Essential Thrombocythemia

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This entry is adapted from the peer-reviewed paper https://medlineplus.gov/genetics/condition/essential-thrombocythemia

Essential thrombocythemia is a condition characterized by an increased number of platelets (thrombocythemia). Platelets (thrombocytes) are blood cells involved in blood clotting. While some people with this condition have no symptoms, others develop problems associated with the excess platelets.

genetic conditions

1. Introduction

Abnormal blood clotting (thrombosis) is common in people with essential thrombocythemia and causes many signs and symptoms of this condition. Clots that block blood flow to the brain can cause strokes or temporary stroke-like episodes known as transient ischemic attacks. Thrombosis in the legs can cause leg pain, swelling, or both. In addition, clots can travel to the lungs (pulmonary embolism), blocking blood flow in the lungs and causing chest pain and difficulty breathing (dyspnea).

Another problem in essential thrombocythemia is abnormal bleeding, which occurs more often in people with a very high number of platelets. Affected people may have nosebleeds, bleeding gums, or bleeding in the gastrointestinal tract. It is thought that bleeding occurs because a specific protein in the blood that helps with clotting is reduced, although why the protein is reduced is unclear.

Other signs and symptoms of essential thrombocythemia include an enlarged spleen (splenomegaly); weakness; headaches; or a sensation in the skin of burning, tingling, or prickling. Some people with essential thrombocythemia have episodes of severe pain, redness, and swelling (erythromelalgia), which commonly occur in the hands and feet.

2. Frequency

Essential thrombocythemia affects an estimated 1 to 24 per 1 million people worldwide.

3. Causes

The JAK2 and CALR genes are the most commonly mutated genes in essential thrombocythemia. The MPL, THPO, and TET2 genes can also be altered in this condition. The JAK2, MPL, and THPO genes provide instructions for making proteins that promote the growth and division (proliferation) of blood cells. The CALR gene provides instructions for making a protein with multiple functions, including ensuring the proper folding of newly formed proteins and maintaining the correct levels of stored calcium in cells. The TET2 gene provides instructions for making a protein whose function is unknown.

The proteins produced from the JAK2, MPL, and THPO genes are part of a signaling pathway called the JAK/STAT pathway, which transmits chemical signals from outside the cell to the cell's nucleus. These proteins work together to turn on (activate) the JAK/STAT pathway, which promotes the proliferation of blood cells, particularly platelets and their precursor cells, megakaryocytes.

Mutations in the JAK2, MPL, and THPO genes that are associated with essential thrombocythemia lead to overactivation of the JAK/STAT pathway. The abnormal activation of JAK/STAT signaling leads to overproduction of megakaryocytes, which results in an increased number of platelets. Excess platelets can cause thrombosis, which leads to many signs and symptoms of essential thrombocythemia.

Although mutations in the CALR and TET2 genes have been found in people with essential thrombocythemia, it is unclear how these gene mutations are involved in development of the condition.

Some people with essential thrombocythemia do not have a mutation in any of the known genes associated with this condition. Researchers are working to identify other genes that may be involved in the condition.

4. Inheritance

Most cases of essential thrombocythemia are not inherited. Instead, the condition arises from gene mutations that occur in early blood-forming cells after conception. These alterations are called somatic mutations.

Less commonly, essential thrombocythemia is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder. When it is inherited, the condition is called familial essential thrombocythemia.

5. Other Names for This Condition

essential thrombocytosis
primary thrombocythemia
primary thrombocytosis

References

Chaligné R, Tonetti C, Besancenot R, Roy L, Marty C, Mossuz P, Kiladjian JJ,Socié G, Bordessoule D, Le Bousse-Kerdilès MC, Vainchenker W, Giraudier S. Newmutations of MPL in primitive myelofibrosis: only the MPL W515 mutations promote a G1/S-phase transition. Leukemia. 2008 Aug;22(8):1557-66. doi:10.1038/leu.2008.137.
Ding J, Komatsu H, Iida S, Yano H, Kusumoto S, Inagaki A, Mori F, Ri M, Ito A,Wakita A, Ishida T, Nitta M, Ueda R. The Asn505 mutation of the c-MPL gene, whichcauses familial essential thrombocythemia, induces autonomous homodimerization ofthe c-Mpl protein due to strong amino acid polarity. Blood. 2009 Oct8;114(15):3325-8. doi: 10.1182/blood-2008-04-149047.
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, ClearyC, Six M, Schalling M, Schönegger A, Bock C, Malcovati L, Pascutto C,Superti-Furga G, Cazzola M, Kralovics R. Somatic mutations of calreticulin inmyeloproliferative neoplasms. N Engl J Med. 2013 Dec 19;369(25):2379-90. doi:10.1056/NEJMoa1311347.
Majka M, Ratajczak J, Villaire G, Kubiczek K, Marquez LA, Janowska-WieczorekA, Ratajczak MZ. Thrombopoietin, but not cytokines binding to gp130protein-coupled receptors, activates MAPKp42/44, AKT, and STAT proteins in normalhuman CD34+ cells, megakaryocytes, and platelets. Exp Hematol. 2002Jul;30(7):751-60.
Merck Manual for Health Care Professionals: Essential Thrombocythemia
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 BJP, Harrison CN, Cross NCP, Ron D, Vannucchi AM, Papaemmanuil E,Campbell PJ, Green AR. Somatic CALR mutations in myeloproliferative neoplasmswith nonmutated JAK2. N Engl J Med. 2013 Dec 19;369(25):2391-2405. doi:10.1056/NEJMoa1312542.
Rumi E, Pietra D, Ferretti V, Klampfl T, Harutyunyan AS, Milosevic JD, ThemNC, Berg T, Elena C, Casetti IC, Milanesi C, Sant'antonio E, Bellini M, FugazzaE, Renna MC, Boveri E, Astori C, Pascutto C, Kralovics R, Cazzola M; AssociazioneItaliana per la Ricerca sul Cancro Gruppo Italiano Malattie MieloproliferativeInvestigators. JAK2 or CALR mutation status defines subtypes of essentialthrombocythemia with substantially different clinical course and outcomes. Blood.2014 Mar 6;123(10):1544-51. doi: 10.1182/blood-2013-11-539098.
Saint-Martin C, Leroy G, Delhommeau F, Panelatti G, Dupont S, James C, Plo I, Bordessoule D, Chomienne C, Delannoy A, Devidas A, Gardembas-Pain M, Isnard F,Plumelle Y, Bernard O, Vainchenker W, Najman A, Bellanné-Chantelot C; FrenchGroup of Familial Myeloproliferative Disorders. Analysis of the ten-eleventranslocation 2 (TET2) gene in familial myeloproliferative neoplasms. Blood. 2009Aug 20;114(8):1628-32. doi: 10.1182/blood-2009-01-197525.
Tefferi A, Pardanani A, Lim KH, Abdel-Wahab O, Lasho TL, Patel J, Gangat N,Finke CM, Schwager S, Mullally A, Li CY, Hanson CA, Mesa R, Bernard O, DelhommeauF, Vainchenker W, Gilliland DG, Levine RL. TET2 mutations and their clinicalcorrelates in polycythemia vera, essential thrombocythemia and myelofibrosis.Leukemia. 2009 May;23(5):905-11. doi: 10.1038/leu.2009.47.
Tefferi A. Novel mutations and their functional and clinical relevance inmyeloproliferative neoplasms: JAK2, MPL, TET2, ASXL1, CBL, IDH and IKZF1.Leukemia. 2010 Jun;24(6):1128-38. doi: 10.1038/leu.2010.69.Review.
Wiestner A, Schlemper RJ, van der Maas AP, Skoda RC. An activating splicedonor mutation in the thrombopoietin gene causes hereditary thrombocythaemia. NatGenet. 1998 Jan;18(1):49-52.

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Nicole Yin

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Table of Contents

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1. Introduction

2. Frequency

3. Causes

4. Inheritance

5. Other Names for This Condition

References

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1. Introduction

2. Frequency

3. Causes

3.1. The Genes Associated with Essential Thrombocythemia

4. Inheritance

5. Other Names for This Condition

References