What is essential thrombocythemia?

Essential Thrombocythemia: Diagnosis, Management, and Complications

Definition and Diagnostic Criteria

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

According to the World Health Organization (WHO) 2016 diagnostic criteria, ET diagnosis requires meeting all four major criteria:

• Sustained platelet count ≥450 × 10^9/L 1
• Bone marrow biopsy showing megakaryocyte proliferation with large and mature morphology, without significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis 1
• Not meeting WHO criteria for polycythemia vera, primary myelofibrosis, BCR-ABL1–positive chronic myelogenous leukemia, myelodysplastic syndrome, or other myeloid neoplasms 1
• Presence of JAK2, CALR, or MPL mutation or, in the absence of these mutations, no evidence of reactive thrombocytosis 1

Pathophysiology

• ET is characterized by clonal expansion of megakaryocyte progenitor cells, leading to overproduction of platelets 2
• JAK2 V617F mutation is present in 50-60% of ET patients, while CALR and MPL mutations account for approximately 25-30% and 3-5% of cases, respectively 1, 3
• These mutations lead to constitutively activated signal transduction pathways, resulting in excessive platelet production 1

Clinical Manifestations

• Many patients are asymptomatic and diagnosed incidentally during routine blood tests 2
• Symptomatic patients may experience:
  • Microvascular disturbances (erythromelalgia, headaches, visual disturbances, lightheadedness, atypical chest pain, distal paresthesias) 4, 2
  • Thrombotic events (cerebrovascular, coronary, and peripheral arterial occlusions; venous thromboembolism) 4, 2
  • Hemorrhagic complications, particularly with platelet counts >1,500 × 10^9/L 4, 3
• Arterial thromboses are more common than venous thromboses (ratio approximately 2:1) 4
• Young adults with ET are not exempt from complications, with potentially life-threatening events reported (myocardial infarction, stroke) 5

Risk Stratification

Risk stratification is essential for treatment decisions:

• Very Low Risk: Age ≤60 years, no JAK2 mutation, no prior thrombosis 6
• Low Risk: Age ≤60 years, with JAK2 mutation, no prior thrombosis 6
• Intermediate Risk: Age >60 years, no prior thrombosis, JAK2 wild-type 6
• High Risk: Prior thrombosis history at any age or age >60 years with JAK2 mutation 6, 3

Management Approach

Treatment goals focus on preventing thrombohemorrhagic complications:

Low-Risk Patients

• Observation alone for very low-risk patients 6
• Low-dose aspirin (81-100 mg/day) for low-risk patients with JAK2 mutation or microvascular symptoms 6, 3
• Management of cardiovascular risk factors 6

High-Risk Patients

• Low-dose aspirin (81-100 mg/day) unless contraindicated 6, 3
• Cytoreductive therapy with hydroxyurea as first-line treatment 6, 3
• Alternative cytoreductive options:
  • Interferon-α (preferred for younger patients and pregnant women) 3
  • Anagrelide (for patients resistant or intolerant to hydroxyurea) 3
  • Busulfan or pipobroman (typically reserved for elderly patients) 4

Special Considerations

• Extreme thrombocytosis (>1,500 × 10^9/L): Consider screening for acquired von Willebrand syndrome before initiating aspirin 6
• Pregnancy: Interferon-α is the preferred cytoreductive agent 3
• Avoid therapeutic phlebotomy in ET, unlike in polycythemia vera 6

Monitoring and Follow-up

• Regular complete blood counts to monitor platelet levels and response to therapy 6
• Low-risk patients: Follow-up visits every 6-12 months 1
• High-risk patients on cytoreductive therapy: Follow-up every 3-4 months 1
• Bone marrow examination if there are signs of disease progression 6

Disease Complications and Prognosis

• Thrombotic events: 1-3% of patients per year 4
• Hemorrhagic complications: 0.33% of patients per year 4
• Disease progression:
  • Transformation to myelofibrosis: 0.16% of patients per year 4
  • Progression to acute leukemia: 0.12% of patients per year 4
• Overall survival is nearly normal, with mortality ratio similar to the general population 4, 2

Treatment Response Evaluation

According to European LeukemiaNet criteria, complete response is defined as:

• Resolution of disease-related symptoms and signs
• Platelet count ≤400 × 10^9/L
• White blood cell count <10 × 10^9/L
• Absence of thrombohemorrhagic events
• Bone marrow histological remission 1

ET is a chronic myeloproliferative neoplasm with generally favorable prognosis when properly managed. Risk stratification and appropriate treatment selection are crucial to prevent thrombohemorrhagic complications while minimizing therapy-related risks.