What is essential thrombocythemia?

Essential Thrombocythemia: Definition, Diagnosis, and Management

Essential thrombocythemia (ET) is a clonal myeloproliferative neoplasm characterized by sustained platelet overproduction, megakaryocytic hyperplasia in the bone marrow, and increased risk of thrombotic and hemorrhagic complications.

Definition and Pathophysiology

• ET is one of the Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs), characterized primarily by excessive production of platelets 1
• Approximately 90% of ET patients have genetic variants that upregulate the JAK-STAT signaling pathway, including JAK2 V617F (64%), calreticulin (CALR, 23%), and myeloproliferative leukemia virus oncogene (MPL, 4%) mutations 2
• The disease involves clonal proliferation primarily of the megakaryocytic lineage, leading to increased numbers of enlarged, mature megakaryocytes in the bone marrow 1

Epidemiology

• The annual incidence rate of ET in the US is approximately 1.5 per 100,000 persons 2
• Median age at diagnosis is 59 years, though ET can occur at any age 2
• There is a female predominance with a female to male ratio of about 2:1 3
• Survival in ET patients is generally favorable, with median overall survival exceeding 35 years in those diagnosed at age 40 or younger 2

Diagnostic Criteria

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

1. Sustained platelet count ≥450 × 10^9/L 1
2. Bone marrow biopsy showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes without significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis 1
3. Not meeting WHO criteria for other myeloid neoplasms (polycythemia vera, primary myelofibrosis, BCR-ABL1–positive chronic myeloid leukemia, or myelodysplastic syndrome) 1
4. Presence of JAK2 V617F or other clonal marker, or in the absence of these, no evidence of reactive thrombocytosis 1

Clinical Manifestations

• Many patients may be asymptomatic and diagnosed incidentally on routine blood counts 3
• Symptomatic patients commonly experience:
  • Thrombotic complications (arterial 11%, venous 7%) 2
  • Hemorrhagic complications (8%) 2
  • Vasomotor symptoms (headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias, erythromelalgia) 3
• Thrombotic complications can occur even at relatively low platelet counts (below 600 × 10^9/L) 4

Risk Stratification

Risk stratification is essential for treatment decisions:

• Very Low Risk: Age ≤60 years, no JAK2 mutation, no prior thrombosis history 5
• Low Risk: Age ≤60 years, with JAK2 mutation, no prior thrombosis history 5
• Intermediate Risk: Age >60 years, no prior thrombosis history, JAK2 wild-type 5
• High Risk: Prior thrombosis history at any age or age >60 years with JAK2 mutation 5

Management Approach

Treatment goals focus on preventing thrombohemorrhagic complications while minimizing the risk of disease transformation:

Very Low Risk Patients

• Observation without cytoreductive therapy 5
• Management of cardiovascular risk factors 5

Low Risk Patients

• Low-dose aspirin (81-100 mg/day) for vascular symptoms 5
• Management of cardiovascular risk factors 5

Intermediate Risk Patients

• Low-dose aspirin (81-100 mg/day) 5
• Consider cytoreductive therapy based on additional risk factors 5

High Risk Patients

• Low-dose aspirin (81-100 mg/day) 5
• Cytoreductive therapy with hydroxyurea as first-line option 5, 1
• For patients intolerant or resistant to hydroxyurea, consider second-line options:
  • Interferon-alpha (particularly for younger patients or pregnant women) 1, 6
  • Anagrelide 1

Monitoring and Follow-up

• Low-risk ET patients: Follow-up visits every 6-12 months 1
• High-risk ET patients on cytoreductive therapy: Follow-up every 3-4 months 1
• Regular complete blood counts to monitor disease status and treatment response 5
• Monitor for disease progression to myelofibrosis (occurs in approximately 10% of patients at 8.5 years) or acute myeloid leukemia (approximately 3% of patients) 2

Treatment Response Criteria

The European LeukemiaNet defines response to treatment as:

• Complete response: Resolution of disease-related symptoms, normalization of platelet count (≤400 × 10^9/L), WBC count <10 × 10^9/L, absence of thrombohemorrhagic events, and bone marrow histological remission 1
• Partial response: Same as complete response but without bone marrow histological remission 1

Important Considerations and Pitfalls

• Avoid therapeutic phlebotomy in ET, unlike in polycythemia vera 5
• Screen for acquired von Willebrand syndrome before initiating aspirin in patients with extreme thrombocytosis 5
• Don't delay cytoreductive therapy in high-risk patients 5
• Carefully monitor for myelosuppression in patients on hydroxyurea, as dose adjustments may be needed 1
• Recognize that thrombotic events can occur even at relatively low platelet counts (300-500 × 10^9/L) 4