Essential Thrombocythemia

Resumen

Summary

Essential thrombocythemia, or ET, is a rare blood condition. Most people with ET have a normal life expectancy, even when the disease is diagnosed at a younger age and is managed appropriately.

People with ET have an increased number of platelets in their blood. Platelets are the smallest of the three main types of circulating blood cells and play an important role in helping the blood clot after an injury. The other two types of blood cells are red blood cells, which carry oxygen to tissues throughout the body, and white blood cells, which help the body fight infections.

In ET, red blood cell and white blood cell numbers are generally normal.  All blood cell numbers are measured by a simple blood test, which counts the number of each type of blood cell separately. In addition, because the red cells comprise the bulk the blood cells in the circulation, they are also measured by calculating the percentage of the total volume of blood that the red cells occupy. This measurement is called the hematocrit, which indicates the percentage of the blood made up by red cells. Normally, the red cells occupy 38-45% of the circulating blood depending on whether the hematocrit is being measured in women or men; the rest of the blood volume consists of the plasma.  White blood cells and platelets are much smaller that red cells are normally present in much lower numbers and occupy a very tiny percentage of the blood volume.

It is important to know that most people who have a high platelet count do not have ET. Platelet counts can be elevated for many other reasons, including iron deficiency, infection, inflammation, other cancers, certain bone marrow conditions, or having had the spleen removed. Rarely, some inherited conditions can cause high platelet counts, which are usually harmless.

In ET, the focus is on distinguishing it from these other, more common causes of high platelets. Treatment focuses on relieving symptoms related to the elevated platelet count and reducing the risk of bleeding, since very high platelet counts are mainly associated with bleeding rather than blood clots in large blood vessels. Some doctors also consider reducing the risk of blood clots as part of overall care, particularly in patients who have other cardiovascular risk factors.

Introduction

ET is one of three blood conditions known as myeloproliferative neoplasms (MPNs). These conditions share certain features, including the overproduction of normal blood cells, red cells, white cells, and platelets, alone or in various combinations. They may also involve scarring in the bone marrow or an enlarged spleen.

These shared features exist because all three MPNs are caused by specific genetic changes (called driver variants) in genes known as JAK2, CALR, and MPL. These variants arise in hematopoietic stem cells (HSCs), which are the cells in the bone marrow responsible for producing all blood cells. The variants are called “gain of function” because they cause the stem cells to produce too many normal blood cells. Although these conditions are called “neoplasms” (a term usually associated with cancer), the blood cells they produce are normal, they are simply made in excess.

The other two MPNs are polycythemia vera (PV), in which the body makes too many red blood cells, white blood cells, and platelets, and primary myelofibrosis (PMF), in which scarring develops in the bone marrow. Both ET and PV can develop some degree of bone marrow scarring over time, but it is usually milder than in PMF. Transformation to acute leukemia is uncommon in ET and PV unless the patient has been exposed to chemotherapy. The genetic changes involved in an ET transformation to AML are different from those seen in PMF.

For the adequate management of ET is essential to make sure that the diagnosis is correct, specifically to rule out polycythemia vera (PV), due to several reasons:

• Both ET and PV can be caused by the same JAK2 gene variant, and both can cause high platelet counts, which can make them look similar.
• PV can sometimes start with only a high platelet count, and it may take years before other signs of PV appear.
• ET and PV behave differently and require different treatment approaches, so getting the right diagnosis is essential.
• A helpful clue is that in true ET, the amount of the JAK2 variant in the blood (called the variant allele frequency, or VAF) is typically not greater than 50%. When the VAF is above 50%, the condition may actually be PV rather than ET. Some experts consider this distinction even more definitive, holding that the VAF in true ET should always be below 50%.

Finally, it must be emphasized that a very high platelet count is not associated with a risk of major vessel blood clots (thrombosis) but, rather, if the platelet count is greater than 900,000/mL, there is a risk of bleeding.

• Ver el reporte completo Muestra menos
• Download report (PDF)

• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Sinónimos

• Essential hemorrhagic thrombocythemia
• Essential thrombocytosis
• ET
• Idiopathic thrombocythemia
• Idiopathic thrombocytosis
• Primary thrombocythemia

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Signos y Síntomas

Possible signs and symptoms of ET may include:

• Headaches, including a type called ocular migraine, are related to activated platelets affecting small blood vessels
• Fatigue or low energy
• Temporary changes in vision
• Dizziness or vertigo
• Ringing in the ears (tinnitus)
• Easy bruising

Arterial blood clots can also occur, particularly in people who use tobacco. Bleeding complications can happen when platelet counts are extremely high (usually above 900,000/µL, though some guidelines use a threshold of 1,000,000/µL), because the large number of platelets can break down a protein needed for normal blood clotting.

In people with ET who have the JAK2 V617F variant, progression to polycythemia vera occurs more often in women than in men, while JAK2 V617F-positive or CALR-positive ET in men is more likely to evolve into secondary myelofibrosis. Over time, ET can sometimes change into myelofibrosis (bone marrow scarring). Transformation to acute leukemia is uncommon and is usually associated with exposure to chemotherapy.

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Causas y Herencia

ET develops when a genetic change (variant) occurs in a hematopoietic stem cell in the bone marrow. Normally, the production of blood cells is carefully controlled by signals from the body. In ET, a genetic change causes one stem cell to grow more than normal and produce too many platelets.

These genetic changes are acquired (called somatic variants), meaning they happen during a person’s lifetime and are not inherited from parents.

The most common genetic change in ET is a variant called V617F in the JAK2 gene, found in about 50–60% of people with ET. The JAK2 gene makes an enzyme, the JAK2 protein, that normally helps control blood cell production. When this variant is present, the enzyme stays “turned on” even when the body does not need more blood cells.

Other people with ET have changes in different genes that affect the same biological process:

• CALR (calreticulin) gene variants, found in about 20–30% of ET patients
• MPL gene variants, found in a smaller percentage of ET patients

The MPL gene encodes the only hematopoietic growth factor receptor expressed by HSC, and its activating protein is a hormone called thrombopoietin (TPO).

Under normal conditions, thrombopoietin signals the bone marrow to produce platelets when they are needed. In ET, the genetic variants disrupt this process, causing the platelet-producing cells (megakaryocytes) to multiply too much.

Together, the variants in JAK2, CALR, or MPL genes account for most ET cases. A small number of people with ET have no identifiable genetic changes (called “triple-negative” ET). These patients generally have a very mild course. There is no significant difference in survival among people with the different driver mutations. The transformation to myelofibrosis in people with the variant  JAK2 V617F usually occurs in men, but with CALR variants both men and women are involved.

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Frecuencia

ET occurs in about 1 in 100,000 people each year, with an estimated 30–60 people per 100,000 living with the condition at any given time. Women are more likely to develop ET than men, especially at younger ages. The average age at diagnosis is in the mid-fifties, but the range is wide and includes women in their childbearing years, an important group with special treatment considerations.

In children, ET is extremely rare and often differs from the adult form. Most childhood cases lack the typical driver mutations found in adults, and the cause often remains unclear. Some cases represent hereditary (inherited) thrombocytosis, where high platelet counts run in families.

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Enfermedades con síntomas similares

Several related conditions can look similar to ET, which is why careful testing is important.

Polycythemia vera is a rare, chronic disorder involving the overproduction of blood cells in the bone marrow (myeloproliferation). It is characterized by an overproduction of red blood cells, white blood cells and platelets. The overproduction of red blood cells may lead to abnormally high numbers of circulating red blood cells, and an increased blood volume which leads to slowing of blood flow (hyperviscosity) through smaller blood vessels. Symptoms of polycythemia vera include headaches, fatigue, weakness, dizziness, pruritis, enlarged spleen (splenomegaly), gastrointestinal issues and the risk of blood clots, which prevents blood flow to vital organs. More than 95% of individuals with polycythemia vera have a variant in the JAK2 gene.

Primary myelofibrosis (PMF) is a rare bone marrow disorder that is characterized by abnormalities in blood cell production (hematopoiesis) and scarring (formation of fibrous tissue) within the bone marrow. In PMF, a change in the DNA of a single hematopoietic stem cell causes the abnormal cell to continually reproduce itself. Eventually, these abnormal cells crowd out normal, healthy cells in the marrow and, along with scarring within the marrow, disrupt the production of red and white blood cells and platelets. The symptoms are related to abnormalities affecting blood cell production. Affected individuals may not have symptoms at the time of diagnosis (asymptomatic) and may remain symptom-free for many years. Eventually, affected individuals may develop fatigue, fever, frequent infections, pale skin, night sweats and unexplained weight loss. An enlarged spleen is a common finding. An enlarged liver may also occur, as may transformation to AML, which is more frequent than in PV or ET and with different variants.

Chronic myelogenous leukemia (CML)is a rare myeloproliferative disorder characterized by the excessive production of white blood cells in the spongy tissue found inside large bones of the body (bone marrow), spleen, liver and blood. As the disease progresses, the leukemic cells invade other areas of the body including the intestinal tract, kidneys, lungs, gonads, and lymph nodes. Importantly, in some CML patients, an elevation of the platelet count may be the presenting sign, mimicking ET.

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Diagnóstico

Many people with ET have no symptoms when they are first diagnosed and the condition is often discovered during routine blood work. Others are identified when they develop symptoms or a complication.

When a high platelet count is found, doctors will first look for common causes such as iron deficiency, infection, or inflammation. Blood tests and genetic tests are used to check for the gene changes seen in ET, PV, PMF, or CML.

If no other obvious cause is found and a blood disorder is suspected, a hematologist will typically recommend a bone marrow biopsy. This is a safe procedure, usually done in an office setting, in which a small sample of bone and liquid bone marrow is taken from the hip bone. Because all blood cells develop in the bone marrow, examining these samples allows doctors to look at the bone marrow cells and their structure directly. Additional genetic and molecular testing on the liquid portion of the sample can also provide valuable information.

It is worth noting that interpreting bone marrow findings in MPNs can sometimes be challenging, different pathologists may occasionally interpret the same samples differently, and it may not always reliably discriminate between the three MPM. For this reason, doctors also rely heavily on blood tests, genetic results, and clinical features to establish the correct diagnosis.

It is also essential to distinguish ET from polycythemia vera (PV). Although both can involve the same JAK2 gene change, they behave differently and require different treatment approaches. Doctors use a combination of blood tests, genetic tests, and other evaluations to make sure the diagnosis is correct. It is also important to follow ET patients periodically to ensure that what appears to be ET has not evolved into PV or PMF.

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Tratamiento

Treatment

The treatment of ET focuses on two main goals, relieving symptoms related to the high levels of platelets and reducing the risk of bleeding and small vessel thrombosis, which is strongly related to acquired cardiovascular disease or health factors such as tobacco use, hyperlipidemia, hypertension, diabetes, or obesity which should be actively managed as part of care.

Genetic testing can be used to help assess risk in ET. The amount of the JAK2 variant in the blood (the variant allele frequency, or VAF) is particularly important. When the JAK2 V617F VAF is below 50%, the risk of complications such as blood clots or progression to myelofibrosis is generally low. For CALR gene variants, risk assessment follows a similar approach based on the VAF.

Many doctors also consider factors such as age and history of prior blood clots when assessing risk. Some guidelines use a scoring system called IPSET-thrombosis that combines age, prior blood clots, and JAK2 status to classify patients into risk groups ranging from very low to high risk. However, some renowned experts believe that blood clots in ET may be caused more by other health conditions, such as cardiovascular disease, or by cases that are actually early PV, rather than by ET itself.

The care team will determine which approach is most appropriate for each individual.

Low-dose aspirin (81–100 mg daily) can be very effective for relieving symptoms such as headaches, burning pain in the hands or feet, and visual disturbances caused by activated platelets in small blood vessels. However, aspirin is not right for everyone with ET. It should be avoided when platelet counts are very high (generally above 900,000/µL) because it could trigger bleeding by worsening a condition called acquired von Willebrand syndrome. The doctors need to check this before recommending aspirin. In patients with CALR variants who have no symptoms, aspirin may not be necessary as it could increase bleeding risk without clear benefit.

While aspirin is clearly effective for relieving microvascular symptoms, its role in preventing blood clots in ET remains debated among experts, and it may not be necessary for all patients. Similarly, in older adults without cardiovascular risk factors, the benefit of preventive aspirin must be weighed carefully against the risk of bleeding. The doctors determine whether aspirin is appropriate based on the specific situation.

Not everyone with ET needs medication to lower their platelet count. Many people with ET have no symptoms and may do well with monitoring and management of cardiovascular risk factors alone. When treatment is needed, it should be guided by symptoms and risk level, not just the platelet number. Lowering the platelet count to normal in a person without symptoms is generally not necessary.

Current treatment options include:

• Interferon therapy (peginterferon alfa-2a and ropeginterferon alfa-2b-njf: These injectable medications work differently from other treatments. Rather than simply lowering blood counts, they may target the abnormal blood-forming stem cells directly and can reduce the amount of the disease-causing genetic variant over time, potentially inducing complete molecular remission. Interferons are preferred by many experts because they may modify the disease itself and do not appear to damage the bone marrow. They can be used in both younger and older patients and are preferred for pregnant patients. Because of this, some well renowned experts consider pegylated interferons preferable to hydroxyurea because they do not carry the same concerns about potential DNA damage. However, while doctors legally and frequently prescribe it because clinical guidelines support it, the FDA has not officially cleared it for this specific condition. The drug maker of a long-acting interferon brand called Besremi (ropeginterferon alfa-2b-njft) has submitted an application for official ET approval. The FDA is currently reviewing this application.
• Hydroxyurea: This is a pill that works quickly to lower blood counts. However, platelet counts may rise rapidly after stopping the medication, sometimes leading to cycles of rising and falling counts (“platelet cycling”) if hydroxyurea is not tapered properly. Hydroxyurea is not always effective or well tolerated. Side effects can include mouth sores, skin changes, fatigue, and lowering of other blood cell counts. Some guidelines list hydroxyurea as a first-line option, particularly for patients considered to be at higher risk. However, because hydroxyurea is a chemotherapy agent, there is a concern about the possibility of long-term bone marrow, and experts have raised concern about a possible long-term risk of acute myelogenous leukemia (AML). Additionally, some experts have noted that it has not clearly demonstrated that hydroxyurea prevents venous thrombosis specifically, though a landmark trial did show a significant reduction in overall thrombotic events in high-risk ET patients. Since ET is generally associated with a normal life expectancy, even small potential long-term treatment risks should be carefully weighed against the expected benefits.

Researchers are exploring new approaches to treating ET and related MPNs. For polycythemia vera, investigational agents such as rusfertide (a hepcidin mimetic that reduces the need for phlebotomy) and givinostat (a histone deacetylase inhibitor) are in advanced clinical development, though their role in ET specifically has not yet been established.

• Ruxolitinib: An oral medication that blocks enzymes involved in blood cell production. It was originally approved for myelofibrosis but may be considered for selected ET patients whose disease does not respond to other treatments, or in combination with a pegylated interferon.
• Anagrelide: A medication that specifically lowers platelet counts, but it can cause significant side effects including heart palpitations, headaches, and in some cases heart or kidney problems. It is generally reserved for patients who cannot tolerate other treatments and require careful monitoring, especially in older adults due to potential cardiac and renal toxicity.

If the first treatment does not work well enough or causes too many side effects, there are other options available. The healthcare team can help find the best approach.

Two medications, epsilon-aminocaproic acid and tranexamic acid, can be used to help prevent or treat minor bleeding episodes in people with ET.

Plateletpheresis is a procedure that removes platelets directly from the blood, similar to the process used at blood donation centers when collecting platelets from healthy donors. It can quickly lower the platelet count and may be used temporarily in rare emergency situations. However, the effect is temporary because it does not treat the underlying cause of ET.

Pregnancy and ET

ET is more common in women and is often diagnosed during the reproductive years. With proper management, most women with ET can have successful pregnancies. Pregnancy management for women with ET may involve the following:

• Platelet counts often decrease naturally during pregnancy.
• Certain medications, including hydroxyurea and anagrelide, should be stopped before pregnancy because they may harm the developing baby.
• Low-dose aspirin is recommended during pregnancy and may help reduce the risk of early miscarriage.
• Peginterferon alfa-2a can be used safely during pregnancy if symptoms cannot be controlled with aspirin alone.

Some guidelines recommend blood-thinning injections during and/or after pregnancy in certain situations, though the evidence for this is limited. The care team will determine the best approach based on the individual situation.

Researchers are exploring new approaches to treating ET. ET caused by CALR gene variants presents a particularly interesting opportunity because the altered protein may be recognized by the immune system. Early research is exploring immunotherapy approaches, including a monoclonal antibody and CAR-T cell therapy, that could directly target the abnormal cells. These are still in early stages of research.

In summary, most people with ET can have a normal life span when the condition is properly diagnosed and managed. An important first step is making sure the diagnosis is correct and that ET is accurately distinguished from related disorders such as polycythemia vera (PV) and myelofibrosis, since these conditions have different treatments and long-term outcomes. Ongoing monitoring, including follow-up of the JAK2 V617F variant allele frequency (VAF) when appropriate, may provide additional information about how the disease is behaving over time.

Avoiding unnecessary treatment is also important. In people who do not have symptoms, lowering the platelet count to a normal range is generally not required. Aspirin can be very effective for relieving microvascular symptoms, such as headaches or visual disturbances, but it may not be necessary for all patients. Some experts believe that patients with CALR variants who do not have symptoms may receive little benefit from aspirin while facing an increased risk of bleeding.

Managing cardiovascular risk factors is an important part of care. This includes avoiding tobacco use and controlling conditions such as high blood pressure, high cholesterol, diabetes, and obesity.

Because treatment recommendations may vary among experts and healthcare providers, it is important for patients to discuss the potential benefits and risks of different management approaches with their healthcare team.

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Investigaciones

Information on current clinical trials is posted on the Internet at https://clinicaltrials.gov/. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Toll-free: (800) 411-1222
TTY: (866) 411-1010
Email: [email protected]

Some current clinical trials also are posted on the following page on the NORD website:
https://rarediseases.org/living-with-a-rare-disease/find-clinical-trials/

For information about clinical trials sponsored by private sources, contact:
https://www.centerwatch.com/

For information about clinical trials conducted in Europe, contact:
https://www.clinicaltrialsregister.eu/

• < Sección anterior
• Sección siguiente >

• < Sección anterior
• Sección siguiente >

Referencias

Spivak, JL. Myeloproliferative Neoplasms. N Engl J Med. 2017;376:2168-2181.

Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, et al. Somatic mutations of calreticulin in myeloproliferative neoplasms. N Engl J Med. 2013; 369:2379-90.

Passamonti F, Rumi E, Pungolino E, Malabarba L, Bertazzoni P, Valentini M, et al. Life expectancy and prognostic factors for survival in patients with polycythemia vera and essential thrombocythemia. The American Journal of Medicine. 2004;117:755-61.

Putti MC, Bertozzi I, Randi ML. Essential Thrombocythemia in Children and Adolescents. Cancers (Basel). 2021;13(23):6147. Published 2021 Dec 6. doi:10.3390/cancers13236147

Randi ML, Geranio G, Bertozzi I, et al. Are all cases of paediatric essential thrombocythaemia really myeloproliferative neoplasms? Analysis of a large cohort. Br J Haematol. 2015;169(4):584-589. doi:10.1111/bjh.13329

Gangat N, Singh A, Ilyas R, et al. Aspirin therapy is associated with a lower risk of pregnancy loss in both JAK2- and CALR-mutated essential thrombocythemia-A Mayo Clinic study of 200 pregnancies. Am J Hematol 2024;99:1862-9.

Buss DH, Stuart JJ, Lipscomb GE. The incidence of thrombotic and hemorrhagic disorders in association with extreme thrombocytosis: an analysis of 129 cases. Am J Hematol 1985;20:365-72.

Spivak JL. Are polycythemia vera, essential thrombocytosis, and primary myelofibrosis 1, 2, or 3 diseases? Leukemia 2021;35:1890-3.

Spivak JL. Narrative review: Thrombocytosis, polycythemia vera, and JAK2 mutations: The phenotypic mimicry of chronic myeloproliferation. Ann Intern Med 2010;152:300-6.

Alvarez-Larran A, Cervantes F, Pereira A, et al. Observation versus antiplatelet therapy as primary prophylaxis for thrombosis in low-risk essential thrombocythemia. Blood 2010;116:1205-10 387.

Rumi E, Pietra D, Ferretti V, et al. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcome.

Kramer F, Mullally A. Antibody targeting of mutant calreticulin in myeloproliferative neoplasms. J Cell Mol Med 2024;28:e17896.

Reis ES, Buonpane R, Celik H, et al. Selective targeting of mutated calreticulin by the monoclonal antibody INCA033989 inhibits oncogenic function of MPN. Blood 2024;144:2336-48.

Tefferi A, Vannucchi AM, Barbui T. Essential thrombocythemia: 2024 update on diagnosis, risk stratification, and management. Am J Hematol. 2024;99(4):697-718. doi:10.1002/ajh.27216.

• < Sección anterior
• Sección siguiente >

• < Sección anterior

Programas & Recursos

• Programas de asistencia
• Organizaciones de pacientes
• More Information

Programas de asistencia RareCare®

NORD strives to open new assistance programs as funding allows. If we don’t have a program for you now, please continue to check back with us.

Programas de Asistencia Adicional

Programa de Asistencia MedicAlert

NORD y la Fundación MedicAlert se han asociado en un nuevo programa para brindar protección a pacientes con enfermedades raras en situaciones de emergencia.

Aprende más https://rarediseases.org/patient-assistance-programs/medicalert-assistance-program/

Programa de Apoyo Educativo de Enfermedades Raras

Asegurarse de que los pacientes y los cuidadores estén equipados con las herramientas que necesitan para vivir su mejor vida mientras manejan su condición rara es una parte vital de la misión de NORD.

Aprende más https://rarediseases.org/patient-assistance-programs/rare-disease-educational-support/

Programa de descanso para cuidadores raros

Este programa de asistencia, primero en su tipo, está diseñado para los cuidadores de un niño o adulto diagnosticado con un trastorno raro.

Aprende más https://rarediseases.org/patient-assistance-programs/caregiver-respite/

Obtenga más información sobre los programas de asistencia al paciente >

• < Sección anterior