What is essential thrombocytosis?

Essential Thrombocythemia: Definition, Diagnosis, and Management

Essential thrombocythemia (ET) is a clonal myeloproliferative neoplasm characterized by sustained platelet elevation, megakaryocytic hyperplasia, and increased risk of thrombohemorrhagic complications. 1

Definition and Pathophysiology

• ET is a Philadelphia chromosome-negative myeloproliferative neoplasm with excessive platelet production, associated with increased risk of thrombosis and bleeding 2
• Approximately 90% of individuals with ET have genetic variants that upregulate the JAK-STAT signaling pathway 2:
  • JAK2 V617F mutation: present in 50-60% of cases
  • CALR mutations: present in 23-30% of cases
  • MPL mutations: present in 3-5% of cases
• The annual incidence rate of ET in the US is approximately 1.5/100,000 persons 2
• The median age at diagnosis is 59 years, with a female to male ratio of about 2:1 2, 3

Diagnostic Criteria

According to the revised World Health Organization (WHO) criteria, diagnosis of ET requires meeting all four of the following criteria 4, 1:

1. Sustained platelet count ≥450 × 10^9/L (lowered from previous threshold of 600 × 10^9/L) 4
2. Bone marrow biopsy showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes; no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis 4
3. Not meeting WHO criteria for other myeloid neoplasms including polycythemia vera (PV), primary myelofibrosis (PMF), BCR-ABL1-positive chronic myeloid leukemia (CML), or myelodysplastic syndrome (MDS) 4
4. Demonstration of JAK2 V617F or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis 4

Bone Marrow Findings in ET

• Bone marrow in ET shows large, mature-appearing megakaryocytes with deeply lobulated and hyperlobulated nuclei 4
• Megakaryocytes are typically dispersed throughout the biopsy sections or found in loose clusters 4
• The bone marrow is normally or only slightly hypercellular for the patient's age 4
• The increased trilineage proliferation (panmyelosis) that characterizes PV or the granulocytic proliferation and highly bizarre megakaryocytes that characterize prefibrotic PMF are not found in ET 4

Differential Diagnosis

The differential diagnosis of thrombocytosis includes 2:

• Other myeloproliferative neoplasms (polycythemia vera, primary myelofibrosis, chronic myeloid leukemia)
• Reactive thrombocytosis due to:
  • Inflammatory conditions (rheumatoid arthritis, systemic lupus erythematosus)
  • Infections
  • Splenectomy
  • Iron deficiency anemia
  • Solid tumors such as lung cancer

Clinical Manifestations

• Some patients with ET are asymptomatic 3
• Others may experience:
  • Vasomotor symptoms: headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia 3
  • Thrombotic complications: arterial thrombosis (11%), venous thrombosis (7%) 2
  • Hemorrhagic complications (8%) 2
  • Microcirculatory disturbances affecting palms, soles, and fingers 5

Risk Stratification

Risk stratification for thrombosis in ET includes the following categories 1, 6:

• Very Low Risk: Age ≤60 years, no thrombosis history, JAK2 wild-type
• Low Risk: Age ≤60 years, no thrombosis history, JAK2 mutation present
• Intermediate Risk: Age >60 years, no thrombosis history, JAK2 mutation present
• High Risk: History of thrombosis or age >60 years with JAK2 mutation

Management Approach

Treatment of ET must aim at preventing thrombosis and bleeding without increasing the risk of disease transformation 7:

• Low-risk patients:

  • Low-dose aspirin (81-100 mg/day) is recommended, especially for those with JAK2 mutation or microvascular symptoms 1, 6
  • Twice-daily low-dose aspirin may be considered for some low-risk patients 6

• High-risk patients:

  • Cytoreductive therapy with hydroxyurea is recommended as first-line treatment 1, 7
  • In a randomized trial of high-risk patients, cytoreduction with hydroxyurea significantly lowered the risk of thrombotic events compared with no cytoreductive therapy (3.6% vs 24%; P < .01) 2

• Special populations:

  • For young patients or pregnant women, interferon-alpha is recommended 7
  • For patients resistant or intolerant to hydroxyurea, anagrelide is recommended as second-line therapy 7
  • Anagrelide has been shown to be effective in reducing platelet counts in patients with ET 8

Disease Progression and Prognosis

• Median survival exceeds 35 years in patients diagnosed at age 40 years or younger 2
• At a median of 8.5 years from diagnosis 2:
  • Approximately 10% of patients develop myelofibrosis
  • About 3% develop acute myeloid leukemia
• Leukemic transformation rate at 10 years is <1% but might be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype 6
• Life expectancy is almost normal in most patients with appropriate management 3

Monitoring and Follow-up

• Regular follow-up visits are recommended 1:
  • Low-risk patients: every 6-12 months
  • High-risk patients: every 3-4 months
• Complete blood counts should be monitored regularly to assess platelet levels and response to therapy 1
• Bone marrow examination is recommended if there are signs of disease progression 1

Important Considerations and Pitfalls

• It is crucial to exclude reactive thrombocytosis before diagnosing ET 4
• Causes of reactive thrombocytosis include iron deficiency, splenectomy, surgery, infection, inflammation, connective tissue disease, metastatic cancer, and lymphoproliferative disorders 4
• The presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if the first three diagnostic criteria are met 4
• Strict control of coexistent cardiovascular risk factors is mandatory for all patients 7
• In iron-deficient patients, it is important to exclude occult polycythemia vera by a trial of iron replacement therapy 4