Essential thrombocytosis (ET) is a myeloproliferative neoplasm characterized by markedly elevated platelet counts and an increased megakaryocyte proliferation in bone marrow. The etiology is unknown.
Clinical Features And Natural History Top
1. Signs and symptoms depend on the stage of the disease as well as the number and severity of functional abnormalities in the platelets; they include features of both small-vessel and large-vessel thrombosis: paresthesias, transient visual impairment, epileptic seizures, hemiparesis, symptoms of ischemic heart disease, erythromelalgia, headache, and vertigo or dizziness. Rare symptoms include mucosal and gastrointestinal bleeding caused by abnormalities of platelet function. A moderate enlargement of the spleen is seen in <50% of patients. Many patients are discovered to have asymptomatic disease on routine complete blood cell analysis that demonstrates thrombocytosis with or without elevations or other cell lines.
2. Natural history: The disease may remain asymptomatic for many years before the development of thrombotic (most frequently), hemorrhagic complications, or both. In ~8% of patients, transformation to myelofibrosis occurs. Transformation to acute leukemia or myelodysplastic syndrome (MDS) is less frequent (~1%).
1. Complete blood count: Persistent elevation of platelet counts (≥450,000/microL), abnormal platelet shape and size, and various abnormalities of platelet function (most frequently impaired aggregation) can be seen.
2. Bone marrow examination: Bone marrow aspiration and/or trephine biopsy reveal increased marrow cellularity with proliferation of the megakaryocytic lineage and an increased proportion of large, mature megakaryocytes. No proliferation or immature cells of granulocytic or erythropoietic lineages are observed.
3. Molecular studies: Most patients are found to harbor the JAK2 V617F mutation or other clonal genetic markers (MPL or CALR mutations).
To establish the diagnosis of ET, all the following criteria must be fulfilled:
1) Persistently elevated platelet counts ≥450,000/microL.
2) Increased marrow cellularity with the proliferation of the megakaryocytic lineage, an increased proportion of large, mature megakaryocytes, and without the concomitant proliferation or presence of immature forms of granulocytic and/or erythropoietic lineages.
3) Exclusion of polycythemia vera (PV), primary myelofibrosis, chronic myelogenous leukemia (CML), MDS, and other myeloid neoplasms.
4) Presence of the JAK2 V617F mutation or other clonal genetic markers; if these are absent, exclude reactive thrombocytosis, which may be caused by solid tumors (mainly lung or pancreatic cancers), iron deficiency anemia, chronic inflammatory or infectious conditions, acute hemorrhage, splenectomy, chronic alcohol abuse, frequent blood donations, as well as hemolytic or drug-induced anemias.
1. Thrombocytosis associated with other myeloproliferative neoplasms: PV, CML, primary myelofibrosis, MDS 5q-, refractory anemia with ringed sideroblasts and thrombocytosis (RARS-T).
2. Reactive thrombocytosis.
3. Familial thrombocytosis (mutations of the thyroperoxidase gene).
4. Apparent thrombocytosis: Cryoglobulinemia, fragmented erythrocytes, or malignant cells in peripheral blood.
The choice of treatment depends on the presence of risk factors for thrombotic complications: age >60 years and prior thrombosis. In patients with neither, use acetylsalicylic acid (ASA) without cytoreductive treatment, and in those with 1 or both, add cytoreductive treatment. This may also be considered in patients with platelet counts >1.5 million/microL, progressive myeloproliferation (eg, progressive enlargement of the spleen), uncontrolled systemic symptoms, or evidence of microcirculatory impairment due to platelet clumping that is clinically resistant to ASA.
1. Cytoreductive treatment: Hydroxyurea (INN hydroxycarbamide) is the first-line drug. Second-line treatments are used in:
1) Patients in whom no significant reduction of platelet counts has been achieved using hydroxyurea.
2) Patients with intolerance of hydroxyurea.
2) Interferon alpha.
3) Busulfan, radioactive phosphate, or pipobroman (consider these in patients with short life expectancy).
2. Antiplatelet agents: ASA 50 mg to 100 mg once daily (bid administration may be considered in patients not responding to the once-daily treatment) in all patients with microcirculation abnormalities (eg, erythromelalgia), except for patients with acquired von Willebrand disease or those treated with anagrelide (due to the risk of hemorrhagic complications). The second-line agents are clopidogrel 75 mg once daily or ticlopidine 250 mg bid.
3. Appropriate preventative measures should be used in patients with either additional risk factors for thrombosis or a history of thrombosis: See Prevention of Cardiovascular Diseases, Venous Thromboembolism.
Examination of platelet counts as required to monitor cytoreductive therapy (to ensure that underdosing or overdosing does not occur). The frequency at which monitoring is required in asymptomatic patients is unknown but should be increased as the platelet count rises >1 million.
Prognosis is established on the basis of International Prognostic Score for ET:
1) Age >60 years: Score 2.
2) White blood cell count >11,000/microL: Score 1.
3) A previous thrombotic event: Score 1.
The mean survival in patients without the above risk factors is similar to that of general population; in patients with scores 1 or 2, the mean survival is 25 years; and in patients with score 3, it is 14 years.