Essential thrombocythemia
Other names	Essential thrombocythaemia, essential thrombocytosis, primary thrombocytosis
Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia.
Specialty	Hematology
Symptoms	Fatigue, insomnia, migraines, headache, and dizziness.[1]
Complications	Thrombosis, transient ischemic attack, acute coronary syndrome, Budd-Chiari syndrome.[1]
Causes	Overproduction of hematopoietic cells, genetic mutations.[1]
Diagnostic method	Clinical criteria.
Differential diagnosis	Chronic myelogenous leukemia, myelodysplastic syndrome, polycythemia vera, primary myelofibrosis, secondary thrombocytosis.[1]
Treatment	Low-dose aspirin, plateletpheresis, cytoreductive therapy.[1]
Prognosis	Median survival is 18 years.[1]
Frequency	0.6-2.5/100,000 cases per year.[2]

In hematology, essential thrombocythemia (ET) is a rare chronic blood cancer (myeloproliferative neoplasm) characterised by the overproduction of platelets (thrombocytes) by megakaryocytes in the bone marrow.^[3] It may, albeit rarely, develop into acute myeloid leukemia or myelofibrosis.^[3] It is one of the blood cancers wherein the bone marrow produces too many white or red blood cells, or platelets.^[3]

Signs and symptoms

Most people with essential thrombocythemia are without symptoms at the time of diagnosis, which is usually made after noting an elevated platelet level on a routine complete blood count (CBC).^[4] The most common symptoms are bleeding (due to dysfunctional platelets), blood clots (e.g., deep vein thrombosis or pulmonary embolism), fatigue, headache, nausea, vomiting, abdominal pain, visual disturbances, dizziness, fainting, and numbness in the extremities; the most common signs are increased white blood cell count, reduced red blood cell count, and an enlarged spleen.^[4][5][6]

Cause

In ET, megakaryocytes are more sensitive to growth factors.^[7] Platelets derived from the abnormal megakaryocytes are activated, which, along with the elevated platelet count, contributes to the likelihood of forming blood clots.^[8] The increased possibility of bleeding when the platelet count is over 1 million is due to von Willebrand factor (vWF) sequestration by the increased mass of platelets, leaving insufficient vWF for platelet adhesion.^[8] A mutation in the JAK2 kinase (V617F) is present in 40–50% of cases and is diagnostic if present.^[3][8] JAK2 is a member of the Janus kinase family.^[3][8]

In 2013, two groups detected calreticulin mutations in a majority of JAK2-negative/MPL-negative patients with essential thrombocythemia and primary myelofibrosis, which makes CALR mutations the second most common in myeloproliferative neoplasms. All mutations (insertions or deletions) affected the last exon, generating a reading frame shift of the resulting protein, that creates a novel terminal peptide and causes a loss of endoplasmic reticulum KDEL retention signal.^[9][10]

Diagnosis

The following revised diagnostic criteria for essential thrombocythemia were proposed in 2005.^[11] The diagnosis requires the presence of both A criteria together with B3 to B6, or of criterion A1 together with B1 to B6.^[12] The criteria are as follows:^[12]

• A1. Platelet count > 400 × 10³/µL 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 with 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

Indications

Not all those affected will require treatment at presentation.^[13][14][15] Patients are usually designated as having a low or high risk of bleeding or developing blood clots based on their age, medical history, blood counts and their lifestyles. Low risk individuals are usually treated with aspirin, whereas those at high risk are treated with hydroxycarbamide, interferon-α or anagrelide).^{[3][13][14][15]} Currently unapproved but in late-stage clinical trials (NCT04254978) are agents that lower platelets such as bomedemstat.

Agents

Hydroxycarbamide, interferon-α and anagrelide can lower the platelet count. Low-dose aspirin is used to reduce the risk of blood clot formation unless the platelet count is very high, where there is a risk of bleeding from the disease, and hence this measure would be counter-productive as aspirin-use increases the risk of bleeding.^{[3][13][14][15]}

The PT1 study compared hydroxyurea plus aspirin to anagrelide plus aspirin as initial therapy for ET. Hydroxyurea treated patients had a lower incidence of arterial thrombosis, lower incidence of severe bleeding and lower incidence of transformation to myelofibrosis, but the risk of venous thrombosis was higher with hydroxycarbamide than with anagrelide. It is unknown whether the results are applicable to all ET patients.^{[3][13][14][15]} In people with symptomatic ET and extremely high platelet counts (exceeding 1 million), plateletpheresis can be used to remove platelets from the blood to reduce the risk of thrombosis.^[16]

Prognosis

Essential thrombocythemia is sometimes described as a slowly progressive disorder with long asymptomatic periods punctuated by thrombotic or hemorrhagic events.^[13] However, well-documented medical regimens can reduce and control the number of platelets, which reduces the risk of these thrombotic or hemorrhagic events. The lifespan of a well-controlled ET person is well within the expected range for a person of similar age but without ET.^[13] ET is the myeloproliferative neoplasm least likely to progress to acute myeloid leukemia.^[17]

Epidemiology

The incidence of ET is 0.6-2.5/100,000 per year, the median age at onset is 65–70 years and it is more frequent in females than in males.^[2] The incidence in children is 0.09/100,000 per year.^[2]

Pregnancy

Hydroxycarbamide and anagrelide are contraindicated during pregnancy and nursing.^[18] Essential thrombocythemia can be linked with a three-fold increase in risk of miscarriage.^[2] Throughout pregnancy, close monitoring of the mother and fetus is recommended.^[18] Low-dose low molecular weight heparin (e.g. enoxaparin) may be used.^[18] For life-threatening complications, the platelet count can be reduced rapidly using plateletpheresis, a procedure that removes platelets from the blood and returns the remainder to the patient.^[18]

In popular culture

Jill Kaplan, the female protagonist of The Pajama Diaries comic strip was diagnosed with essential thrombocythemia.^[19]