Essential thrombocythemia (ET) is a clonal disorder of hematopoietic stem cells, characterized by an increased platelet count in peripheral blood, excessive proliferation of megakaryocytes in the bone marrow, and in some cases, thrombotic or bleeding complications. The peak incidence occurs between the ages of 50 and 70.
Pathogenesis
Approximately 80% of ET patients have detectable mutations in the JAK2 V617F, CALR, or MPL genes, with occasional mutations in the LNK gene. In addition, mutations affecting epigenetic regulation and histone structure may also be present.
Clinical Presentation
The onset is insidious, and early stages may be asymptomatic, with the condition often discovered incidentally during routine blood cell counts. Thrombosis is the leading cause of morbidity and mortality in ET, predominantly involving arterial thrombosis. Severe bleeding is less common than thrombosis. Additional manifestations include fatigue, weakness, and mild splenomegaly.
Laboratory Findings
Peripheral Blood Findings
Persistent thrombocytosis (≥450 × 109/L); in some cases, the platelet count may exceed 1,000 × 109/L. Hemoglobin (Hb) levels are typically normal, though anemia may occur in cases with bleeding. White blood cell counts are usually normal but may occasionally be mildly elevated, with a normal differential. Peripheral blood smears often show large platelets with poor staining quality.
Bone Marrow Examination
Bone marrow cellularity is typically normal, with primarily megakaryocytic hyperplasia. Megakaryocytes are large, with hyperlobulated nuclei resembling antlers. Reticulin fibrosis is not prominent, typically grade 0 or 1.
Genetic Testing
JAK2 V617F mutations are found in 50–60% of cases, CALR mutations in 15–35%, and MPL mutations in 2–4%. These mutations are collectively referred to as driver mutations. At least one non-driver mutation, such as TET2, ASXL1, IDH1/2, SRSF2, SF3B1, U2AF1, and TP53, is found in 20–30% of ET patients.
Cytogenetics
The Philadelphia chromosome (Ph) is absent. Karyotypic abnormalities are observed in approximately 5% of patients.
Diagnosis and Differential Diagnosis
Diagnosis (2022 WHO Criteria)
Major Criteria:
- Persistent platelet count ≥450 × 109/L.
- Bone marrow biopsy shows megakaryocytic hyperplasia with a predominance of large, mature megakaryocytes with hyperlobulated nuclei. Granulocytic and erythroid proliferation are not significant or left-shifted, and reticulin fibrosis is grade 0 or 1.
- Diagnostic criteria for BCR::ABL1-positive chronic myeloid leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), myelodysplastic syndromes (MDS), or other myeloid neoplasms are not met.
- Presence of mutations in JAK2, CALR, or MPL genes.
Minor Criterion:
- Evidence of clonal markers other than driver mutations or exclusion of reactive thrombocytosis.
A diagnosis of ET is confirmed by meeting all four Major Criteria or the first three Major Criteria along with the Minor Criterion.
Differential Diagnosis
Reactive Thrombocytosis
Reactive thrombocytosis is observed in conditions such as infections, inflammation, malignancy, iron deficiency anemia, or after splenectomy.
Other Hematologic Disorders with Thrombocytosis
Other myeloproliferative neoplasms (MPNs) or myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) can present with increased platelet counts.
Treatment
The primary objective of treatment is the prevention and management of thrombotic complications. Treatment plans are developed based on thrombotic risk stratification, with the platelet count maintained at <600 × 109/L. For low-risk, asymptomatic patients aged ≤60 years with no history of thrombosis, treatment is not required. In contrast, for intermediate- or high-risk patients aged >60 years and/or those with a history of thrombosis, active management is necessary.
Antiplatelet Therapy
Aspirin is recommended for all ET patients with appropriate indications. A platelet count >1,000 × 109/L may increase the risk of bleeding.
Cytoreductive Therapy
Commonly used medications include hydroxyurea and interferon, with administration methods consistent with those used in the treatment of PV. Platelet apheresis can quickly reduce platelet counts and is often utilized during pregnancy, perioperative preparation, or in cases where cytoreductive agents are ineffective.
Prognosis
The International Prognostic Score for Thrombosis in ET (IPSET-thrombosis) and the International Prognostic Score for ET (IPSET) are utilized for thrombotic risk assessment and survival prognosis evaluation, respectively.