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).
• 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][4][5][6][7][8]}

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) ^[9][10]

A diagnosis of polycythemia vera requires:

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

Major criteria
Evidence of increased RBCs ↑ Hemoglobin (♂: Hb > 16.5 g/dL / ♀: Hb > 16 g/dL) OR ↑ Hematocrit (♂: Hct > 49% / ♀: Hct > 48%) OR ↑ Red cell mass Bone marrow biopsy showing hypercellularity with trilineage growth (increased erythropoiesis, granulopoiesis, and megakaryopoiesis) Evidence of a genetic mutation in the JAK2 gene
Minor criterion
↓ EPO levels

References:^[2][11][12]

Secondary erythrocytosis

		EPO	Expected plasma volume	RBC mass	Oxygen saturation	Underlying conditions
Relative polycythemia		↔︎	↓	↔︎ / ↑	↔︎	Severe dehydration Stress erythrocytosis
Absolute polycythemia
Appropriate absolute polycythemia		↑	↔︎	↑	↓	High-altitude exposure Hypoxia: chronic pulmonary and cardiac disease
Inappropriate absolute polycythemia		↑↑	↔︎	↑	↔︎	Paraneoplastic syndrome, especially with: Renal cell carcinoma (RCC) Hepatocellular carcinoma (HCC) Polycystic kidney disease (PKD)

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

References:^[13]

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^[14]
• 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][14]

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.
• Primary myelofibrosis: fibrotic transformation of the bone marrow

References:^{[2][4][10][16]}

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