Essential thrombocythemia (ET) is a chronic blood disorder characterized by the overproduction of platelets, which are tiny blood cells that help with clotting. While ET is rare, the vast majority of cases are acquired during a person’s lifetime. There are, however, very rare instances of familial forms where a genetic predisposition can be inherited.
Understanding Essential Thrombocythemia
Essential thrombocythemia is classified as a myeloproliferative neoplasm (MPN), a group of rare blood cancers that originate in the bone marrow, the soft, spongy tissue inside bones where blood cells are made. In ET, abnormal stem cells in the bone marrow produce an excessive number of platelets.
Patients with ET may experience a range of symptoms, though many are initially asymptomatic. Common symptoms can include fatigue, headaches, dizziness, and visual disturbances. Some individuals also report burning or tingling sensations in their hands and feet, a condition known as erythromelalgia. The overabundance of platelets can lead to complications such as an increased risk of blood clots (thrombosis) in veins or arteries, which can result in serious events like stroke or heart attack. Less commonly, extremely high platelet counts can paradoxically lead to bleeding problems, as the platelets may not function correctly.
The Development of Essential Thrombocythemia
The overwhelming majority of ET cases are acquired, meaning the genetic changes occur spontaneously in a single bone marrow stem cell after birth and are not passed down from parents. These acquired mutations lead to abnormal signaling within the bone marrow cells, causing them to produce an uncontrolled number of platelets. The most common acquired mutation is in the JAK2 gene, found in about 50% of ET patients. This mutation causes the JAK2 protein to be constantly active, which promotes the overproduction of blood cells, including platelets.
The CALR (Calreticulin) gene is another frequently mutated gene in ET, observed in about 25% of patients, particularly those without the JAK2 mutation. CALR mutations, like JAK2 mutations, can also activate the JAK/STAT signaling pathway, leading to increased platelet production. A smaller percentage of patients, around 3-8%, have mutations in the MPL (Myeloproliferative Leukemia virus oncogene) gene, which is involved in thrombopoietin receptor signaling and drives platelet production. Approximately 10-15% of ET patients are considered “triple negative,” meaning they do not have identified JAK2, CALR, or MPL mutations.
Familial Essential Thrombocythemia
Familial essential thrombocythemia is significantly rarer than the acquired forms, representing a small percentage of all ET cases. In these instances, a genetic predisposition to the condition is inherited, typically in an autosomal dominant pattern, meaning one copy of an altered gene is enough to cause the disorder. Specific genes have been linked to inherited forms, such as mutations in the THPO (Thrombopoietin) gene. These THPO mutations can lead to abnormally high levels of thrombopoietin, a hormone that stimulates platelet production, contributing to the excessive platelet count seen in familial ET.
In some very rare cases, an inherited predisposition to develop JAK2, CALR, or MPL mutations may exist, which differs from the more common acquired somatic mutations. Genetic counseling is often recommended for families with a history of ET to assess individual risk and discuss the implications of such inherited predispositions.
Diagnosis and Treatment
Diagnosing essential thrombocythemia typically involves a combination of tests, starting with a complete blood count (CBC) to check for a persistently high platelet count. A blood smear is also examined under a microscope to assess the size and shape of platelets. A bone marrow biopsy, where a small sample of bone marrow tissue is taken, is often performed to confirm the diagnosis and observe the presence of increased megakaryocytes, the cells that produce platelets.
Genetic testing for common mutations like JAK2, CALR, and MPL is also a routine part of the diagnostic process, helping to confirm ET and differentiate it from other conditions. Treatment goals for ET focus on reducing the platelet count and preventing serious complications such as blood clots and bleeding. Low-dose aspirin is frequently prescribed to reduce the risk of blood clots and can also help alleviate symptoms like erythromelalgia. For patients at higher risk, cytoreductive therapies are used to lower platelet counts. Regular monitoring through blood tests and clinical evaluations is also a standard part of managing ET.