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/mcL ( 450 10/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 rearrangement), or reactive disorders that cause thrombocytosis. No treatment is required in most patients who are asymptomatic. The presence of extreme thrombocytosis (platelet count > 1,500,000/mcL [> 1,500,000 10/L]) may increase risk of bleeding. 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 increased incidence in females .
A Janus kinase 2 (JAK2) enzyme mutation, JAK2V617F, is present in about 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. Tefferi A, Wassie EA, Guglielmelli P, et al. Type 1 versus Type 2 calreticulin mutations in essential thrombocythemia: a collaborative study of 1027 patients. Am J Hematol 2014;89(8):E121-E124. doi:10.1002/ajh.23743
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, about 1.5 million platelets/mcL [1500 × 109/L]); it is due to an acquired deficiency of von Willebrand factor caused because the 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
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.
Transient ischemic attacks 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, 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 are excluded.
If essential thrombocythemia is suspected, complete blood count (CBC), peripheral blood smear, and (because thrombocytosis can be caused by iron deficiency) iron studies should be done .
In essential thrombocythemia, the platelet count is > 450,000/mcL (> 450 × 109/L), but can be >1,000,000/mcL (> 1000 × 109/L). The platelet count may decrease 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], and the 5q- syndrome) may present with an elevated platelet count. If cytopenias are identified, a myelodysplastic syndrome should be considered.
Genetic studies should be done, including a quantitative JAK2 V617F assay (by next-generation sequencing [NGS] or quantitative polymerase chain reaction), 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 done. 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 about 25% of patients (primarily women) with what initially appears to be essential thrombocythemia, transformation to overt polycythemia vera occurs over time (about 12 years), leading to an increase in hematocrit and an increase in the JAK2V617F allele burden.
World Health Organization guidelines suggest 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 (1). The allele burden is usually >50% in polycythemia vera and primary myelofibrosis.
Diagnosis reference
1. 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-
Treatment of Essential Thrombocythemia
Sometimes aspirin
Rarely plateletpheresis
Rarely stem cell transplantation
JAK2 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. 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.
von Willebrand syndrome during minor procedures such as dental work. Major procedures may require optimization of platelet counts. Platelet function can be assessed by measuring ristocetin cofactor activity.
Allogeneic stem cell transplantation is rarely used in essential thrombocythemia but can be effective if there is transformation to acute leukemia.
Lowering platelet count
Because prognosis is usually good and there is no correlation between degree of thrombocytosis and thrombosis, potentially toxic drugs 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
Cardiovascular risk factors
Transient ischemic attacks
Tobacco use
Significant bleeding
Need for a surgical procedure in patients with extreme thrombocytosis and low ristocetin cofactor activity
Sometimes severe migraine
However, there are no data that prove cytotoxic therapy to reduce the platelet count lowers thrombotic risk or improves survival.
Drugs used to lower platelet count
Hydroxyurea, once considered the drug of choice for essential thrombocythemia therapy, has no benefit and is myelotoxic when used long-term.
< 4000/mcL (< 4 × 109
Because anagrelide and hydroxyurea cross the placenta, they are not used during pregnancy; pegylated interferon alfa-2a can be used in pregnant women when necessary.
Interferon is the safest therapy for migraine when dedicated migraine drugs are not effective.
1).
Platelet removal (plateletpheresis)
Treatment reference
1. Harrison CN, Nangalia J, Boucher R, et al. Ruxolitinib Versus Best Available Therapy for Polycythemia Vera Intolerant or Resistant to Hydroxycarbamide in a Randomized Trial. J Clin Oncol 2023;41(19):3534-3544. doi:10.1200/JCO.22.01935
Prognosis for Essential Thrombocythemia
Life expectancy is nearly normal. Although symptoms are common, the course of the disease is usually benign.
Serious arterial thrombotic complications are rare but can be life-threatening. Leukemic transformation occurs in <
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 have a good prognosis.
Key Points
Essential thrombocythemia is a clonal abnormality of a multipotent hematopoietic stem cell resulting in increased platelets.
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.
