until a HCT of ≤ 0.45 is established^[15]
• Antiplatelet prophylaxis: aspirin
• Cytoreductive therapy: determined on an individual basis; recommended if risk factors are present
  • Hydroxyurea
  • Interferon alpha
  • JAK2 inhibitor: ruxolitinib

If platelet count is > 1 million/μL, platelet function is very likely to be impaired, and the risk of bleeding is significantly increased. Aspirin should be discontinued!

References:^[15][16][17]

Polycythemia vera is a life-threatening disease because of the numerous complications associated with it.

Thrombotic complications

• Venous thrombosis
  • Renal vein thrombosis
  • Mesenteric venous thrombosis
  • Portal vein obstruction
  • Splenic vein thrombosis
  • Deep vein thrombosis
  • Pulmonary embolism
  • Budd-Chiari syndrome
• Arterial thrombosis
  • Stroke
  • Peripheral arterial emboli
  • Myocardial infarction (MI)

Hemorrhagic complications

• Petechiae
• Epistaxis
• Bleeding gums

Late stages

• Acute myeloid leukemia (AML), myelodysplastic syndrome (MDS): Additional genetic mutations may cause polycythemia vera to transition to other hematological diseases.
• Myelofibrosis: fibrotic transformation of the bone marrow

References:^{[2][5][11][17]}

We list the most important complications. The selection is not exhaustive.

1. Prchal JT. Molecular pathogenesis of congenital polycythemic disorders and polycythemia vera. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/molecular-pathogenesis-of-congenital-polycythemic-disorders-and-polycythemia-vera.Last updated: August 8, 2016. Accessed: April 14, 2017.
2. Nagalla S. Polycythemia Vera. Polycythemia Vera. New York, NY: WebMD. http://emedicine.medscape.com/article/205114-overview. Updated: December 2, 2016. Accessed: April 14, 2017.
3. Khattak SA, Ahmed S, Anwar J, Bozdar M. Frequency of Janus associated kinase 2 (V617F) mutation in patients of polycythemia vera.. J Coll Physicians Surg Pak. 2012; 22 (2): p.80-3.
4. Wollina U. Burning feet in polycythemia vera – peripheral sensorimotor axonal neuropathy with erythromelalgia. International Journal of General Medicine. 2015 : p.69. doi: 10.2147/ijgm.s78848 . | Open in Read by QxMD
5. Raedler LA. Diagnosis and Management of Polycythemia Vera: Proceedings from a Multidisciplinary Roundtable. Am Health Drug Benefits. 2014; 7 (7 Suppl 3): p.S36-47.
6. Jackson N, Burt D, Crocker J, Boughton B. Skin mast cells in polycythaemia vera relationship to the pathogenesis and treatment of pruritus. Br J Dermatol. 1987; 116 (1): p.21–29. doi: 10.1111/j.1365-2133.1987.tb05787.x . | Open in Read by QxMD
7. Saini KS, Patnaik MM, Tefferi A. Polycythemia vera-associated pruritus and its management. Eur J Clin Invest. 2010; 40 (9): p.828-834. doi: 10.1111/j.1365-2362.2010.02334.x . | Open in Read by QxMD
8. Saliba AN. Erythromelalgia. Erythromelalgia. New York, NY: WebMD. http://emedicine.medscape.com/article/200071-overview. Updated: November 17, 2016. Accessed: April 14, 2017.
9. Martin L. Cyanosis. In: Mosenifar Z, Cyanosis. New York, NY: WebMD. https://emedicine.medscape.com/article/303533-overview. Updated: December 11, 2015. Accessed: November 6, 2017.
10. Arber DA, Orazi A, Hasserjian R, et al. The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia. Blood. 2016; 127 (20): p.2391-2405. doi: 10.1182/blood-2016-03-643544 . | Open in Read by QxMD
11. Tefferi A. Clinical manifestations and diagnosis of polycythemia vera. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-polycythemia-vera.Last updated: November 3, 2016. Accessed: April 14, 2017.
12. Polycythemia Vera. https://www.msdmanuals.com/en-gb/professional/hematology-and-oncology/myeloproliferative-disorders/polycythemia-vera. Updated: December 1, 2016. Accessed: April 14, 2017.
13. Tefferi A, Vardiman JW. Classification and diagnosis of myeloproliferative neoplasms: the 2008 World Health Organization criteria and point-of-care diagnostic algorithms. Leukemia. 2007; 22 (1): p.14-22. doi: 10.1038/sj.leu.2404955 . | Open in Read by QxMD
14. Tefferi A. Diagnostic approach to the patient with polycythemia. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/diagnostic-approach-to-the-patient-with-polycythemia.Last updated: February 15, 2017. Accessed: April 14, 2017.
15. Marchioli R, Finazzi G, Specchia G, et al. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013; 368 (1): p.22-33. doi: 10.1056/NEJMoa1208500 . | Open in Read by QxMD
16. Le T, Bhushan V, Chen V, King M. First Aid for the USMLE Step 2 CK. McGraw-Hill Education ; 2015
17. Tefferi A. Prognosis and treatment of polycythemia vera. In: Post TW, ed. UpToDate. Waltham, MA: UpToDate. https://www.uptodate.com/contents/prognosis-and-treatment-of-polycythemia-vera.Last updated: July 11, 2016. Accessed: April 14, 2017.