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Essential Thrombocythemia

(Essential Thrombocytosis; Primary Thrombocythemia)

by Jane Liesveld, MD, Patrick Reagan, MD

Essential thrombocythemia (ET) is 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 require cytotoxic drugs to decrease risk of thromboses. Data suggest that risk of thrombosis does not correlate with platelet count, although anecdotal experience suggests otherwise.

Pathophysiology

ET is a typically clonal abnormality of a multipotent hematopoietic stem cell. However, some women who fulfill diagnostic criteria for ET have polyclonal hematopoiesis. ET usually occurs with bimodal peaks of between ages 50 and 70 yr and a separate peak among young females.

Platelet production is increased. Platelet survival is usually normal, although it may decrease due to splenic sequestration or, in patients with erythromelalgia, digital ischemia.

Increased platelets may lead to serious bleeding or, more commonly, thrombosis. Thrombosis is the major cause of morbidity and mortality. Recent studies indicate that an elevated leukocyte count is a major independent risk factor for thromboses. Although anecdotally (and intuitively), elevated platelet count may increase the risk of thrombosis, one study found an inverse relationship between absolute platelet count and thrombotic risk. Bleeding is more likely with extreme thrombocytosis (ie, > 1.5 million platelets/μL) due to an acquired deficiency of von Willebrand factor.

Symptoms and Signs

Common symptoms are

  • Weakness

  • Bruising and bleeding

  • Gout

  • Ocular migraines

  • Paresthesias of the hands and feet

  • Thrombosis and thromboembolic 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. 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

  • Possibly bone marrow examination

ET is a diagnosis of exclusion and should be considered in patients in whom common reactive causes (see Reactive Thrombocytosis (Secondary Thrombocythemia)) are excluded. If ET is suspected, CBC, peripheral blood smear, and cytogenetic studies, including Philadelphia chromosome or BCR-ABL assay, should be done. Some authorities recommend bone marrow examination, especially in patients with anemia, macrocytosis, leukopenia, or evidence of extramedullary hematopoiesis (eg, enlarged liver and/or spleen or other soft-tissue infiltration). However, although classic ET morphologic abnormalities have been described, the diagnostic value of bone marrow examination is not established.

The platelet count can be >1,000,000/μL but may be as low as 450,000/μL. Platelet count may decrease spontaneously during pregnancy. The peripheral smear may show platelet aggregates, giant platelets, and megakaryocyte fragments. The bone marrow shows megakaryocytic hyperplasia, with an abundance of platelets being released. Bone marrow iron is present.

To distinguish 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-ABL translocation; and absence of teardrop-shaped RBCs, although there may be significant increase in bone marrow fibrosis (present in idiopathic myelofibrosis). The JAK2V617F mutation occurs in about 50% of patients, and if present, helps distinguish ET from other causes of thrombocythemia. A small minority of ET patients have acquired somatic thrombopoietin receptor gene mutations ( c-mpl ). A few others have mutations of exon 9 of the calreticulin gene.

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, especially alkylating agents.

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 may be sufficient. Also, most pregnant patients are given aspirin. Use in low-risk patients is acceptable but not data-proven.

Because prognosis is often good, potentially toxic drugs that lower the platelet count should be used sparingly. Generally agreed indications for such therapy are

  • Previous thromboses or transient ischemic attack

  • Age > 60 yr

Other indications are controversial. Patients with significant bleeding or extreme thrombocytosis (high-risk patients) may need therapy to lower the platelet count. It is unclear whether asymptomatic patients < 60 yr need platelet-lowering drugs. Myelosuppressive drugs to lower platelet count include anagrelide, interferon alfa-2b, and hydroxyurea (sometimes with low-dose aspirin). Hydroxyurea is generally considered the drug of choice, although some clinicians prefer anagrelide. Because anagrelide and hydroxyurea cross the placenta, they are not used during pregnancy; interferon alfa-2b can be used in pregnant women when necessary.

Dosage and monitoring of hydroxyurea are described in the treatment of polycythemia vera (see Polycythemia Vera). The conventional aim of therapy is a platelet count <450,000/μL without significant clinical toxicity or suppression of other bone marrow elements. Some experts recommend a lower platelet count.

Platelet removal (plateletpheresis) has been used in rare patients with serious hemorrhage and recurrent thrombosis or before emergency surgery to immediately reduce the platelet count; this procedure, however, is rarely necessary. Due to the long half-life of platelets (7 days), hydroxyurea and anagrelide do not provide an immediate effect.

Allogeneic stem cell transplantation (see Hematopoietic Stem Cell Transplantation) is rarely used in ET but can be effective in younger patients if other treatments are unsuccessful and a good donor is available.

Key Points

  • ET is typically a clonal abnormality of a multipotent hematopoietic stem cell resulting in increased platelets.

  • Patients have an increased risk of both thrombosis and, to a lesser extent, hemorrhage.

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

  • Treat most patients with aspirin.

  • Other treatments are controversial, but high-risk patients (eg, those > 60 yr, with significant bleeding, recurrent thromboses, extreme thrombocytosis) may benefit from more aggressive treatment with myelosuppressive drugs, interferon alfa-2b, plateletpheresis.

Drugs Mentioned In This Article

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

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