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, absence of myelofibrosis, the Philadelphia chromosome (or BCR-ABL rearrangement), and 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 and in patients with erythromelalgia with digital ischemia.

In elderly patients with atherosclerosis, 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 von Willebrand's factor deficiency.

Symptoms and Signs

Common symptoms are

• Weakness
• Hemorrhage
• Gout
• Ocular migraines
• Paresthesias of the hands and feet

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. Digital ischemia may occur, and splenomegaly (usually not extending > 3 cm below the left costal margin) occurs in < 50% of patients. Hepatomegaly may rarely occur. In pregnant patients, thrombosis may cause recurrent spontaneous abortions.

Diagnosis

• CBC and peripheral blood smear
• Cytogenetic studies
• Possibly bone marrow examination

ET should be considered in patients in whom common reactive causes (see Myeloproliferative Disorders: Thrombocytosis) 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, but 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 produce 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; there may be significant increase in bone marrow fibrosis (present in idiopathic myelofibrosis). The JAK2V617F mutation occurs in about 50% of patients, and a small minority of ET patients has acquired somatic thrombopoietin receptor gene mutations (c-mpl).

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

• AspirinSome Trade Names
  BUFFERIN
  ECOTRIN
  GENACOTE
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• Platelet-lowering drugs (eg, hydroxyureaSome Trade Names
  HYDREA
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  , anagrelideSome Trade Names
  AGRYLIN
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  )
• Rarely plateletpheresis

For mild vasomotor symptoms (eg, headache, mild digital ischemia, erythromelalgia) and to decrease the risk of thrombosis in low-risk patients, aspirinSome Trade Names
BUFFERIN
ECOTRIN
GENACOTE
Click for Drug Monograph
81 mg po once/day may be sufficient. Also, most pregnant patients are given aspirinSome Trade Names
BUFFERIN
ECOTRIN
GENACOTE
Click for Drug Monograph
. 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 and 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 anagrelideSome Trade Names
AGRYLIN
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, interferon alfa-2bSome Trade Names
ROFERON
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, and hydroxyureaSome Trade Names
HYDREA
Click for Drug Monograph
(sometimes with low-dose aspirinSome Trade Names
BUFFERIN
ECOTRIN
GENACOTE
Click for Drug Monograph
). HydroxyureaSome Trade Names
HYDREA
Click for Drug Monograph
is generally considered the drug of choice, although some clinicians prefer anagrelideSome Trade Names
AGRYLIN
Click for Drug Monograph
. Because anagrelideSome Trade Names
AGRYLIN
Click for Drug Monograph
and hydroxyureaSome Trade Names
HYDREA
Click for Drug Monograph
cross the placenta, they are not used during pregnancy; interferon alfa-2bSome Trade Names
ROFERON
Click for Drug Monograph
can be used in pregnant women when necessary.

Dosage and monitoring are described in the treatment of polycythemia vera (see Myeloproliferative Disorders: 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; however, this goal needs to be reevaluated in view of recent data suggesting an inverse relationship between platelet count and thrombotic risk.

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), hydroxyureaSome Trade Names
HYDREA
Click for Drug Monograph
and anagrelideSome Trade Names
AGRYLIN
Click for Drug Monograph
do not provide an immediate effect.

Thrombocytosis

(Secondary Thrombocythemia)

Thrombocytosis can develop secondary to

• Chronic inflammatory disorders, eg, RA, inflammatory bowel disease, TB, sarcoidosis, Wegener's granulomatosis
• Acute infection
• Hemorrhage
• Iron deficiency
• Hemolysis
• Cancer (particularly Hodgkin lymphoma, non-Hodgkin lymphoma)
• Splenectomy
• Myeloproliferative and hematologic disorders (eg, polycythemia vera, chronic myelocytic leukemia, sideroblastic anemia, myelodysplasia [5q- syndrome], idiopathic myelodysplasia)

There are also congenital familial thrombocytoses such as those due to thrombopoietin and thrombopoietin receptor gene mutations.

Platelet function is usually normal. Unlike ET, thrombocytosis does not increase the risk of thrombotic or hemorrhagic complications unless patients have severe arterial disease or prolonged immobility. With secondary thrombocytosis, the platelet count is usually < 1,000,000/μL, and the cause may be obvious from the history and physical examination (perhaps with confirmatory testing). CBC and peripheral blood smear should help suggest iron deficiency or hemolysis. If a cause is not obvious, evaluation for a myeloproliferative disorder should be considered.

Treatment of the underlying disorder usually returns the platelet count to normal.

Last full review/revision September 2009 by Josef T. Prchal, MD; Scott Samuelson, MD

Content last modified February 2012