Essential thrombocythemia

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Essential thrombocythemia
Other namesEssential thrombocythaemia, essential thrombocytosis, primary thrombocytosis
Essential thrombocythemia (2).jpg
Histopathological image representing a bone marrow aspirate in a patient with essential thrombocythemia.
Specialty Hematology   OOjs UI icon edit-ltr-progressive.svg
Symptoms Fatigue, insomnia, migraines, headache, and dizziness. [1]
Complications Thrombosis, transient ischemic attack, acute coronary syndrome, Budd-Chiari syndrome. [1]
CausesOverproduction 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]
Frequency0.6-2.5/100,000 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]

Contents

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]

There are three known genetic mutations that cause ET. The most common genetic mutation is a JAK2 mutation. Roughly 50% of the population of ET patients have this mutation. The JAK 2 gene signals a protein that promotes the growth of cells. The protein is part of a signaling pathway called the JAK/STAT pathway. The JAK2 protein controls the production of blood cells from hematopoietic stem cells which are located in the bone marrow and can eventually become platelets, red blood cells or white blood cells. Specifically in ET, a JAK2 mutation is acquired rather than inherited. The most common JAK2 mutation is V617F which is the replacement of a valine amino acid with phenylalanine amino acid at the 617 position, hence the name V617F. This mutation results in the JAK2 protein constantly being turned on, which leads to the overproduction of abnormal blood cells, in ET it is platelets or megakaryocytes. There is also another JAK2 mutation found in exon 12, however much less common.

There is also a small number of people who have a different mutation called CALR, which is abbreviated from calreticulin. CALR is a protein found in the endoplasmic reticulum (ER). Its purpose is to maintain calcium homeostasis and control protein folding. There are three parts to CALR including an amino acid domain, a proline rich P-domain, and a carboxyl domain. All of these parts facilitate the function of CALR. CALR mutation is caused by insertions or deletions of amino acids in exon 9 that cause a reading shift, which then leads to the formation of a novel C terminus. There are two common types of CALR mutations, type 1 and type 2. Type 1 mutations are a 52-bp deletion and type 2 mutations are a 5-bp insertion. In type 1 mutations, the negativle charged amino acids in the CALR C terminus are completely eliminated, and in the type 2 mutations, roughly half are eliminated. There are other mutations involving CALR, however these two are the most common. [11]

Lastly, the least common mutation found in patients with ET are MPL mutations. The MPL gene is responsible for making thrombopoeitin receptor proteins which promote the growth and division of cells. This receptor protein is vital in producing platelets. There are various MPL mutations, but most typical are point mutations that cause amino acid changes. The MPL mutation activates the thrombopoeitin receptor despite the absence of the ligand. This causes the constant proliferation of cells. [12]

Diagnosis

The following revised diagnostic criteria for essential thrombocythemia were proposed in 2005. [13] The diagnosis requires the presence of both A criteria together with B3 to B6, or of criterion A1 together with B1 to B6. [14] The criteria are as follows: [14]

Treatment

Indications

Not all those affected will require treatment at presentation. [15] [16] [17] 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] [15] [16] [17] 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] [15] [16] [17]

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] [15] [16] [17] 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. [18]

Prognosis

Essential thrombocythemia is sometimes described as a slowly progressive disorder with long asymptomatic periods punctuated by thrombotic or hemorrhagic events. [15] 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. [15] ET is the myeloproliferative neoplasm least likely to progress to acute myeloid leukemia. [19]

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. [20] 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. [20] Low-dose low molecular weight heparin (e.g. enoxaparin) may be used. [20] 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. [20]

Jill Kaplan, the female protagonist of The Pajama Diaries comic strip was diagnosed with essential thrombocythemia. [21]

Related Research Articles

<span class="mw-page-title-main">Polycythemia vera</span> Overproduction of red blood cells by the bone marrow

In oncology, polycythemia vera (PV) is an uncommon myeloproliferative neoplasm in which the bone marrow makes too many red blood cells. The majority of cases are caused by mutations in the JAK2 gene, most commonly resulting in a single amino acid change in its protein product from valine to phenylalanine at position 617.

<span class="mw-page-title-main">Polycythemia</span> Laboratory diagnosis of high hemoglobin content in blood

Polycythemia is a laboratory finding in which the hematocrit and/or hemoglobin concentration are increased in the blood. Polycythemia is sometimes called erythrocytosis, and there is significant overlap in the two findings, but the terms are not the same: polycythemia describes any increase in hematocrit and/or hemoglobin, while erythrocytosis describes an increase specifically in the number of red blood cells in the blood.

<span class="mw-page-title-main">Megakaryocyte</span> Type of bone marrow cell

A megakaryocyte is a large bone marrow cell with a lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal clotting. In humans, megakaryocytes usually account for 1 out of 10,000 bone marrow cells, but can increase in number nearly 10-fold during the course of certain diseases. Owing to variations in combining forms and spelling, synonyms include megalokaryocyte and megacaryocyte.

<span class="mw-page-title-main">Thrombopoietin</span> Mammalian protein found in Homo sapiens

Thrombopoietin (THPO) also known as megakaryocyte growth and development factor (MGDF) is a protein that in humans is encoded by the THPO gene.

<span class="mw-page-title-main">Thrombocythemia</span> Abnormally high platelet count in the blood

In hematology, thrombocythemia is a condition of high platelet (thrombocyte) count in the blood. Normal count is in the range of 150×109 to 450×109 platelets per liter of blood, but investigation is typically only considered if the upper limit exceeds 750×109/L.

Primary myelofibrosis (PMF) is a rare bone marrow blood cancer. It is classified by the World Health Organization (WHO) as a type of myeloproliferative neoplasm, a group of cancers in which there is activation and growth of mutated cells in the bone marrow. This is most often associated with a somatic mutation in the JAK2, CALR, or MPL genes. In PMF, the bony aspects of bone marrow are remodeled in a process called osteosclerosis; in addition, fibroblast secrete collagen and reticulin proteins that are collectively referred to as (fibrosis). These two pathological processes compromise the normal function of bone marrow resulting in decreased production of blood cells such as erythrocytes, granulocytes and megakaryocytes, the latter cells responsible for the production of platelets.

<span class="mw-page-title-main">Myeloproliferative neoplasm</span> Overproduction of blood cells in the bone marrow

Myeloproliferative neoplasms (MPNs) are a group of rare blood cancers in which excess red blood cells, white blood cells or platelets are produced in the bone marrow. Myelo refers to the bone marrow, proliferative describes the rapid growth of blood cells and neoplasm describes that growth as abnormal and uncontrolled.

<span class="mw-page-title-main">Anagrelide</span> Chemical compound

Anagrelide is a drug used for the treatment of essential thrombocytosis, or overproduction of blood platelets. It also has been used in the treatment of chronic myeloid leukemia.

<span class="mw-page-title-main">GATA1</span> Protein-coding gene in humans

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

<span class="mw-page-title-main">Chronic myelomonocytic leukemia</span> Medical condition

Chronic myelomonocytic leukemia (CMML) is a type of leukemia, which are cancers of the blood-forming cells of the bone marrow. In adults, blood cells are formed in the bone marrow, by a process that is known as haematopoiesis. In CMML, there are increased numbers of monocytes and immature blood cells (blasts) in the peripheral blood and bone marrow, as well as abnormal looking cells (dysplasia) in at least one type of blood cell.

<span class="mw-page-title-main">Thrombopoietin receptor</span> Protein-coding gene in the species Homo sapiens

The thrombopoietin receptor also known as the myeloproliferative leukemia protein or CD110 is a protein that in humans is encoded by the MPL oncogene.

<span class="mw-page-title-main">Acute megakaryoblastic leukemia</span> Medical condition

Acute megakaryoblastic leukemia (AMKL) is life-threatening leukemia in which malignant megakaryoblasts proliferate abnormally and injure various tissues. Megakaryoblasts are the most immature precursor cells in a platelet-forming lineage; they mature to promegakaryocytes and, ultimately, megakaryocytes which cells shed membrane-enclosed particles, i.e. platelets, into the circulation. Platelets are critical for the normal clotting of blood. While malignant megakaryoblasts usually are the predominant proliferating and tissue-damaging cells, their similarly malignant descendants, promegakaryocytes and megakaryocytes, are variable contributors to the malignancy.

<span class="mw-page-title-main">Lestaurtinib</span> Chemical compound

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<span class="mw-page-title-main">Fedratinib</span> Chemical compound

Fedratinib, sold under the brand name Inrebic, is an anti-cancer medication used to treat myeloproliferative diseases including myelofibrosis. It is used in the form of fedratinib hydrochloride capsules that are taken by mouth. It is a semi-selective inhibitor of Janus kinase 2 (JAK-2). It was approved by the FDA on 16 August 2019.

<span class="mw-page-title-main">Gandotinib</span> Chemical compound

Gandotinib (LY-2784544) is an experimental drug developed by Eli Lilly for treatment of cancer. It is a small molecule JAK2 inhibitor, with additional minor inhibition of STAT3.

Clonal hypereosinophilia, also termed primary hypereosinophilia or clonal eosinophilia, is a grouping of hematological disorders all of which are characterized by the development and growth of a pre-malignant or malignant population of eosinophils, a type of white blood cell that occupies the bone marrow, blood, and other tissues. This population consists of a clone of eosinophils, i.e. a group of genetically identical eosinophils derived from a sufficiently mutated ancestor cell.

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Prefibrotic primary myelofibrosis (Pre-PMF) is a rare blood cancer, classified by the World Health Organization as a distinct type of myeloproliferative neoplasm in 2016. The disease is progressive to overt primary myelofibrosis, though the rate of progression is variable and not all patients progress. Symptoms and presentation can mimic essential thrombocythemia, with the main differentiator for pre-PMF being the presence of fibrosis in the bone marrow.

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.

References

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  5. ↑ Frewin, R; Dowson, A (October 2012). "Headache in essential thrombocythaemia". International Journal of Clinical Practice. 66 (10): 976–983. doi:10.1111/j.1742-1241.2012.02986.x. PMC   3469735 . PMID   22889110.
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  10. ↑ Klampfl T, Gisslinger H, Harutyunyan AS, Nivarthi H, Rumi E, Milosevic JD, Them NC, Berg T, Gisslinger B, Pietra D, Chen D, Vladimer GI, Bagienski K, Milanesi C, Casetti IC, Sant'Antonio E, Ferretti V, Elena C, Schischlik F, Cleary C, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C, Superti-Furga G, Cazzola M, Kralovics R (Dec 2013). "Somatic mutations of calreticulin in myeloproliferative neoplasms". The New England Journal of Medicine. 369 (25): 2379–90. doi: 10.1056/NEJMoa1311347 . PMID   24325356. S2CID   14787432.
  11. ↑ Prins, Daniel; González Arias, Carlos; Klampfl, Thorsten; Grinfeld, Jacob; Green, Anthony R. (February 2020). "Mutant Calreticulin in the Myeloproliferative Neoplasms". HemaSphere. 4 (1): e333. doi:10.1097/HS9.0000000000000333. ISSN   2572-9241. PMC   7000472 . PMID   32382708.
  12. ↑ Guglielmelli, Paola; Calabresi, Laura (2021), "The MPL mutation", International Review of Cell and Molecular Biology, vol. 365, Elsevier, pp. 163–178, doi:10.1016/bs.ircmb.2021.09.003, ISBN   978-0-323-89939-0, PMID   34756243 , retrieved 2024-05-07
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  18. ↑ Boddu, Prajwal; Falchi, Lorenzo; Hosing, Chitra; Newberry, Kate; Bose, Prithviraj; Verstovsek, Srdan (2017-07-01). "The role of thrombocytapheresis in the contemporary management of hyperthrombocytosis in myeloproliferative neoplasms: A case-based review". Leukemia Research. 58: 14–22. doi:10.1016/j.leukres.2017.03.008. ISSN   0145-2126. PMC   5466892 . PMID   28380402.
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  21. ↑ "The Pajama Diaries".
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