What is thrombocythemia?

What is Thrombocythemia?

Thrombocythemia (also called thrombocytosis) refers to an elevated platelet count ≥450 × 10⁹/L that can be either clonal (essential thrombocythemia) or reactive (secondary thrombocytosis). 1

Essential Thrombocythemia (ET): The Clonal Myeloproliferative Neoplasm

Essential thrombocythemia is a chronic myeloproliferative neoplasm characterized by clonal proliferation of the megakaryocytic lineage, resulting in persistently elevated platelet counts in the absence of a secondary cause. 2, 3

Pathophysiology and Molecular Basis

• ET is driven by somatic mutations that upregulate the JAK-STAT signaling pathway, found in approximately 90% of patients: JAK2 mutations (64%), CALR mutations (23%), and MPL mutations (4%). 2, 3
• The bone marrow shows proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes with deeply lobulated and hyperlobulated nuclei, typically dispersed throughout the biopsy but sometimes in loose clusters. 1, 3
• The bone marrow is often normally or only slightly hypercellular for the patient's age, distinguishing it from other myeloproliferative neoplasms. 1

Diagnostic Criteria

The revised WHO criteria for ET require all four of the following: 1

1. Sustained platelet count ≥450 × 10⁹/L (lowered from the previous threshold of 600 × 10⁹/L to improve detection of early-phase disease) 1
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 1
3. Not meeting WHO criteria for polycythemia vera, primary myelofibrosis, chronic myeloid leukemia, myelodysplastic syndromes, or other myeloid neoplasm 1
4. Demonstration of JAK2V617F or other clonal marker (CALR, MPL), or in the absence of a clonal marker, no evidence for reactive thrombocytosis 1

Clinical Consequences and Risk Stratification

• The clinical consequences of ET include both thrombosis and hemorrhage. Patients face an 11% risk of arterial thrombosis, 7% risk of venous thrombosis, and 8% risk of hemorrhagic complications. 2
• Advanced age (>60 years) and history of thrombosis are the most consistent risk factors for thrombotic events. 1
• JAK2 mutation is associated with higher thrombosis risk compared to CALR-mutated or triple-negative ET. 1, 2, 3

Four risk categories are recognized: 1, 4, 3

• 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 wild-type
• High risk: Thrombosis history present OR age >60 years with JAK2 mutation

Prognosis and Disease Transformation

• Median survival is approximately 18 years overall but exceeds 35 years in patients diagnosed at age 40 or younger. 2, 4
• Life expectancy in ET is inferior to the control population. 4
• At 10 years from diagnosis, approximately 10% of patients develop myelofibrosis and about 3% develop acute myeloid leukemia. 2
• Leukemic transformation rates at 10 years are estimated at <1% but may be higher in JAK2-mutated patients with extreme thrombocytosis and those with abnormal karyotype. 4, 3

Management Principles

The main goal of therapy is to prevent thrombohemorrhagic complications. 4, 3

• Very low-risk patients may not require therapy beyond observation. 1, 4
• Low-dose aspirin (81-100 mg/day) is advised for most patients with ET to lower thrombosis risk. 1, 2, 4
• Cytoreductive therapy is recommended for high-risk disease and optional for intermediate-risk disease. 1, 4, 3
• First-line cytoreductive drugs are hydroxyurea (mainly in older patients) and pegylated interferon-α (primarily in younger patients); second-line is busulfan. 5, 4, 3

Reactive Thrombocytosis (Secondary Thrombocytosis)

Reactive thrombocytosis is a non-clonal elevation of platelet count caused by an underlying condition that stimulates platelet production. 1

Common Causes of Reactive Thrombocytosis

Causes include: 1

• Iron deficiency anemia
• Splenectomy or functional asplenia
• Surgery or tissue trauma
• Infection and inflammation
• Connective tissue diseases (rheumatoid arthritis, systemic lupus erythematosus)
• Metastatic cancer and lymphoproliferative disorders
• Chronic inflammatory conditions

Key Diagnostic Distinction

The presence of a condition associated with reactive thrombocytosis does not exclude the possibility of ET if the first three WHO criteria are met. 1 However, in JAK2-negative patients, careful clinical assessment is required to exclude reactive causes before diagnosing ET. 1

Critical Diagnostic Pitfalls

• Bone marrow biopsy is mandatory to differentiate ET from reactive thrombocytosis in JAK2-negative patients and to exclude cellular phase/prefibrotic primary myelofibrosis and myelodysplastic syndromes. 1
• In iron-deficient patients, it is essential to exclude occult polycythemia vera by a trial of iron replacement therapy before diagnosing ET. 1
• Thrombocytosis (platelet count >1,000 × 10⁹/L) has been associated with an immediate risk of major hemorrhage but not with increased risk of thrombosis; in fact, some studies report lower thrombosis rates at extreme platelet counts. 1