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.
Low riskHigh risk
Target Hct< 45% < 45%
Therapeutic phlebotomy++
Low dose aspirin++
Cytoreductive therapy– *+
Correction of cardiovascular risk factors++
*Low risk patients may be eligible for cytoreductive therapy if they have extensive disease-related symptoms, progressive/symptomatic splenomegaly, extreme/progressive thrombocytosis, and/or persistent leukocytosis.

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