Essential thrombocytosis (ET, also known as essential thrombocythemia) is a rare chronic blood disorder characterized by the overproduction of platelets by megakaryocytes in the bone marrow in the absence of an alternative cause. In some cases this disorder may be progressive, and rarely may evolve into acute myeloid leukemia or myelofibrosis. It is one of four myeloproliferative disorders.

Epidemiology

Essential thrombocytosis is diagnosed at a rate of about 2 to 3 per 100,000 individuals annually.^[1][2] The disease usually affects middle aged to elderly individuals, with an average age at diagnosis of 50-60 years, although it can affect children and young adults as well.^[3]

Pathophysiology

The pathologic basis for this disease is unknown. However, essential thrombocytosis resembles polycythemia vera in that cells of the megakaryocytic series are more sensitive to growth factors. Platelets derived from the abnormal megakaryocytes do not function properly, which contributes to the clinical features of bleeding and thrombosis.

In 2005, a mutation in the JAK2 kinase (V617F) was found by multiple research groups ^{[4][5] [6]} to be associated with essential thrombocytosis in around 30% of cases. JAK2 is a member of the Janus kinase family. This mutation may be helpful in making a diagnosis or as a target for future therapy.

Clinical features

The major symptoms are bleeding and thrombosis. Other symptoms include epistaxis (nosebleeds) and bleeding from gums and gastrointestinal tract. One characteristic symptom is throbbing and burning of the hands and feet due to the occlusion of small arterioles by platelets (erythromelalgia). An enlarged spleen (splenomegaly) may be found on examination.

Diagnostic criteria

The diagnosis of essential thrombocytosis requires the presence of a persistent thrombocytosis of greater than 600 x10⁹/L in the absence of an alternative cause.

The following revised diagnostic criteria for essential thrombocytosis were proposed in 2005 ^[7]. The diagnosis requires the presence of both A criteria together with B3 to B6, or of criterion A1 together with B1 to B6.

• A1. Platelet count > 600 x 10⁹/L for at least 2 months
• A2. Acquired V617F JAK2 mutation present
• B1. No cause for a reactive thrombocytosis
  • normal inflammatory indices
• B2. No evidence of iron deficiency
  • stainable iron in the bone marrow or normal red cell mean corpuscular volume
• B3. No evidence of polycythemia vera
  • hematocrit < midpoint of normal range or normal red cell mass in presence of normal iron stores
• B4. No evidence of chronic myeloid leukemia

But the Philadelphia chromosome may be present in up to 10% of cases. Patients withe the Philadelphia chromosome have a potential for the development of acute leukemia, especially acute lymphocytic leukemia.

• B5. No evidence of myelofibrosis
  • no collagen fibrosis and ≤ grade 2 reticulin fibrosis (using 0–4 scale)
• B6. No evidence of a myelodysplastic syndrome
  • no significant dysplasia
  • no cytogenetic abnormalities suggestive of myelodysplasia

Treatment

Not all patients will require treatment at presentation. In those who are at increased risk of thrombosis or bleeding (older age, prior history of bleeding or thrombosis, or very high platelet count), reduction of the platelet count to the normal range can be achieved using hydroxyurea (also known as hydroxycarbamide), interferon-α or anagrelide. Low-dose aspirin is widely used to reduce the risk of thrombosis, but there may be an increased risk of bleeding if aspirin is initiated whilst the platelet count is very high.

The PT1 study ^[8] compared hydroxyurea in combination with aspirin to anagrelide in combination with Aspirin as initial therapy for essential thrombocytosis. Hydroxyurea was superior, with lower risk of arterial thrombosis, lower risk of severe bleeding and lower risk of transformation to myelofibrosis (although the rate of venous thrombosis was higher with hydroxycarbamide than with anagrelide).

In rare cases where patients have life-threatening complications, the platelet count can be reduced rapidly using platelet apheresis (a procedure that removes platelets from the blood directly).

Prognosis

Essential thrombocytosis is a slowly progressive disorder with long asymptomatic periods punctuated by thrombotic or hemorrhagic events.

Special care related to pregnancy

Hydroxyrea and anagrelide are counter-indicated during pregnancy and nursing. There is current debate as to the safety of interferon during pregnancy and nursing. Essential thrombocytosis can be linked with increased risk of spontaeous abortion or miscarriage in the first trimester of pregnancy. Throughout pregnancy, close monitoring of the mother for thrombosis and placenta is recommended to ensure blood clots are caught. Post partum, often daily injections of low dose low molecular weight heparin (e.g. enoxaparin) are prescribed for several weeks as this is a period where the mother is at higher risk of developing a blood clot.

References