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Essential Thrombocythemia

(Essential Thrombocytosis; Primary Thrombocythemia)

By

Jane Liesveld

, MD, James P. Wilmot Cancer Institute, University of Rochester Medical Center

Last full review/revision Sep 2020| Content last modified Sep 2020
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Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by an increased platelet count, megakaryocytic hyperplasia, and a hemorrhagic or microvascular thrombotic tendency. Symptoms and signs may include weakness, headaches, paresthesias, bleeding, and erythromelalgia with digital ischemia. Diagnosis is based on a platelet count > 450,000/mcL (> 450,000 × 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 could cause thrombocytosis. Treatment is controversial but may include aspirin. Patients > 60 years and those with previous thromboses and transient ischemic attacks are at higher risk for subsequent thromboembolic events. There is no correlation between the risk of macrovascular thrombosis and the platelet count.

Etiology

Essential thrombocythemia is a clonal hematopoietic stem cell disorder that causes increased platelet production. Essential thrombocythemia usually occurs with bimodal peaks; an early peak among young females and a later peak after age 50 in both woman and men.

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) among other entities. Other patients have mutations in exon 9 of the calreticulin gene (CALR), and a few have acquired somatic thrombopoietin receptor gene mutations (MPL).

Some myelodysplastic syndromes (eg, refractory anemia with ringed sideroblasts and thrombocytosis [RARS-T],and the 5q- syndrome) may present with elevated platelet count.

Pathophysiology

Thrombocythemia may lead to

  • Microvascular occlusions (usually reversible)

  • 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.

Whether the risk of large vessel thrombosis causing deep venous thrombosis or pulmonary embolism is increased in essential thrombocythemia is unclear, particularly because platelets are primarily involved in arterial thrombosis and there is no correlation between the platelet count and large vessel thrombosis.

Bleeding is more likely with extreme thrombocytosis (ie, about 1.5 million platelets/mcL [1.5 million × 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 an acquired von Willebrand syndrome.

Symptoms and Signs

Common symptoms are

  • Weakness

  • Bruising and bleeding

  • Gout

  • Ocular migraines

  • Paresthesias of the hands and feet

  • Thrombotic events

Thrombosis may cause symptoms in the affected site (eg, neurologic deficits with stroke or transient ischemic attack).

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 cases with extreme thrombocytosis.

Erythromelalgia (burning pain in hands and feet, with warmth, erythema, and sometimes digital ischemia) may occur. The spleen may be palpable but significant splenomegaly is unusual and should suggest another myeloproliferative neoplasm.

Diagnosis

  • Complete blood count (CBC) and peripheral blood smear

  • Exclusion of causes of secondary thrombocytosis

  • Cytogenetic studies

  • JAK2 mutation by polymerase chain reaction, and, if negative, CALR or MPL mutation analysis

  • Possibly a bone marrow examination

The platelet count is > 450,000/mcL (> 450,000 × 109/L) but can be >1,000,000/mcL (> 1,000,000 × 109/L). The platelet count may decrease during pregnancy. The peripheral smear may show giant platelets and megakaryocyte fragments.

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 cytopenias are identified, myelodysplastic syndrome should be considered.

If essential thrombocythemia is suspected, complete blood count (CBC), peripheral blood smear, iron studies, and genetic studies, including a quantitative JAK2 V617F assay, should be done, along with a BCR-ABL assay to exclude chronic myeloid leukemia (CML, which can manifest with thrombocytosis alone). If the JAK2 and BCR-ABL assays are negative, CALR and MPL mutation assays should be done. The diagnosis of essential thrombocythemia is suggested by normal hematocrit, WBC count, mean corpuscular volume (MCV), and iron studies, as well as absence of the BCR-ABL translocation.

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 two disorders can present with thrombocytosis alone, and in polycythemia vera, plasma volume expansion can mask the presence of an expanded red cell mass. Also, about 25% of patients (primarily women), with what initially appears to be essential thrombocythemia over time transform to overt polycythemia vera, with 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. However, a marrow biopsy can be used to determine if there is significant fibrosis.

Prognosis

Life expectancy is near normal. Although symptoms are common, the course of the disease is often benign. 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. Some patients develop secondary myelofibrosis, particularly men with the JAK2V617F or CALR type 1 mutations.

Treatment

  • Aspirin

  • Platelet-lowering drugs (eg, hydroxyurea, anagrelide)

  • Rarely plateletpheresis

  • Rarely cytotoxic agents

  • Rarely interferon

  • Rarely stem cell transplantation

For mild vasomotor symptoms (eg, headache, mild digital ischemia, erythromelalgia) and to decrease the risk of thrombosis in low-risk patients, aspirin 81 mg orally once a day is usually sufficient, 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.

Aminocaproic acid or tranexamic acid is effective for controlling hemorrhage due to acquired von Willebrand syndrome during minor procedures such as dental work. Major procedures may require optimization of platelet counts.

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 asymptomatic patients. Generally agreed-upon indications for platelet-lowering therapy include

  • Cardiovascular risk factors

  • Transient ischemic attacks

  • Older age

  • 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. Those who are JAK2-positive and/or older than 65 are at greatest risk for thromboembolic complications.

Drugs used to lower platelet count include anagrelide, interferon alfa-2b, and hydroxyurea. Hydroxyurea is generally considered the drug of choice for short-term use. Because anagrelide and hydroxyurea cross the placenta, they are not used during pregnancy; 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. 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).

Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring. It is started at a dose of 500 to 1000 mg orally once a day. Patients are monitored with a weekly CBC. If the WBC count falls to < 4000/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 rather than platelet count normalization. Too-rapid withdrawal of hydroxyurea can result in rapid rebound and platelet cycling.

Ruxolitinib, a drug that is used in polycythemia vera and primary myelofibrosis, has been studied in patients with essential thrombocythemia who are resistant to other treatments.

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 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.

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, hemorrhage, and rarely macrovascular thrombosis.

  • Essential thrombocythemia is a diagnosis of exclusion; in particular, other myeloproliferative neoplasms and reactive (secondary) thrombocytosis must be ruled out.

  • Asymptomatic patients require no therapy. Aspirin is usually effective for microvascular events (ocular migraine, erythromelalgia and transient ischemic attacks).

  • Some patients with extreme thrombocytosis require more aggressive treatment to control the platelet count; such measures include hydroxyurea, anagrelide, interferon alfa-2b, and plateletpheresis.

Drugs Mentioned In This Article

Drug Name Select Trade
AMICAR
CYKLOKAPRON
JAKAFI
HYDREA
AGRYLIN
No US brand name
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