Editing Essential thrombocythemia

{{short description|Overproduction of platelets in the bone marrow}}
{{Infobox medical condition (new)
| name            = Essential thrombocythemia
| synonyms        = Essential thrombocythaemia, essential thrombocytosis, primary thrombocytosis
| image           = Essential thrombocythemia (2).jpg
| caption         = [[Histopathology|Histopathological]] image representing a [[Bone marrow examination|bone marrow aspirate]] in a patient with essential thrombocythemia. 
| pronounce       =
| field           =
| symptoms        = [[Fatigue]], [[insomnia]], [[migraines]], [[headache]], and [[dizziness]].<ref name=statpearls>{{cite book|first1=Damilola|last1=Ashorobi|first2=Pouyan|last2=Gohari|title=Essential Thrombocytosis|url=http://www.ncbi.nlm.nih.gov/books/NBK539709/|publisher=StatPearls Publishing|date= August 6, 2023 |location=Treasure Island (FL)|pmid=30969531 |via=PubMed}}</ref>
| complications   = [[Thrombosis]], [[transient ischemic attack]], [[acute coronary syndrome]], [[Budd–Chiari syndrome|Budd-Chiari syndrome]].<ref name=statpearls/>
| onset           =
| duration        =
| types           =
| causes          = Overproduction of [[Haematopoiesis|hematopoietic cells]], [[Mutation|genetic mutations]].<ref name=statpearls/>
| risks           =
| diagnosis       = Clinical criteria.
| differential    = [[Chronic myelogenous leukemia]], [[myelodysplastic syndrome]], [[polycythemia vera]], [[primary myelofibrosis]], [[secondary thrombocytosis]].<ref name=statpearls/>
| prevention      =
| treatment       = [[Low dose aspirin|Low-dose aspirin]], plateletpheresis, cytoreductive therapy.<ref name=statpearls/>
| medication      =
| prognosis       = Median survival is 18 years.<ref name=statpearls/>
| frequency       = 0.6-2.5/100,000 cases per year.<ref name="emerg"/>
| deaths          =
}}

In [[hematology]], '''essential thrombocythemia''' ('''ET''') is a rare chronic blood cancer ([[myeloproliferative neoplasm]]) characterised by the [[thrombocythemia|overproduction]] of [[platelets]] (thrombocytes) by [[megakaryocyte]]s in the [[bone marrow]].<ref name="path" /> It may, albeit rarely, develop into [[acute myeloid leukemia]] or [[myelofibrosis]].<ref name="path" /> It is one of the blood cancers wherein the bone marrow produces too many [[White blood cell|white]] or [[red blood cells]], or platelets.<ref name="path">{{cite journal |last1=Beer |first1=PA |last2=Green |first2=AR |title= Pathogenesis and management of essential thrombocythemia|journal=Hematology |volume=2009 |date=2009 |pages=621–628 |doi=10.1182/asheducation-2009.1.621 |pmid=20008247 |doi-access=free }}</ref>

==Signs and symptoms==
Most people with essential thrombocythemia are [[asymptomatic|without symptoms]] at the time of diagnosis, which is usually made after noting an elevated platelet level on a routine [[complete blood count]] (CBC).<ref name="paed">{{cite journal |last1=Fu |first1=R |last2=Zhang |first2=L |last3=Yang |first3=R |title=Paediatric essential thrombocythaemia: clinical and molecular features, diagnosis and treatment |journal=British Journal of Haematology |date=November 2013 |volume=163 |issue=3 |pages=295–302 |doi=10.1111/bjh.12530 |pmid=24032343|s2cid=10880402 }}</ref> The most common symptoms are bleeding (due to dysfunctional platelets), [[thrombosis|blood clots]] (e.g., [[deep vein thrombosis]] or [[pulmonary embolism]]), fatigue, headache, nausea, vomiting, abdominal pain, visual disturbances, dizziness, [[Syncope (medicine)|fainting]], and numbness in the extremities; the most common signs are [[leukocytosis|increased white blood cell count]], [[anaemia|reduced red blood cell count]], and an [[splenomegaly|enlarged spleen]].<ref name="paed"/><ref>{{cite journal |last1=Frewin |first1=R |last2=Dowson |first2=A |title=Headache in essential thrombocythaemia.|journal=International Journal of Clinical Practice |date=October 2012 |volume=66 |issue=10 |pages=976–983 |doi=10.1111/j.1742-1241.2012.02986.x |pmid=22889110 |pmc=3469735}}</ref><ref>{{cite journal |last=Tefferi |first=A |title=Annual Clinical Updates in Hematological Malignancies: a continuing medical education series: polycythemia vera and essential thrombocythemia: 2011 update on diagnosis, risk-stratification, and management. |journal=American Journal of Hematology |date=March 2011 |volume=86 |issue=3 |pages=292–301 |doi=10.1002/ajh.21946 |pmid=21351120|s2cid=205293800 }}</ref>

==Cause==
In ET, [[megakaryocyte]]s are more sensitive to [[growth factors]].<ref>{{cite journal|doi=10.1111/j.1600-0609.1975.tb01087.x|vauthors=Branehog I, Ridell B, Swolin B, Weinfeld A | year=1975 |title=Megakaryocyte quantifications in relation to thrombokinetics in primary thrombocythaemia and allied diseases |journal=Scand. J. Haematol.| volume=15 | pages=321–32|pmid=1060175|issue=5}}</ref> Platelets derived from the abnormal megakaryocytes are activated, which, along with the elevated platelet count, contributes to the likelihood of forming blood clots.<ref name="path2">{{cite journal |last=Vannucchi |first=AM |s2cid=510829 |title=Insights into the pathogenesis and management of thrombosis in polycythemia vera and essential thrombocythemia |journal=Internal and Emergency Medicine |date=June 2010 |volume=5 |issue=3 |pages=177–84 |doi=10.1007/s11739-009-0319-3 |pmid=19789961}}</ref> 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.<ref name="path2" /> A mutation in the [[JAK2]] [[kinase]] (V617F) is present in 40–50% of cases and is diagnostic if present.<ref name="path" /><ref name="path2" /> ''JAK2'' is a member of the [[Janus kinase]] family.<ref name="path" /><ref name="path2" />

In 2013, two groups detected [[calreticulin]] mutations in a majority of [[Janus kinase 2|JAK2]]-negative/[[thrombopoietin receptor|MPL]]-negative patients with essential thrombocythemia and [[myelofibrosis|primary myelofibrosis]], which makes ''CALR'' mutations the second most common in [[myeloproliferative disease|myeloproliferative neoplasms]]. All mutations (insertions or deletions) affected the last exon, generating a reading [[Frameshift mutation|frame shift]] of the resulting protein, that creates a novel terminal peptide and causes a loss of endoplasmic reticulum [[ER retention|KDEL retention signal]].<ref name="pmid24325359">{{cite journal |vauthors=Nangalia J, Massie CE, Baxter EJ, Nice FL, Gundem G, Wedge DC, Avezov E, Li J, Kollmann K, Kent DG, Aziz A, Godfrey AL, Hinton J, Martincorena I, Van Loo P, Jones AV, Guglielmelli P, Tarpey P, Harding HP, Fitzpatrick JD, Goudie CT, Ortmann CA, Loughran SJ, Raine K, Jones DR, Butler AP, Teague JW, O'Meara S, McLaren S, Bianchi M, Silber Y, Dimitropoulou D, Bloxham D, Mudie L, Maddison M, Robinson B, Keohane C, Maclean C, Hill K, Orchard K, Tauro S, Du MQ, Greaves M, Bowen D, Huntly BJ, Harrison CN, Cross NC, Ron D, Vannucchi AM, Papaemmanuil E, Campbell PJ, Green AR |title=Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2 |journal=The New England Journal of Medicine |volume=369 |issue=25 |pages=2391–405 |date=Dec 2013 |pmid=24325359 |pmc=3966280 |doi=10.1056/NEJMoa1312542}}</ref><ref name="pmid24325356">{{cite journal |vauthors=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 |s2cid=14787432 |title=Somatic mutations of calreticulin in myeloproliferative neoplasms |journal=The New England Journal of Medicine |volume=369 |issue=25 |pages=2379–90 |date=Dec 2013 |pmid=24325356 |doi=10.1056/NEJMoa1311347|doi-access=free }}</ref>

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 negatively 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.<ref>{{Cite journal |last1=Prins |first1=Daniel |last2=González Arias |first2=Carlos |last3=Klampfl |first3=Thorsten |last4=Grinfeld |first4=Jacob |last5=Green |first5=Anthony R. |date=February 2020 |title=Mutant Calreticulin in the Myeloproliferative Neoplasms |journal=HemaSphere |language=en |volume=4 |issue=1 |pages=e333 |doi=10.1097/HS9.0000000000000333 |issn=2572-9241 |pmc=7000472 |pmid=32382708}}</ref>

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.<ref>{{Citation |last1=Guglielmelli |first1=Paola |title=The MPL mutation |date=2021 |journal=International Review of Cell and Molecular Biology |volume=365 |pages=163–178 |url=https://linkinghub.elsevier.com/retrieve/pii/S1937644821001076 |access-date=2024-05-07 |publisher=Elsevier |language=en |doi=10.1016/bs.ircmb.2021.09.003 |isbn=978-0-323-89939-0 |last2=Calabresi |first2=Laura|pmid=34756243 |url-access=subscription }}</ref>

==Diagnosis==
The following revised diagnostic criteria for essential thrombocythemia were proposed in 2005.<ref name="Campbell">{{cite journal |vauthors=Campbell PJ, Green AR |volume= 2005|pages=201–208 |year=2005 |pmid=16304381 |doi=10.1182/asheducation-2005.1.201 |url=https://ashpublications.org/hematology/article/2009/1/621/19882/Pathogenesis-and-management-of-essential |title= Management of polycythemia vera and essential thrombocythemia |journal= Hematology|url-access=subscription }}</ref> The diagnosis requires the presence of both A criteria together with B3 to B6, or of criterion A1 together with B1 to B6.<ref name="WHO" /> The criteria are as follows:<ref name="WHO">{{cite journal |last1=Vardiman |first1=JW |last2=Thiele |first2=J |last3=Arber |first3=DA |last4=Brunning |first4=RD |last5=Borowitz |first5=MJ |last6=Porwit |first6=A |last7=Harris |first7=NL |last8=Le Beau |first8=MM |last9=Hellström-Lindberg |first9=E |last10=Tefferi |first10=A |last11=Bloomfield |first11=CD |title=The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: Rationale and important changes |journal=Blood |date=July 2009 |volume=114 |issue=5 |pages=937–951 |doi=10.1182/blood-2009-03-209262 |pmid=19357394 |s2cid=3101472 |url=https://ashpublications.org/blood/article/114/5/937/103719/The-2008-revision-of-the-World-Health-Organization }}</ref>
* A1. [[Platelet count]] > 400 × 10<sup>3</sup>/μL for at least 2 months.
* A2. Acquired V617F [[JAK2]] mutation present
* B1. No cause for a reactive thrombocytosis
** normal inflammatory indices
* B2. No evidence of iron deficiency
** stainable iron in the bone marrow or normal red cell mean corpuscular volume
* B3. No evidence of [[polycythemia vera]]
** hematocrit < midpoint of normal range or normal red cell mass in presence of normal iron stores
* B4. No evidence of [[chronic myeloid leukemia]]
** But the [[Philadelphia chromosome]] may be present in up to 10% of cases. Patients with the Philadelphia chromosome have a potential for the development of acute leukemia, especially [[acute lymphocytic leukemia]].
* B5. No evidence of [[myelofibrosis]]
** no collagen fibrosis and ≤ grade 2 reticulin fibrosis (using 0–4 scale)
* B6. No evidence of a [[myelodysplastic syndrome]]
** no significant dysplasia
** no cytogenetic abnormalities suggestive of [[myelodysplasia]]

==Treatment==

===Indications===
Not all those affected will require treatment at presentation.<ref name="man1">{{cite journal |last=Cervantes |first=F |s2cid=18862829 |title= Management of Essential Thrombocythemia|journal=Hematology |date=2011 |volume=2011 |pages=215–21 |doi=10.1182/asheducation-2011.1.215 |pmid=22160037 |doi-access=free }}</ref><ref name="man2">{{cite journal |last=Birgegård |first=G |s2cid=11357000 |title=Pharmacological management of essential thrombocythemia. |journal=Expert Opinion on Pharmacotherapy |date=July 2013 |volume=14 |issue=10 |pages=1295–306 |doi=10.1517/14656566.2013.797408 |pmid=23668666}}</ref><ref name="man3">{{cite journal |last1=Tefferi |first1=A |last2=Barbui |first2=T |title=Personalized management of essential thrombocythemia-application of recent evidence to clinical practice. |journal=Leukemia |date=August 2013 |volume=27 |issue=8 |pages=1617–20 |doi=10.1038/leu.2013.99 |pmid=23558521 |pmc=3740400}}</ref> 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]].<ref name="path" /><ref name="man1" /><ref name="man2" /><ref name="man3" /> 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.<ref name="path" /><ref name="man1" /><ref name="man2" /><ref name="man3" />

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.<ref name="path" /><ref name="man1" /><ref name="man2"/><ref name="man3"/> 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.<ref>{{Cite journal|last1=Boddu|first1=Prajwal|last2=Falchi|first2=Lorenzo|last3=Hosing|first3=Chitra|last4=Newberry|first4=Kate|last5=Bose|first5=Prithviraj|last6=Verstovsek|first6=Srdan|date=2017-07-01|title=The role of thrombocytapheresis in the contemporary management of hyperthrombocytosis in myeloproliferative neoplasms: A case-based review|journal=Leukemia Research|language=en|volume=58|pages=14–22|doi=10.1016/j.leukres.2017.03.008|pmid=28380402 |pmc=5466892 |issn=0145-2126}}</ref>

==Prognosis==
Essential thrombocythemia is sometimes described as a slowly progressive disorder with long asymptomatic periods punctuated by thrombotic or hemorrhagic events.<ref name="man1" /> 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.<ref name="man1" /> ET is the myeloproliferative neoplasm least likely to progress to acute myeloid leukemia.<ref>{{cite web |url=https://www.lecturio.com/concepts/essential-thrombocythemia/| title=Essential Thrombocythemia
|website=The Lecturio Medical Concept Library |access-date= 22 July 2021}}</ref>

==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.<ref name="emerg">{{cite journal |last1=Fabris |first1=F |last2=Randi |first2=ML |s2cid=43185338 |title=Essential thrombocythemia: past and present.|journal=Internal and Emergency Medicine |date=October 2009 |volume=4 |issue=5 |pages=381–8 |doi=10.1007/s11739-009-0284-x |pmid=19636672}}</ref> The incidence in children is 0.09/100,000 per year.<ref name="emerg" />

==Pregnancy==
[[Hydroxycarbamide]] and [[anagrelide]] are contraindicated during [[pregnancy]] and [[nursing]].<ref name="preg" /> Essential thrombocythemia can be linked with a three-fold increase in risk of [[miscarriage]].<ref name="emerg" /> Throughout pregnancy, close monitoring of the mother and [[fetus]] is recommended.<ref name="preg" /> Low-dose [[low molecular weight heparin]] (e.g. [[enoxaparin]]) may be used.<ref name="preg" /> 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.<ref name="preg">{{cite journal |last1=Valera |first1=MC |last2=Parant |first2=O |last3=Vayssiere |first3=C |last4=Arnal |first4=JF |last5=Payrastre |first5=B |title=Essential thrombocythemia and pregnancy |journal=European Journal of Obstetrics, Gynecology, and Reproductive Biology |date=October 2011 |volume=158 |issue=2 |pages=141–7 |doi=10.1016/j.ejogrb.2011.04.040 |pmid=21640467}}</ref>

==In popular culture==

Jill Kaplan, the female protagonist of [[The Pajama Diaries]] comic strip was diagnosed with essential thrombocythemia.<ref>{{cite web | url=https://comicskingdom.com/pajama-diaries/2023-03-18 | title=The Pajama Diaries }}</ref>

==References==
{{Reflist|refs=citation number 10 is not a dead link. its fully functional and very good publication}}

== External links ==
{{Medical resources
|  ICD10          = {{ICD10|D|75|2|d|70}}, {{ICD10|D|47|3|d|37}}
|  ICD9           = {{ICD9|238.71}}
|  ICDO           = {{ICDO|9962|3}}
|  OMIM           = 187950
|  DiseasesDB     = 4522
|  MedlinePlus    = 000543
|  eMedicineSubj  = med
|  eMedicineTopic = 2266
|  MeshID         = D013920
}}

{{Diseases of megakaryocytes|us=y}}
{{Myeloid malignancy|us=y}}

[[Category:Myeloid neoplasia]]
[[Category:Coagulopathies]]