overview 

Essential thrombocythaemia (ET) - also known as essential thrombocytosis, is a rare chronic blood cancer that causes the bone marrow to produce too many platelets (the blood cells responsible for clotting). ET belongs to a family of conditions called myeloproliferative neoplasms (MPNs), where blood cells are made in an uncontrolled way. It usually develops slowly and most often affects middle-aged and older adults (average age at diagnosis ~ 65), though it can occur at any age. Many people with ET feel well at diagnosis and may have few or no symptoms initially, often the condition is picked up incidentally on a routine blood test.¹ 

However, ET matters because an abnormally high platelet count can lead to serious complications: blood clots (thromboses) that may cause strokes, heart attacks or other issues, as well as bleeding problems in some cases. Over time, ET can also progress to more severe conditions like myelofibrosis (a scarring of the bone marrow) or, rarely, acute leukaemia. Understanding what causes ET, particularly the genetic mutations driving it is important for confirming the diagnosis, assessing your risks, and guiding personalized treatment. In this article, we’ll explain in plain language how mutations in three key genes (JAK2, CALR, and MPL) play a role in ET, and what their presence or absence means for you.²

Understanding key terms

• Myeloproliferative Neoplasm (MPN): An MPN is a group of chronic blood cancers where the bone marrow makes too many blood cells. In ET, the marrow specifically overproduces platelets. Other MPNs include polycythaemia vera (too many red cells) and myelofibrosis (scarred marrow with abnormal cells). All are “BCR-ABL-negative” (lacking the Philadelphia chromosome seen in CML leukemia) and can cause elevated blood counts³
• Somatic Mutation: A genetic change acquired during a person’s life that is present only in certain cells (in ET, in the blood-forming stem cells) and not inherited from parents. In ET these arise by chance, for example, due to copying mistakes when cells divide. You aren’t born with these mutations and you cannot pass them on to your children⁴
• Driver Mutation: A mutation that directly contributes to disease development. In ET, “driver” mutations in genes like JAK2, CALR, or MPL give the affected cells a growth advantage, causing platelet overproduction. These are distinct from secondary or “passenger” mutations, the driver mutations are the critical ones that drive the MPN⁵

Genetic drivers of ET: JAK2, CALR, and MPL

Researchers have discovered that about 85-90% of people with essential thrombocythaemia carry a mutation in one of three genes: JAK2, CALR, or MPL. These mutations are somatic driver mutations, they occur in the bone marrow cells during life and cause the disease. Identifying which mutation is present can confirm the diagnosis and provide insights into the disease’s behaviour.⁶

JAK2 mutations in ET

JAK2 (Janus kinase 2) is a gene that encodes a protein important for blood cell growth signals. In healthy cells, JAK2 helps transmit signals from growth factors like erythropoietin and thrombopoietin, telling stem cells when to become red cells, platelets, etc. The most common mutation in ET is JAK2 V617F, a single-letter DNA change that causes the JAK2 protein to be stuck in the “on” position. In other words, the mutant JAK2 keeps signaling the marrow to make more blood cells (including platelets) even when it shouldn’t.^6,7

• How common? JAK2 mutations are found in roughly 50-60% of ET cases
• What it means: JAK2 mutations are associated with higher risk of blood clots and sometimes more severe progression. Doctors often tailor prevention strategies (e.g., aspirin) more aggressively in JAK2-positive patients

CALR mutations in ET

CALR (calreticulin) mutations, discovered in 2013, are the second most common driver in ET. These mutations (insertions or deletions in exon 9) produce an abnormal calreticulin protein that abnormally activates the thrombopoietin receptor (MPL).⁸

• How common? CALR mutations occur in 20-30% of ET patients, especially those without JAK2 mutations
• What it means: CALR-mutated ET tends to affect younger patients with very high platelets but paradoxically lower clotting risk. Prognosis is often more favourable than JAK2-positive ET, though there may be higher risk of progression to myelofibrosis long-term

MPL mutations in ET

MPL encodes the thrombopoietin receptor, which stimulates platelet production. Mutations (commonly at codon W515) activate the receptor abnormally, driving platelet overproduction.⁹

• How common? MPL mutations are the least common, seen in 3-10% of ET patients
• What it means: They confirm diagnosis but are less well-studied. Risk appears intermediate between JAK2 and CALR cases

Triple-negative ET

About 10-15% of ET patients have none of the three mutations (“triple-negative” ET). This form is harder to diagnose and more common in younger patients. Risk of thrombosis may be lower, similar to CALR-positive ET.¹⁰

Diagnosis

Diagnosis of ET involves:

• Blood counts - showing persistently high platelets
• Excluding reactive causes - e.g., infection, iron deficiency
• Genetic testing - for JAK2, CALR, MPL mutations (positive in 85-90%)
• Bone marrow biopsy – showing increased megakaryocytes with clustering
• Other tests - e.g., BCR-ABL to rule out CML, ultrasound for spleen size¹¹

Why mutations matter for risks

• Thrombosis: JAK2 mutations raise clot risk significantly; CALR lowers it; MPL intermediate
• Bleeding: Very high platelets (1 million) can cause bleeding via acquired von Willebrand deficiency
• Progression: Any ET can progress to myelofibrosis (10% over 15-20 years). Leukemic transformation is rare (2-5% over 10-15 years)¹¹

Treatment

Treatment is risk-based:

• Low-risk ET (under 60, no clot history, often CALR/MPL-positive): aspirin and monitoring
• High-risk ET (over 60 or prior thrombosis, often JAK2-positive): aspirin + cytoreductive therapy (first-line hydroxycarbamide; alternatives include interferon-alpha or anagrelide)
• Intermediate cases (e.g., middle-aged JAK2-positive): management personalised, often leaning toward cytoreduction
• Special cases: Pregnancy (interferon preferred), progression to myelofibrosis (may need ruxolitinib or other therapy)¹³

Summary

Most ET patients carry mutations in JAK2, CALR, or MPL, which drive abnormal platelet production. Testing for these mutations confirms diagnosis and informs risk. JAK2 confers higher clot risk; CALR is more favourable but may carry fibrosis risk; MPL is rare. Even triple-negative ET can be diagnosed. With appropriate monitoring and treatment (aspirin, cytoreductive therapy where needed), most patients live long, full lives.