(Essential Thrombocytosis; Primary Thrombocythemia)
(See also Overview of Myeloproliferative Neoplasms.)
Essential thrombocythemia is a clonal hematopoietic stem cell disorder that causes increased platelet production. Essential thrombocythemia usually occurs with bimodal peaks of between ages 50 and 70 years and a separate peak among young 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) 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], the 5q- syndrome) may present with elevated platelet count.
Thrombocythemia may lead to
Microvascular occlusions often involve small vessels of the distal extremities (causing erythromelalgia), the eye (causing ocular migraine), or the CNS (causing transient ischemic attack). Not all patients experience microvascular symptoms even when platelet counts are high.
The risk of large vessel thrombosis causing deep venous thrombosis or pulmonary embolism is increased in essential thrombocythemia. However, there is no correlation between the platelet count and thrombosis.
Bleeding is more likely with extreme thrombocytosis (ie, about 1.5 million platelets/mcL); 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.
Common symptoms are
Thrombosis may cause symptoms in the affected site (eg, neurologic deficits with stroke or transient ischemic attack; leg pain, swelling, or both with lower extremity thrombosis; chest pain and dyspnea with pulmonary embolism).
Bleeding is usually mild, rarely spontaneous, and manifests as epistaxis, easy bruisability, or GI 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.
The platelet count is > 450,000/mcL but can be >1,000,000/mcL. 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 requires normal hematocrit, WBC count, MCV, and iron studies, and 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 %; this finding suggests polycythemia vera or primary myelofibrosis.
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. Cytogenetic studies can be done on marrow aspirate material, and the marrow can be used to determine if there is significant fibrosis.
Polycythemia vera can initially manifest with thrombocytosis and be confused with essential thrombocythemia (thrombocytosis may predominate in polycythemia vera either because of plasma volume expansion or because the other manifestations of polycythemia have not yet appeared). 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.
Life expectancy is near normal. Although symptoms are common, the course of the disease is often benign. Serious arterial and venous 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.
For mild vasomotor symptoms (eg, headache, mild digital ischemia, erythromelalgia) and to decrease the risk of thrombosis in low-risk patients, aspirin 81 mg po once/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.
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
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 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 - 2b can be used in pregnant women when necessary. Interferon is the safest therapy for migraine.
Hydroxyurea should be prescribed only by specialists familiar with its use and monitoring. It is started at a dose of 500 to 1000 mg po once/day. Patients are monitored with a weekly CBC. If the WBC count falls to < 4000/mcL, 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. The role of ruxolitinib, A JAK1/JAK2 inhibitor, is currently under study.
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.
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|
interferon alfa - 2b
|Interferon Alfa - 2b|
|No US brand name|