Essential thrombocytosis is also known as essential thrombocythemia (ET). It was first recognized in 1934; however, at that time, it was described as hemorrhagic thrombocythemia. Essential thrombocytosis is one of the myeloproliferative neoplasms. It was classified as a myeloproliferative neoplasm in 1951 by Damesheck. Myeloproliferative neoplasm includes polycythemia vera, primary myelofibrosis, and essential polycythemia. The three types of myeloproliferative neoplasm are similar as they share the same mutations. Approximately 55% of patients with essential thrombocytosis have the JAK2 mutation. Essential thrombocytosis is characterized by thrombocytosis with the presence of megakaryocytic hyperplasia in the bone marrow. Due to thrombocytosis, there are risks of vascular events such as thrombosis and hemorrhage and sometimes the conversion to a blast phase of myelofibrosis. According to the World Health Organization, essential thrombocytosis is a disease that occurs when the platelet count is more than 450000 with the presence of Janus kinase 2 (JAK2), Calreticulin (CALR) or myeloproliferative leukemia virus oncogene (MPL) mutation, lacking clonal or reactive causes. This review article will focus on reviewing the etiology, epidemiology, pathophysiology, evaluation, and treatment of this disease.
The primary cause of essential thrombocythemia is the overproduction of hematopoietic cells due to the mutation of JAK2, CALR or MPL gene. These genes are known as driver mutations due to the role they play in the development of a myeloproliferative neoplasm.
Essential thrombocytosis is the most common type of myeloproliferative neoplasm. Reports are that 1.0 to 2.5 individuals per 100000 have essential thrombocytosis yearly. The prevalence was reported to be 38 to 57 per 100000 between 2008 and 2010 and mostly occurring in females. The incidence of essential thrombocytosis increases with age, with most patients presenting between the ages of 50 and 60.
The driver genes JAK2, CALR, and MPL, have specific functions which when mutated cause myeloproliferative effects. In 2005, research showed that a single point mutation of the JAK2 leads to a myeloproliferative neoplasm. The point mutation causes a change in the amino acid from valine to phenylalanine at codon 617, hence, the abbreviation JAK2V617F. JAK 2 is a non-receptor tyrosine kinase found in the cytoplasm playing a pivotal role in hematopoiesis. Its mutation aids in the gain of function leading to the activation of intracellular signaling pathways associated with the receptors of hematopoietic cytokines: erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor. About half of patients with essential thrombocytosis have JAK2 mutation. CALR mutation occurs due to insertions or deletions causing a shift in the amino acid reading frame which leads to the formation of a novel C terminus. CALR is normally involved in cellular proliferation, differentiation, and apoptosis. MPL gene, on the other hand, is reported to be mutated via point mutation and about 3 to 15% of essential thrombocytosis patients are affected by this mutation.
The bone marrow cellularity helps define essential thrombocytosis. In essential thrombocytosis, the bone marrow microscopic examinations show clustered enlarged megakaryocytes with matured cytoplasm containing multilobulated nuclei.
Essential thrombocytosis patients could present with variable symptoms. In asymptomatic patients, thrombocytosis is usually an incidental finding on complete blood count. For symptomatic patients, the most common symptoms are migraines, headache, and dizziness. They can also present with various levels of thrombosis including hepatic vein thrombosis which is the hallmark of the disease, or they can present with symptoms like transient ischemic attack, erythromelalgia, and easy bruising. The most common physical finding in essential thrombocytosis is splenomegaly, which is mild when compared to other myeloproliferative neoplasms.
The evaluation of patients with essential thrombocytosis includes getting a complete blood count, a bone marrow biopsy and genetic testing to evaluate for gene mutations. Platelet count should be more than 450000. The bone marrow biopsy should show evidence of increased proliferation of the megakaryocytic cell lines with increased numbers of enlarged, matured megakaryocytes. Because the symptoms of myeloproliferative neoplasms overlap, it is important to also rule out other causes of thrombocytosis, including clonal and reactive causes, before reaching a definite diagnosis of essential thrombocytosis. To differentiate from reactive thrombocytosis, it is recommended to get acute phase reactants and an iron panel. The abnormality in these two has been shown to cause thrombocytosis. In the inflammatory process, there will be an elevation of acute phase reactant such as CRP which has been reported as elevated in a patient with reactive thrombocytosis. Once there is resolution of inflammation, thrombocytosis is expected to resolve. Also in iron deficiency, thrombocytosis is expected to resolve with iron repalcement.
It is helpful to recognize which genetic mutation a patient has whether it is JAK2, CALR or MPL because each of these mutations determines the clinical features, complications, and survival of myeloproliferative neoplasm. Research shows that genetic testing will help to determine the phenotype and prognosis of essential thrombocytosis. For instance, a patient with CALR mutations of essential thrombocytosis has a better prognosis. The presence of a mutation strengthens the diagnosis of all myeloproliferative neoplasms as 97% of patients have some form of mutations, whether JAK2, CALR, or MPL.
The goal of treatment of essential thrombocytosis is to prevent vascular complications such as thrombotic and hemorrhagic events; this is because thrombosis and hemorrhage are the leading causes of morbidity and mortality. Risk stratification is used to determine whether the patient should receive treatment or not. Therefore, treatment strategy depends on whether the patient is low or high risk for thrombosis. Low-risk patients are young (under age 60) with no prior thrombosis, and high-risk patients are as older (over age 60) with a previous history of thrombosis. For a low-risk patient, it is recommended to treat with aspirin if there are no major contraindications for aspirin. There should be careful consideration of possible acquired von Willebrand syndrome when platelets are more than 1000 x 10^9/L. In the setting of abnormal von Willebrand laboratory parameters and/or bleeding aspirin should not be used. For a patient with microvascular thrombosis event such as erythromelalgia, aspirin is also the indicated treatment. For a high-risk patient, antiplatelet and cytoreductive therapy is the choice.
Hydroxyurea is the first line cytoreductive therapy used. If not well tolerated or patient is resistance to hydroxyurea, then anagrelide is used. Hydroxyurea has been shown to reduce both the number of platelets and the number of leukocytes causing a reduction in thrombosis and myelofibrosis. Anagrelide, on the other hand, is a second line therapy used to reduce platelet count. It does this by inhibiting the differentiation of megakaryocytes and platelet aggregation. Compared to hydroxyurea, anagrelide is superior in preventing venous thrombosis, but it increases the rate of hemorrhage when combined with aspirin. Other drugs used in essential thrombocytosis include radioactive phosphorous, pipobroman, interferon, and busulfan. These are still used in older patients who cannot tolerate hydroxyurea. Many clinical trials have proven the use of cytoreductive therapy to reduce the number of thrombotic events including the one reported by Cortelazzo et al. (1995). Cortelazzo et al. followed high risks patients taking either hydroxyurea or placebo for 6 months, and he found that 3.6% of patients receiving hydroxyurea suffered from thrombotic events compared to the 24% of people not taking hydroxyurea in the placebo group. For pregnant patients with essential thrombocytosis, it is recommended to use low molecular weight heparin during pregnancy for 6 weeks after delivery as well as cytoreduction with pegylated interferon. Also, in pregnant females who have extremely high platelets, the action of interferon is slow to bring down the platelets; plateletpheresis was reported to be an option to reduce the number of platelets.
The differential diagnosis of essential thrombocytosis is broad. Differential diagnosis includes other causes of clonal neoplasms, reactive and spurious thrombocytosis. Clonal causes include different types of myeloproliferative disorders including polycythemia vera and primary myelofibrosis. The presentation of essential thrombocytosis and other myeloproliferative disorders overlap considerably, and the only way to be sure of the diagnosis is to rule out the other myeloproliferative disorders. In essential thrombocytosis, there is thrombocytosis but no fibrosis of the bone marrow unlike in primary myelofibrosis where there is fibrosis of the bone marrow. Reactive thrombocytosis could occur due to infection, inflammation, tissue damage, hyposplenism, iron deficiency, malignancy, and hemolysis. Spurious thrombocytosis is due to the miscount of structures that are not platelets as platelets. For instance, the automated counter in labs has been reported to miscount cryoglobulin crystals, cytoplasmic fragments of circulating leukemic cells, and bacteria as platelets leading to thrombocytosis.
Essential thrombocytosis is an indolent disease and has a good prognosis. The reported life expectancy of patients with essential thrombocytosis was as high as 33 years in patients younger than 60 years. Compared to polycythemia vera, the life expectancy of patients with essential thrombocytosis is superior. Even though essential thrombocytosis is an indolent disease, they have a poorer life expectancy compared to the general population due to thrombotic events that could complicate the disease.
The most common cause of mortality and morbidity in patients with essential thrombocytosis is thrombosis. Thrombosis occurs 20% of the time followed by hemorrhage which is reported to be 10%, and the estimates of risk for conversion are less than 1%. Thrombosis is the formation of a clot in the vasculature. It could occur in the cerebral, coronary, hepatic vessels. When it occurs in the cerebral vessels, it causes transient ischemic attack or stroke, in the coronary arteries, it can lead to the acute coronary syndrome, and when it occurs in the hepatic vein can lead to Budd-Chiari syndrome. Patients who are older than 60 with a history of thrombosis are reported to be high risk for a thrombotic event.
Essential thrombocytosis is also associated with pregnancy complications. Complications could include eclampsia, placental abruption intrauterine growth retardation, and stillbirth.
Essential thrombocytosis is not curable; however, patients should be aware that to prevent complications from the disease, they have to be compliant with recommended medications. It is also vital for patients to follow up with their health care providers for close monitoring of their platelets values. Some patients with extreme thrombocytosis could also be required to get hydroxyurea because of the high risk of thrombosis so patients should follow up their platelet levels.
Essential thrombocytosis usually presents as an incidental finding. Once diagnosed, the most important step is to risk-stratify patients. Patients could be categorized under low, intermediate or high risk. This stratification guides healthcare professionals to decide what treatment strategy to perform. Educating patients on their risk of thrombosis and hemorrhage is imperative as this could encourage patient compliance. Some low-risk patients are only required to take aspirin daily. It is essential that a patient who is younger than 12-years-old should not be treated with aspirin to avoid Reye syndrome. Younger age indicates low risk, and these patients can be monitored closely instead of treating them with aspirin. It is also important for patients to be aware of the side effects of some of the cytoreductive medications. Hydroxyurea could lead to side effects such as the mouth, genital and skin ulcers, fever and interstitial pneumonitis. Older patients on hydroxyurea could develop non-melanotic skin cancers. These side effects require stoppage of the medication and the switch to another alternative cytoreductive medication.
Although the cytoreductive medications currently available help to reduce thrombotic, hemorrhagic events and conversion to myelofibrosis or acute leukemia, more research needs to be done by pharmaceutical companies and physicians to find a cure. The current goal of managing essential thrombocytosis is to prevent vascular events. It is imperative to find a cure as complications due to stroke, and myocardial infarction could be deadly and cause untimely deaths in high-risk patients.
Treatment and management of essential thrombocytopenia require an interprofessional team approach, involving physicians, nursing staff, and pharmacy, working together to achieve optimal patient outcomes. [Level V]
|||Cervantes F, Management of essential thrombocythemia. Hematology. American Society of Hematology. Education Program. 2011; [PubMed PMID: 22160037]|
|||Barbui T,Thiele J,Gisslinger H,Finazzi G,Vannucchi AM,Tefferi A, The 2016 revision of WHO classification of myeloproliferative neoplasms: Clinical and molecular advances. Blood reviews. 2016 Nov; [PubMed PMID: 27341755]|
|||Tefferi A,Pardanani A, Myeloproliferative Neoplasms: A Contemporary Review. JAMA oncology. 2015 Apr; [PubMed PMID: 26182311]|
|||Michiels JJ,Kutti J,Stark P,Bazzan M,Gugliotta L,Marchioli R,Griesshammer M,van Genderen PJ,Brière J,Kiladjian JJ,Barbui T,Finazzi G,Berlin NI,Pearson TC,Green AC,Fruchtmann SM,Silver RT,Hansmann E,Wehmeier A,Lengfelder E,Landolfi R,Kvasnicka HM,Hasselbalch H,Cervantes F,Thiele J, Diagnosis, pathogenesis and treatment of the myeloproliferative disorders essential thrombocythemia, polycythemia vera and essential megakaryocytic granulocytic metaplasia and myelofibrosis. The Netherlands journal of medicine. 1999 Feb; [PubMed PMID: 10079679]|
|||Tefferi A,Vannucchi AM,Barbui T, Essential thrombocythemia treatment algorithm 2018. Blood cancer journal. 2018 Jan 10; [PubMed PMID: 29321520]|
|||Nangalia J,Green AR, Myeloproliferative neoplasms: from origins to outcomes. Hematology. American Society of Hematology. Education Program. 2017 Dec 8; [PubMed PMID: 29222295]|
|||Meier B,Burton JH, Myeloproliferative Disorders. Hematology/oncology clinics of North America. 2017 Dec; [PubMed PMID: 29078922]|
|||Mehta J,Wang H,Iqbal SU,Mesa R, Epidemiology of myeloproliferative neoplasms in the United States. Leukemia [PubMed PMID: 23768070]|
|||Kralovics R,Passamonti F,Buser AS,Teo SS,Tiedt R,Passweg JR,Tichelli A,Cazzola M,Skoda RC, A gain-of-function mutation of JAK2 in myeloproliferative disorders. The New England journal of medicine. 2005 Apr 28; [PubMed PMID: 15858187]|
|||Falchi L,Kantarjian HM,Verstovsek S, Assessing the thrombotic risk of patients with essential thrombocythemia in the genomic era. Leukemia. 2017 Sep; [PubMed PMID: 28529308]|
|||Okoli S,Harrison C, Emerging treatments for essential thrombocythemia. Journal of blood medicine. 2011; [PubMed PMID: 22287874]|
|||Bleeker JS,Hogan WJ, Thrombocytosis: diagnostic evaluation, thrombotic risk stratification, and risk-based management strategies. Thrombosis. 2011; [PubMed PMID: 22084665]|
|||Ferreira Cristina S,Polo B,Lacerda JF, Somatic Mutations in Philadelphia Chromosome-Negative Myeloproliferative Neoplasms. Seminars in hematology. 2018 Oct; [PubMed PMID: 30502850]|
|||Besses C,Alvarez-Larrán A, How to Treat Essential Thrombocythemia and Polycythemia Vera. Clinical lymphoma, myeloma [PubMed PMID: 27521307]|
|||Cortelazzo S,Finazzi G,Ruggeri M,Vestri O,Galli M,Rodeghiero F,Barbui T, Hydroxyurea for patients with essential thrombocythemia and a high risk of thrombosis. The New England journal of medicine. 1995 Apr 27; [PubMed PMID: 7700286]|
|||Vannucchi AM,Guglielmelli P, What are the current treatment approaches for patients with polycythemia vera and essential thrombocythemia? Hematology. American Society of Hematology. Education Program. 2017 Dec 8; [PubMed PMID: 29222296]|
|||Tefferi A,Guglielmelli P,Larson DR,Finke C,Wassie EA,Pieri L,Gangat N,Fjerza R,Belachew AA,Lasho TL,Ketterling RP,Hanson CA,Rambaldi A,Finazzi G,Thiele J,Barbui T,Pardanani A,Vannucchi AM, Long-term survival and blast transformation in molecularly annotated essential thrombocythemia, polycythemia vera, and myelofibrosis. Blood. 2014 Oct 16; [PubMed PMID: 25037629]|
|||Tefferi A,Barbui T, Polycythemia vera and essential thrombocythemia: 2019 update on diagnosis, risk-stratification and management. American journal of hematology. 2019 Jan; [PubMed PMID: 30281843]|