About the Condition

Description/definition:

The terms erythrocytosis and polycythemia are often used interchangeably to describe an elevated hematocrit.

Classification of polycythemia:

• Absolute vs. apparent:
  • Absolute – elevated red cell mass
  • Apparent (relative):
    • Contracted plasma volume: 
      • Vomiting
      • Diarrhea
      • Diuretics
      • Burns
      • Fever
    • Gaïsbock syndrome – associated with obesity, heavy smoking, alcohol, and hypertension.
• Congenital vs acquired:
  • Congenital
  • Acquired
• Primary vs. secondary:
  • Primary:
    • Congenital mutations in erythropoietin receptor gene (EPOR)
    • Polycythemia vera
  • Secondary:
    • Congenital:
      • Changes in hemoglobin oxygen affinity.
      • Mutations in oxygen sensing/hypoxia-inducible factor (HIF) signaling pathway.
    • Acquired:
      • Adaptive erythropoietin production in response to chronic or intermittent hypoxia:
        • Pulmonary disease
        • Heart disease
        • Sleep apnea
        • High altitude
      • Abnormal erythropoietin (EPO) production:
        • Androgens
        • Steroids
        • EPO-producing tumors:
          • Renal carcinomas
          • Cerebellar hemangioblastomas
          • Adrenal carcinomas
          • Adrenal adenomas
          • Hepatomas
          • Uterine leiomyomas
        • Renal disorders
        • Post-renal transplantation

Polycythemia vera (PV) is a chronic myeloproliferative neoplasm associated with increased risk of thrombosis and bleeding, and disease progression to either myelofibrosis and/or acute leukemia. PV is currently defined by:

• An acquired increase in hemoglobin/hematocrit level above 16.5 gm/dL/49% in men and 16 g/dL/48% in women.
• In the context of a JAK2 mutation and characteristic bone marrow morphology.

Pathophysiology:

Primary polycythemia

Polycythemia vera is caused by somatic mutations in JAK2 (Janus kinase), namely V617F in about 97% of patients and mutations in exon 12 in about 3% of patients, resulting in erythrocytosis, often accompanied by leukocytosis and/or thrombocytosis.

Secondary polycythemia

Usually caused by elevated erythropoietin (EPO), which is either increased as an “appropriate” response to decreased oxygen delivery to EPO-producing cells in the kidney or is elevated by virtue of EPO-producing tumors. The mechanism by which testosterone increases erythropoiesis is not entirely clear (see more here).

Clinical presentation:

Patients with polycythemia of any cause may present with:

• Plethora
• Hypertension
• Symptoms and signs of hyperviscosity including:
  • Fatigue
  • Dizziness
  • Blurred vision
  • Parasthesias
  • Headache

Patients with polycythemia vera may also present with:

• Vasomotor disturbances, including erythromelalgia
• Constitutional symptoms including:
  • Drenching night sweats
  • Weight loss
  • Unexplained fever
• Iron deficiency
• History of thrombosis – in up to about one-third of patients before/at diagnosis.
• History of bleeding (less common than thrombosis)
• Aquagenic pruritus
• Gout

Diagnosis:

Consider the diagnosis of elevated red cell mass if:

• Hemoglobin or hematocrit > 99th percentile of reference range for age, sex, and altitude of residence.
• Hematocrit > 52% in men and > 48% in women persisting for > 2 months.
• Hemoglobin > 17 g/dL in men, > 15 g/dL in women if associated with documented and sustained increase at least 2 g/dL from baseline value that is not attributable to correction of iron deficiency.
• Red cell mass > 25% above mean normal predicted value.

Consider the diagnosis of polycythemia vera if:

• An acquired increase in hemoglobin/hematocrit level above 16.5 gm/dL/49% in men and 16 g/dL/48% in women
  • Hemoglobin thresholds for men and women were lowered in the 2016 revision to the WHO diagnostic criteria (16.5 g/dL for men or 16 g/dL for women) to include most cases of masked PV that were missed by the 2008 WHO criteria (18.5 g/dL for men and 16.5 g/dL for women).
• In the context of a JAK2 mutation and characteristic bone marrow morphology.

Treatment:

Management of polycythemia vera

• Current therapy is based on risk of developing thrombotic complications:
  • Low risk – < 60 years old and no prior thrombosis.
  • High risk – ≥ 60 years old and/or prior thrombosis.

Management of secondary polycythemia

Management of underlying cause may reduce or resolve erythrocytosis.

Prognosis:

Complications of polycythemia vera (PV) include:

• Thrombosis (the leading cause of morbidity and mortality)
• Bleeding
• Iron deficiency from bleeding
• Pruritis
• Erythromelalgia
• Transformation to acute leukemia