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.

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.

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.

• 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.

• 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.

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.