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Essential Thrombocythemia

(Essential Thrombocytosis; Primary Thrombocythemia)

By Jane Liesveld, MD, University of Rochester ; Patrick Reagan, MD, University of Rochester Medical Center

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Essential thrombocythemia (ET) is a myeloproliferative disorder characterized by an increased platelet count, megakaryocytic hyperplasia, and a hemorrhagic or thrombotic tendency. Symptoms and signs may include weakness, headaches, paresthesias, bleeding, splenomegaly, and erythromelalgia with digital ischemia. Diagnosis is based on a platelet count >450,000/μL, normal RBC mass or normal Hct in the presence of adequate iron stores, and the absence of myelofibrosis, the Philadelphia chromosome (or BCR-ABL rearrangement), or any other disorder that could cause thrombocytosis. Treatment is controversial but may include aspirin. Patients > 60 yr and those with previous thromboses and transient ischemic attacks are at higher risk for subsequent thromboembolic events. Data suggest that risk of thrombosis is not proportional to platelet count.

Etiology

Essential thrombocythemia is a clonal hematopoietic stem cell disorder that causes increased platelet production. ET usually occurs with bimodal peaks of between ages 50 and 70 yr 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 (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

  • Serious bleeding

Microvascular occlusions often involve small vessels of the distal extremities (causing erythromelalgia), the eye (causing ocular migraine), or the CNS (causing transient ischemic attack).

The risk of large vessel thrombosis causing deep venous thrombosis or pulmonary embolism is increased, but the risk does not increase proportional to the platelet count.

Bleeding is more likely with extreme thrombocytosis (ie, about 1.5 million platelets/μL); it is due to an acquired deficiency of von Willebrand factor caused because the platelets adsorb and proteolyze high molecular weight von Willebrand multimers.

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; leg pain, swelling or both with lower extremity thrombosis,;chest pain and dyspnea with pulmonary embolism).

Bleeding is usually mild and manifests as epistaxis, easy bruisability, or GI bleeding. However, serious bleeding may occur in a small percentage of cases.

Erythromelalgia (burning pain in hands and feet, with warmth, erythema, and sometimes digital ischemia) may occur. Splenomegaly (usually not extending > 3 cm below the left costal margin) occurs in < 50% of patients. Hepatomegaly may rarely occur. Thrombosis may cause recurrent spontaneous abortions.

Diagnosis

  • CBC and peripheral blood smear

  • Exclusion of causes of secondary thrombocythemia

  • Cytogenetic studies

  • JAK2 mutation by PCR, and, if negative, CALR or MPLmutation analysis

  • Possibly bone marrow examination

Essential thrombocythemia is a diagnosis of exclusion and should be considered in patients in whom common reactive causes (see Reactive Thrombocytosis (Secondary Thrombocythemia)) and other myeloproliferative disorders are excluded.

If ET is suspected, CBC, peripheral blood smear, iron studies and cytogenetic studies, including Philadelphia chromosome or BCR-ABL assay, should be done to distinguish essential thrombocythemia from other myeloproliferative disorders that cause thrombocytosis. The diagnosis of ET requires a normal Hct, MCV, and iron studies; absence of the Philadelphia chromosome and BCR-ABLtranslocation; and absence of teardrop-shaped RBCs.

The platelet count can be >1,000,000/μL but may be as low as 450,000/μL. Platelet count may decrease during pregnancy. The peripheral smear may show giant platelets and megakaryocyte fragments.

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, so biopsy is recommended, if possible. Biopsy will also help rule out other myeloproliferative or myelodysplastic syndromes, such as primary myelofibrosis, which often initially manifests as isolated thrombocytosis. The bone marrow in ET shows megakaryocytic hyperplasia, with an abundance of platelets being released. Bone marrow iron is usually present.

Testing for the JAK2V617Fmutation should be done; its presence helps distinguish ET from other causes of thrombocythemia. However, the JAK2V617F mutation also is present in many patients with polycythemia vera (PV). Thus, those few cases of PV that initially manifest with thrombocytosis can be confused with ET (thrombocytosis may predominate in PV either because of plasma volume expansion or because the other manifestations of polycythemia have not yet appeared.

If the JAK2 mutation is not present, testing for CALR and MPL should be done.

Prognosis

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.

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 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.

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

Allogeneic stem cell transplantation is rarely used in ET but can be effective in younger patients if other treatments are unsuccessful and a suitable donor is available.

Lowering platelet count

Because prognosis is usually good, 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

  • Previous thromboses or transient ischemic attack

  • Age > 60 yr

  • 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 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/μL, 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 wk and then to 4 wk. There is no specific target platelet count; the aim of therapy is a platelet count that restores ristocetin cofactor activity if bleeding is the problem or that alleviates symptoms.

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 and its effects are transient. Hydroxyurea or anagrelide do not provide an immediate effect but should be started at the same time as pheresis.

Key Points

  • ET 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.

  • ET is a diagnosis of exclusion; in particular, other myeloproliferative disorders 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; and such measures include hydroxyurea, anagrelide, interferon alfa-2b, or plateletpheresis.

Drugs Mentioned In This Article

  • Drug Name
    Select Trade
  • No US brand name
  • AGRYLIN
  • HYDREA

* This is the Professional Version. *