Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increased platelet count, megakaryocytic hyperplasia, and a hemorrhagic or microvascular vasospastic tendency. Symptoms and signs may include headache (ocular migraine), paresthesias, bleeding, erythromelalgia, or digital ischemia. Diagnosis is based on an isolated platelet count > 450,000 platelets/mcL (> 450 × 109/L), normal red blood cell mass or normal hematocrit in the presence of adequate iron stores, and the absence of myelofibrosis, the Philadelphia chromosome (or BCR-ABL rearrangement), or reactive disorders that cause thrombocytosis. No treatment is required in most patients who are asymptomatic. The presence of extreme thrombocytosis (platelet count > 1,000,000 platelets/mcL [> 1000 × 109/L]) may increase the risk of bleeding, which is not usually spontaneous. There is no correlation between the platelet count and risk of macrovascular thrombosis.
(See also Overview of Myeloproliferative Neoplasms.)
Etiology of Essential Thrombocythemia
Essential thrombocythemia is a clonal hematopoietic stem cell disorder that causes increased platelet production. Essential thrombocythemia usually occurs after age 50 years with an increased incidence in females.
A Janus kinase 2 (JAK2) enzyme mutation, JAK2V617F, is present in approximately 50% of patients; JAK2 is a member of the tyrosine kinase family of enzymes and is involved in signal transduction for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor (G-CSF).
Other patients have mutations in exon 9 of the calreticulin gene (CALR). CALR mutations are usually of 2 types, called type 1 and type 2. Patients with CALR mutations tend to have higher platelet counts than patients with JAK2 mutations (1).
A few patients have an acquired somatic thrombopoietin receptor gene (MPL) mutation.
Etiology reference
1. Bellani V, Mora B, Iurlo A, Passamonti F. CALR-mutated myeloproliferative neoplasms. Leuk Lymphoma. 2025;66(7):1198-1210. doi:10.1080/10428194.2025.2465551
Pathophysiology of Essential Thrombocythemia
Thrombocythemia may lead to:
Microvascular occlusions
Large vessel thrombosis
Bleeding
Microvascular occlusions involve small vessels of the distal extremities (causing erythromelalgia), the eye (causing ocular migraine), or the central nervous system (causing transient ischemic attacks). Not all patients experience microvascular symptoms even when platelet counts are high.
It is unclear whether the risk of large vessel thrombosis causing deep venous thrombosis or pulmonary embolism is increased in essential thrombocythemia, particularly because platelets are primarily involved in arterial thrombosis and there is no correlation between the platelet count and large vessel thrombosis. Large vessel thrombosis is more likely to occur in patients with masked polycythemia vera, and these patients, particularly females, may have been erroneously diagnosed as having essential thrombocythemia.
Bleeding is more likely with extreme thrombocytosis (ie, approximately 1,000,000 platelets/mcL [1000 × 109/L]); it is due to an acquired deficiency of von Willebrand factor caused because platelets adsorb and proteolyze high molecular weight von Willebrand multimers, causing type 2 acquired von Willebrand syndrome.
Symptoms and Signs of Essential Thrombocythemia
Common symptoms are:
Bruising and bleeding
Headache (especially ocular migraine)
Paresthesias of the hands and feet (manifesting as erythromelalgia)
Neurologic deficits
Bleeding is usually mild, rarely spontaneous, and manifests as epistaxis, easy bruisability, or gastrointestinal bleeding. However, serious bleeding may occur in a small percentage of patients with extreme thrombocytosis.
Erythromelalgia (burning pain in hands and feet, with warmth, erythema, and sometimes digital ischemia with ulcers) may occur.
Thrombotic events may be arterial or venous. Transient ischemic attacks may cause neurologic deficits depending upon which part of the brain is affected.
The spleen may be palpable, but significant splenomegaly is unusual. Significant splenomegaly should suggest another myeloproliferative neoplasm or a cause for spleen enlargement that is not directly related to the platelet count elevation.
Diagnosis of Essential Thrombocythemia
Complete blood count (CBC) and peripheral blood smear
Exclusion of causes of secondary thrombocytosis and other myeloproliferative neoplasms
Cytogenetic studies
JAK2 mutation and BCR-APL assays and, if negative, CALR or MPL mutation analysis
Rarely, bone marrow aspirate and biopsy
Essential thrombocythemia is a diagnosis of exclusion and should be considered in patients in whom common reactive causes of thrombocytosis and other myeloproliferative neoplasms such as chronic myeloid leukemia (CML) are excluded.
If essential thrombocythemia is suspected, CBC, peripheral blood smear, and (because thrombocytosis can be caused by iron deficiency) iron studies should be performed.
In essential thrombocythemia, the platelet count is > 450,000 platelets/mcL (> 450 × 109/L), but can be >1,000,000 platelets/mcL (> 1000 × 109/L). The platelet count usually decreases during pregnancy.
The diagnosis is suggested by normal hematocrit, white blood cell count, mean corpuscular volume (MCV), and iron studies, as well as absence of the BCR-ABL translocation.
The peripheral smear may show giant platelets and megakaryocyte fragments.
Some myelodysplastic syndromes (eg, refractory anemia with ringed sideroblasts and thrombocytosis [RARS-T, now called myelodysplastic/myeloproliferative neoplasm with SF3B1 mutation and thrombocytosis], and the 5q deletion syndrome) (1) may present with an elevated platelet count. If cytopenias are identified, a myelodysplastic syndrome should be considered.
Genetic studies should be performed, including a quantitative JAK2 V617F assay (by next-generation sequencing [NGS] or quantitative polymerase chain reaction [PCR]), along with a BCR-ABL assay to exclude chronic myeloid leukemia (CML, which can manifest with thrombocytosis alone). If the JAK2 V617F and BCR-ABL assays are negative, CALR and MPL mutation assays should be performed. Some patients test negative for all 3 mutations; many have rare variants of the myeloproliferative neoplasm driver mutations and others have germline mutations in MPL or JAK2. Patients who do not have JAK2 V617F, CALR, or MPL gene mutations (called triple negative) are rare.
Mutation analysis should always be quantitative because the driver gene allele burden in JAK2 V617F-positive essential thrombocythemia does not exceed 50%. A quantitative allele burden > 50% suggests polycythemia vera or primary myelofibrosis. However, a quantitative allele burden < 50% does not definitely exclude polycythemia vera or primary myelofibrosis because these disorders can present with thrombocytosis alone, and in polycythemia vera (particularly in female patients), plasma volume expansion can mask the presence of an expanded red cell mass. Also, in approximately 25% of patients (primarily women) with what initially appears to be essential thrombocythemia, transformation to overt polycythemia vera occurs over time (approximately 12 years), leading to an increase in hematocrit and an increase in the JAK2V617F allele burden.
World Health Organization guidelines have suggested that a bone marrow biopsy showing increased numbers of enlarged, mature megakaryocytes is required for a diagnosis of essential thrombocythemia, but this criterion has never been validated prospectively, and a marrow examination will not distinguish essential thrombocythemia from polycythemia vera (2, 3).
Diagnosis references
1. Khoury JD, Solary E, Abla O, et al. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Myeloid and Histiocytic/Dendritic Neoplasms. Leukemia. 2022;36(7):1703-1719. doi:10.1038/s41375-022-01613-1
2. Barbui T, Thiele J, Gisslinger H, et al. The 2016 WHO classification and diagnostic criteria for myeloproliferative neoplasms: document summary and in-depth discussion. Blood Cancer J. 2018;8(2):15. doi:10.1038/s41408-018-0054
3. Pasquer H, Kiladjian JJ, Benajiba L. Current myeloproliferative neoplasm scoring systems for clinical practice. Blood. 2025;145(3):257-276. doi.org/10.1182/blood.2024025459
Treatment of Essential Thrombocythemia
Aspirin for most patients
Platelet-lowering medications (eg, peginterferon, anagrelide) for high risk patientsPlatelet-lowering medications (eg, peginterferon, anagrelide) for high risk patients
Rarely plateletpheresis
Rarely cytotoxic agents such as hydroxyurea, when indicated Rarely cytotoxic agents such as hydroxyurea, when indicated
Rarely stem cell transplantation
The primary treatment goals for patients with essential thrombocythemia are to alleviate vasomotor symptoms and to prevent thrombotic and hemorrhagic complications. There are no therapies available that reliably prevent progression to myelofibrosis or acute leukemia, but these complications often occur many years after the original diagnosis and therefore patients with essential thrombocytopenia need to be monitored. The approach to treatment is guided by the presence of symptoms and risk factors for thrombotic complications.
Thrombosis risk stratification is based on age, history of thrombosis and JAK2 mutation status, and includes 4 risk categories (1):
Very low risk (age ≤ 60 years, no thrombosis history, JAK2 wild type)
Low risk (age ≤ 60 years, no thrombosis history, JAK2 gene variant)
Intermediate risk (age > 60 years, no thrombosis history, JAK2 wild type)
High risk (thrombosis history or age > 60 years with JAK2 gene variant)
For patients who are asymptomatic and very low risk for thrombosis, observation is generally appropriate, but some clinicians do recommend aspirin if bleeding risk is low.For patients who are asymptomatic and very low risk for thrombosis, observation is generally appropriate, but some clinicians do recommend aspirin if bleeding risk is low.
Low-dose aspirin
For patients with vasomotor symptoms in any risk category, low-dose aspirin is generally considered the cornerstone of therapy. Aspirin 81 mg orally once a day is usually sufficient for mild vasomotor symptoms (eg, headache, mild digital ischemia, erythromelalgia) in low-risk patients (without cardiovascular disease or tobacco use) who do not have the For patients with vasomotor symptoms in any risk category, low-dose aspirin is generally considered the cornerstone of therapy. Aspirin 81 mg orally once a day is usually sufficient for mild vasomotor symptoms (eg, headache, mild digital ischemia, erythromelalgia) in low-risk patients (without cardiovascular disease or tobacco use) who do not have theJAK2 mutation, but a higher dose may be used if necessary. Severe migraine may require platelet count reduction for control.
The utility of aspirin during pregnancy is unproven and may provoke bleeding in patients with essential thrombocythemia and the CALR mutation. Women with essential thrombocythemia are thought to have a higher incidence of fetal loss in the first trimester.
Patients without symptoms who use tobacco or have cardiovascular disease or cardiovascular risk factors are also treated with aspirin. However, the use of aspirin for cardiovascular prophylaxis in the absence of cardiovascular disease or risk factors in patients > 65 years of age is associated with an unacceptable incidence of adverse effects, particularly gastrointestinal hemorrhage. There is no proof that patients > 65 years without symptoms benefit from aspirin therapy.
Platelet lowering medications
Because prognosis is usually favorable and there is no correlation between degree of thrombocytosis and thrombosis, potentially toxic medications that lower the platelet count should not be used just to normalize the platelet count in patients without symptoms. Generally agreed-upon indications for platelet-lowering therapy include:
Age > 60 years with a JAK2 mutation
History of thrombosis
Microvascular symptoms (not controlled with aspirin) such as headache Microvascular symptoms (not controlled with aspirin) such as headache
Cardiovascular risk factors (eg, hypertension, diabetes, hyperlipidemia, tobacco use)
Significant bleeding
Need for a surgical procedure in patients with extreme thrombocytosis and low ristocetin cofactor activity
However, there are no data that prove cytotoxic therapy to reduce the platelet count lowers thrombotic risk or improves survival.
Medications used to lower platelet count include anagrelide, peginterferon alfa-2a, peginterferon alfa-2b, and hydroxyurea when indicated. In include anagrelide, peginterferon alfa-2a, peginterferon alfa-2b, and hydroxyurea when indicated. InCALR-mutated essential thrombocythemia is antibodies against the mutation are being investigated as a target for immunotherapy (2, 3).
Hydroxyurea, once considered the medication of choice for essential thrombocythemia therapy, may be myelotoxic when used long-term.
Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring and never for long-term use. Patients are monitored with a weekly complete blood count (CBC). If the white blood cell (WBC) count falls to Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring and never for long-term use. Patients are monitored with a weekly complete blood count (CBC). If the white blood cell (WBC) count falls to< 4000 cells/mcL (< 4 × 109/L), hydroxyurea is withheld and reinstituted at 50% of the dose when the value normalizes. When a steady state is achieved, the interval between CBCs is lengthened to 2 weeks and then to 4 weeks. The aim is relief of symptoms and never for platelet count normalization. Too-rapid withdrawal of hydroxyurea can result in rapid rebound to very high platelet levels and platelet cycling./L), hydroxyurea is withheld and reinstituted at 50% of the dose when the value normalizes. When a steady state is achieved, the interval between CBCs is lengthened to 2 weeks and then to 4 weeks. The aim is relief of symptoms and never for platelet count normalization. Too-rapid withdrawal of hydroxyurea can result in rapid rebound to very high platelet levels and platelet cycling.
Because anagrelide and hydroxyurea cross the placenta, they are not used during pregnancy; peginterferon alfa-2a and peginterferon alfa-2b can be used in pregnant women when necessary. cross the placenta, they are not used during pregnancy; peginterferon alfa-2a and peginterferon alfa-2b can be used in pregnant women when necessary.
Anagrelide should be used with caution in older patients because of its effects on the cardiovascular system (eg, palpitations, arrhythmias) and the kidneys (eg, fluid retention, renal failure).Anagrelide should be used with caution in older patients because of its effects on the cardiovascular system (eg, palpitations, arrhythmias) and the kidneys (eg, fluid retention, renal failure).
Peginterferon alfa-2a and peginterferon alfa-2b are effective in essential thrombocythemia for lowering the driver mutation allele burden and alleviating symptoms. Interferon is the safest therapy for migraine when dedicated migraine medications are not effective.Peginterferon alfa-2a and peginterferon alfa-2b are effective in essential thrombocythemia for lowering the driver mutation allele burden and alleviating symptoms. Interferon is the safest therapy for migraine when dedicated migraine medications are not effective.
JAK2 inhibitors such as ruxolitinib may be effective, but more data are needed (JAK2 inhibitors such as ruxolitinib may be effective, but more data are needed (4). One randomized trial found that ruxolitinib was not superior to standard therapy in achieving a hematologic response, reducing thrombotic or hemorrhagic events, or preventing disease progression (). One randomized trial found that ruxolitinib was not superior to standard therapy in achieving a hematologic response, reducing thrombotic or hemorrhagic events, or preventing disease progression (5). However, some study limitations included the use of prohibitively high doses of ruxolitinib in patients with partially treated essential thrombocythemia. ). However, some study limitations included the use of prohibitively high doses of ruxolitinib in patients with partially treated essential thrombocythemia.
Platelet removal (plateletpheresis) has been used in rare patients with serious hemorrhage or recurrent thrombosis or before emergency surgery to immediately reduce the platelet count. However, plateletpheresis is rarely necessary. Its effects are transient with a prompt rebound in the platelet count. Hydroxyurea or anagrelide do not provide an immediate effect but should be started at the same time as plateletpheresis.has been used in rare patients with serious hemorrhage or recurrent thrombosis or before emergency surgery to immediately reduce the platelet count. However, plateletpheresis is rarely necessary. Its effects are transient with a prompt rebound in the platelet count. Hydroxyurea or anagrelide do not provide an immediate effect but should be started at the same time as plateletpheresis.
Other interventions
Allogeneic stem cell transplantation is rarely used in essential thrombocythemia but can be effective if there is transformation to acute leukemia or development of secondary myelofibrosis.
Aminocaproic acid or tranexamic acid is effective for controlling hemorrhage due to acquired Aminocaproic acid or tranexamic acid is effective for controlling hemorrhage due to acquiredvon Willebrand syndrome during minor procedures such as dental work. Major procedures may require reduction of platelet counts. Platelet function can be assessed by measuring ristocetin cofactor activity.
Treatment references
1. Tefferi A, Barbui T. Polycythemia vera and essential thrombocythemia: 2021 update on diagnosis, risk-stratification and management. Am J Hematol. 2020;95(12):1599-1613. doi:10.1002/ajh.26008
2. Cimen Bozkus C, Roudko V, Finnigan JP, et al. Immune Checkpoint Blockade Enhances Shared Neoantigen-Induced T-cell Immunity Directed against Mutated Calreticulin in Myeloproliferative Neoplasms. Cancer Discov. 2019;9(9):1192-1207. doi:10.1158/2159-8290.CD-18-1356
3. Faiz M, Riedemann M, Jutzi JS, et al. Mutant Calreticulin in MPN: Mechanistic Insights and Therapeutic Implications. Curr Hematol Malig Rep. 2025;20(1):4. Published 2025 Jan 8. doi:10.1007/s11899-024-00749-4
4. Ferrer-Marín F, Hernández-Boluda JC, Alvarez-Larrán A. Essential thrombocythaemia: A contemporary approach with new drugs on the horizon. Br J Haematol. 2024;204(5):1605-1616. doi:10.1111/bjh.19403
5. Harrison CN, Mead AJ, Panchal A, et al. Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide. . Ruxolitinib vs best available therapy for ET intolerant or resistant to hydroxycarbamide.Blood. 2017;130(17):1889-1897. doi:10.1182/blood-2017-05-785790
Prognosis for Essential Thrombocythemia
Life expectancy can be normal. Although symptoms are common, the course of the disease is usually benign, particularly in women (1).
Serious arterial thrombotic complications are rare but can be life threatening. Leukemic transformation occurs in < 2% of patients but may increase after exposure to cytotoxic therapy, including hydroxyurea. 2% of patients but may increase after exposure to cytotoxic therapy, including hydroxyurea.
Some patients develop secondary myelofibrosis, particularly men with the JAK2V617F or CALR type 1 mutations.
Patients with essential thrombocythemia who test negative for all 3 mutations (JAK2 V617F, CALR, MPL) are rare and usually have a good prognosis.
Prognosis reference
1. Tefferi A, Gangat N, Loscocco GG, et al. Essential Thrombocythemia: A Review. JAMA. 2025;333(8):701-714. doi:10.1001/jama.2024.25349
Key Points
Essential thrombocythemia is a clonal abnormality of a multipotent hematopoietic stem cell resulting in increased platelet production.
Patients are at risk of microvascular thrombosis and hemorrhage.
Essential thrombocythemia is a diagnosis of exclusion; in particular, other myeloproliferative neoplasms and reactive (secondary) thrombocytosis must be ruled out.
Patients without symptoms require no therapy. Aspirin is usually effective for microvascular events (ocular migraine, erythromelalgia, and transient ischemic attacks). Patients without symptoms require no therapy. Aspirin is usually effective for microvascular events (ocular migraine, erythromelalgia, and transient ischemic attacks).
Patients with extreme thrombocytosis may require more aggressive treatment to control the platelet count; such measures include peginterferon alfa-2a; peginterferon alfa-2b; hydroxyurea; anagrelide; ruxolitinib; or rarely, plateletpheresis.Patients with extreme thrombocytosis may require more aggressive treatment to control the platelet count; such measures include peginterferon alfa-2a; peginterferon alfa-2b; hydroxyurea; anagrelide; ruxolitinib; or rarely, plateletpheresis.
Drugs Mentioned In This Article
