Overview

The year 1934 marks the discovery of Essential thrombocytosis (ET), also known as primary thrombocythemia or thrombocytosis. This condition was later classified as a myeloproliferative neoplasm(MPN) in 1951 by Damesheck. Around 1.0 - 2.5 new cases are occurring per one lakh individuals per year. Overall presence of new and old cases of the disease in the population was reported to be 38 - 57 per one lakh persons between 2008 and 2010. It had a notably higher incidence rate in women. The manifestations of ET increase with age. Most patients affected are between 50 and 60 years of age.¹

What is Essential Thrombocythemia (ET)?

Essential thrombocythemia (ET) is a rare chronic form of blood cancer. In this case, the stem cells in the bone marrow are responsible for the production of platelets (thrombocytes) in excess of the body's requirement. According to the World Health Organisation, essential thrombocytosis is defined by a platelet count of more than 450×10³/µL(> 450,000/µL) with the presence of JAK2, calreticulin (CALR), or myeloproliferative leukemia virus oncogene (MPL) mutations, along with the absence of uncontrolled stem cell growth or infections or inflammation. This method helps in understanding the cause of the disease, distribution across the globe, mechanism of action, evaluation, and treatment. ET is a slow-progressing disease, with a median survival of 18 to 20 years. Patients less than 60 years of age can expect a life expectancy of 33 years.¹

Symptoms

In individuals with no symptoms, a complete blood count, if done for any purpose, might reveal the disorder. For individuals with symptoms, the most common symptoms are 

• Weakness (in 90% of patients)
• Insomnia(sleep disturbances) 
• Migraines, headaches, and dizziness
• Various manifestations of the disorder include thrombosis, such as hepatic vein thrombosis, which is a hallmark of the disease
• Thrombosis in the legs (Deep vein thrombosis) arises due to the clots, leading to leg pain, swelling, or both
• Transient ischemic attacks are Strokes or temporary stroke-like episodes that take place due to clots that block blood flow to the brain
• Erythromelalgia(sensation in the skin of burning, tingling, or prickling, severe pain, redness, and swelling in hands and feet)
• Easy bruising
• Pulmonary embolism and difficulty breathing (dyspnea) due to the clots that travel to the lungs, block the blood flow in the lungs, and cause chest pain and dyspnea
• Abnormal bleeding(nosebleeds, bleeding gums, or bleeding in the gastrointestinal tract) occurs more often in people with a very high number of platelets^1,2

Molecular markers in essential thrombocythemia

ET, along with polycythemia vera and primary myelofibrosis, belongs to the BCR-ABL–negative myeloproliferative neoplasms (MPN) group. Most cases of essential thrombocythemia are not inherited. It is an acquired genetic disorder, as this condition arises from gene mutations that take place in early blood-forming cells after conception. These alterations are called somatic mutations. In ET cases, the genes that mutate affect the activity of stem cells in your bone marrow that make blood cells. 

The most commonly mutated genes in essential thrombocythemia are the JAK2 and CALR genes. Other genes, MPL, THPO, and TET2, can also be altered in this condition.

• JAK2, or Janus kinase 2, is a gene that instructs cells on how to produce the JAK2 protein, which helps regulate the stem cells responsible for the production of blood cells
• The CALR gene provides instructions for making the calreticulin protein, which helps to control gene activity, growth, and division of cells, and cell death. The CALR gene provides instructions for creating a protein with multiple functions, which includes ensuring the proper folding of newly formed proteins and maintenance of the appropriate levels of stored calcium in cells
• MPL, or myeloproliferative leukaemia virus, is an oncogene. Oncogenes are genes that may cause cancer
• The JAK2, MPL, and THPO genes provide instructions for making proteins that promote the growth and division (proliferation) of blood cells
• The TET2 gene provides instructions for the production of a protein whose function is yet to be discovered

When these genes mutate, they trigger a chain reaction that significantly stimulates stem cell production, leading to excess platelet production that your body can use. Researchers are working to find out other genes that may be involved in the condition, as some people with essential thrombocythemia do not have a mutation in any of the known genes associated with this condition.^2,3

Though 90% of adults have JAK2, CALR, or MPL mutations, it is not unusual for children to exhibit a trip-negative (wild-type) molecular profile.¹

Diagnostic and prognostic implications

Mutations in JAK2, CALR, and MPL are referred to as “driver mutations” because they help in the determination of the type of MPN you are affected by. In addition, based on the WHO’s 2016 revision to the classification of myeloid neoplasms and acute leukaemia, these mutations, together with the clinical, biological, and histological features, aid in the diagnosis. 

Because there are many causes of reactive thrombocytosis, using driver or nondriver mutations to prove clonality is essential for making an ET diagnosis. Driver mutations in JAK2, CALR, and MPL are detected in 60–65%, 20–25%, and 5% of patients with ET, respectively. However, a subset (10–15%) of patients with MPN, called triple-negative (TN) patients, do not present any of the driver mutations.⁴

The World Health Organization (WHO) diagnostic criteria for ET are established if all 4 major or 3 major and 1 minor criteria are met.¹ 

Major criteria

• The platelet count is greater than or equal to 450 × 10³/µL
• The bone marrow biopsy shows proliferation of the megakaryocytes(platelet-producing cells). These cells are increased in number, larger than normal, and have nuclei with many lobes. There is no major increase in white or red blood cell production, and only rarely a slight rise in supporting fibers (reticulin)
• Not meeting WHO criteria for BCR-ABL1-positive chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, myelodysplastic syndromes, or other myeloid neoplasms
• A JAK2, CALR, or MPL mutation is present

Minor criteria

• There is a clonal marker or absence of evidence for reactive thrombocytosis

Genetic mutations, such as JAK2, CALR, or MPL, determine the clinical features, complications, and prognosis of MPNs. For example, patients with ET and CALR mutations generally have a lower risk of thrombosis and more favourable outcomes than those with JAK2 mutations. Approximately 85% to 90% of patients with ET carry one of these driver mutations, thus emphasising the diagnostic significance of molecular testing. Diagnosis relies on WHO criteria and requires exclusion of reactive thrombocytosis.¹

FAQs

What are platelets(thrombocytes)?⁵

Platelets are blood cells produced by your bone marrow that help control the blood flow during any injury by forming blood clots, thus stopping further blood loss. Platelets are sticky by nature, and they clump together instantly to plug holes in the damaged blood vessels.

What are stem cells in the bone marrow? ⁶

The stem cells are the mother cells in your bone marrow (present inside the bone) that give  rise to other blood cells such as white blood cells, red blood cells, and platelets. 

How to manage ET cases?

Management strategies range from administering low-dose aspirin in low-risk individuals to cytoreductive therapy in higher-risk cases. Patient education plays a key role in improving therapy adherence to treatment and reducing adverse events related to thrombotic risks and blood loss.¹

A comprehensive approach to care would include full cardiovascular risk assessment and monitoring, which could include telemedicine, as well as access to a specialist services, for example, fertility support, pregnancy, management of menopause, and services for patients who are frail or who are medically complex, in addition to dermatology, endocrinology, nutrition, health psychology, and management of challenging symptoms such as fatigue, which should be assessed using standard scoring tools.⁷

Summary

For the majority of patients with essential thrombocythemia (ET), clinical diagnosis can be aided by findings on mutations in JAK2, CALR, or MPL genes. Mutations in JAK2, CALR, and MPL in ET have prognostic implications besides diagnostic value. ET without mutations in JAK2, CALR, and MPL seems to be a rare circumstance, and thus an extended analysis for mutations in these genes is the priority in diagnosis. A more extended genetic analysis of ET patients will reveal the validity of these entities.⁸