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 Table of Contents  
REVIEW ARTICLE
Year : 2020  |  Volume : 33  |  Issue : 3  |  Page : 733-738

Pathobiology and management of essential thrombocythemia: a systematic review


1 Department of Internal Medicine, Faculty of Medicine, Menoufia University, Menoufia, Egypt
2 Department of Internal Medicine, Ministry of Health, Menoufia, Egypt

Date of Submission05-Feb-2019
Date of Decision03-Mar-2019
Date of Acceptance10-Mar-2019
Date of Web Publication30-Sep-2020

Correspondence Address:
Ahmed A Fathallah
Rashid City, El Behera Governorate
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/mmj.mmj_54_19

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  Abstract 


Objective
The objective of this study was to review the pathobiology and management of essential thrombocythemia (ET).
Materials and methods
A systematic search of MEDLINE (PubMed, Medscape, Science Direct, EMF-Portal) and Internet was conducted on all articles published from 1996 to 2017. English language reports of the pathobiology and management of ET were included. The initial search presented 155 articles; of which, 27 satisfied the inclusion criteria. Articles not reporting on the pathobiology and management of ET in the title or abstract were not included. Eleven independent investigators extracted data on methods. Comparisons were made by structured review with the results tabulated. The included articles were eight studies about the pathogenesis of the thrombosis, eight about prognostic factors and risk stratification, and 11 about management of ET.
Results
The pathogenesis of the thrombosis seen in ET is not fully understood. Advanced age and previous history of thrombosis are the more important determinants of thrombosis. The possible importance in myeloproliferative neoplasm thrombosis of leukocytes and JAK 2 mutational status and allele burden has been a field of intense investigation. Antiplatelet therapy reduced the risk of venous thrombosis in JAK2-positive patients and the risk of arterial thrombosis in those with cardiovascular risk factors, whereas it was associated with an excess of bleeding episodes in patients with platelet counts above 1000 × 109/l.
Conclusion
ET is a chronic disease that has no cure. It may not need treatment in a mild condition, whereas in severe condition, it may need medicine that lowers platelet count, blood thinners, or both. Treatment is controversial but may include aspirin.

Keywords: essential thrombocythemia, management, pathobiology


How to cite this article:
Shoeib SA, Abdel-Hafez MA, Abd El Hamid AE, Fathallah AA. Pathobiology and management of essential thrombocythemia: a systematic review. Menoufia Med J 2020;33:733-8

How to cite this URL:
Shoeib SA, Abdel-Hafez MA, Abd El Hamid AE, Fathallah AA. Pathobiology and management of essential thrombocythemia: a systematic review. Menoufia Med J [serial online] 2020 [cited 2020 Nov 24];33:733-8. Available from: http://www.mmj.eg.net/text.asp?2020/33/3/733/296703




  Introduction Top


Platelets, also called thrombocytes (thrombocyte or blood clot cell), are a component of blood whose function (along with the coagulation factors) is to stop bleeding by clumping and clotting blood vessel injuries [1]. The normal range for platelets is 150 000–400 000/cmm 3. Low platelet concentration is thrombocytopenia and is owing to either decreased production or increased destruction. Elevated platelet concentration is thrombocytosis, which is either congenital, reactive, or owing to unregulated production or certain other myeloid neoplasms [2]. Thrombopoiesis refers to the process of thrombocyte generation. Thrombocytes are ligations of the cytoplasm from megakaryocytes. The megakaryocyte is a giant cell, and pieces of its cytoplasm and cell membrane bud off to form thrombocytes. One megakaryocyte can produce up to 1000–6000 thrombocytes [3]. Thrombopoietin stimulates megakaryopoiesis, the process of megakaryocyte maturation and differentiation. Thrombopoietin is mainly produced in the liver and is regulated by a negative feedback system [4]. Essential thrombocythemia (ET) is a nonreactive, chronic myeloproliferative disorder in which sustained megakaryocyte proliferation leads to an increase in the number of circulating platelets [5]. WHO diagnostic criteria for ET include sustained platelet count more than 600 × 109/l and bone marrow biopsy showing proliferation mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes with no evidence of other myeloproliferative disorders or myelodysplasia [6]. Treatment options include aspirin for mild vasomotor symptoms and to decrease the risk of thrombosis in low-risk patients. Patients with significant bleeding or extreme thrombocytosis may need therapy to lower the platelet count. Elosuppressive drugs to lower platelet count include hydroxyurea, anagrelide, and interferon (IFN) α-2b. Platelet removal has been used in rare patients with serious hemorrhage and recurrent thrombosis or before emergency surgery to immediately reduce the platelet count; this procedure, however, is rarely necessary. Allogeneic stem cell transplantation is rarely used in ET but can be effective in younger patients if other treatments are unsuccessful and a good donor is available [4]. Therefore, the aim of this work was to review recent advances in ET regarding thrombopoiesis, pathogenesis, and management.


  Materials and Methods Top


Data sources

A systematic search was conducted on the recent advances in ET regarding thrombopoiesis, pathogenesis, and management. Using MEDLINE (PubMed, Medscape, Science Direct, and EMF-Portal) and Internet, a search was conducted on all articles published from 1997 to 2017. During the research, the focus was on pathogenesis of the thrombosis/prognostic factors/risk stratification/management of ET as searching terms. Additional records were identified by reference lists in retrieved articles. The search was established in the electronic databases from 1997 to 2017.

Study selection

Eligible articles were published in peer-reviewed journals and written in English. Articles not reporting on pathogenesis and management of ET in the title or abstract were not included. Full-text articles were screened, and the final inclusion decisions were made according to the following criteria: original studies; systematic reviews or meta-analyses; primary or first-line treatment and, if necessary, secondary treatment described; and treatment success, complications, and adverse effects described.

Data extraction

Articles not reporting on pathogenesis and management of ET in the title or abstract were excluded. Eleven independent investigators extracted data on methods, health outcomes, and traditional protocol. Surveys about symptoms and health without exposure assessment, report without peer-review, not within national research program, letters/comments/editorials/news, and studies not focused on exposure from the pathogenesis and management of ET were excluded.

The analyzed publications were evaluated according to evidence-based medicine (EBM) criteria using the classification of the US Preventive Services Task Force and UK National Health Service protocol for EBM in addition to the Evidence Pyramid [6].

US Preventive Services Task Force [6] classification is as follows:

  1. Level I: evidence obtained from at least one properly designed randomized controlled trial
  2. Level II-1: evidence obtained from well-designed controlled trials without randomization
  3. Level II-2: evidence obtained from well-designed cohort or case–control analytic studies, preferably from more than one center or research group
  4. Level II-3: evidence obtained from multiple time series with or without the intervention. Dramatic results in uncontrolled trials might also be regarded as this type of evidence
  5. Level III: opinions of respected authorities, based on clinical experience, descriptive studies, or reports of expert committees.


Study quality assessment

Quality of all the studies was assessed. Important factors included study design, ethical approval, calculation of evidence power, specified eligibility criteria, appropriate controls, adequate information, and specified assessment measures. It was expected that confounding factors would be reported and controlled for and appropriate data analysis made in addition to an explanation of missing data.

Data synthesis

A structured systematic review was done with the results tabulated. There were eight studies about the pathogenesis of the thrombosis, eight about prognostic factors and risk stratification, and 11 about management of ET.


  Results Top


Study selection and characteristics

A systematic search was conducted on the recent advances in ET regarding thrombopoiesis, pathogenesis, and management. Using MEDLINE (PubMed, Medscape, Science Direct, EMF-Portal) and Internet, a search was conducted on all articles published from 1997 to 2017. Articles not reporting on pathogenesis of the thrombosis, prognostic factors, risk stratification, and management of ET in the title or abstract were not included. Eleven independent investigators extracted data on methods, health outcomes, and traditional protocol. Potentially relevant publications were identified. Overall, 73 articles were excluded as they are away from our inclusion criteria. Overall, 27 studies were reviewed as they met the inclusion criteria, including 8 studies about the pathogenesis of the thrombosis, eight about prognostic factors and risk stratification, and 11 about management of ET. Regarding the pathogenesis of thrombosis, three randomized control studies [7],[8],[9] were in level I or (level A) and reported that ET is one of the classical clonal myeloproliferative neoplasms (MPNs) that constitute a clinical entity distinct from the other MPNs such as polycythemia vera and primary myelofibrosis, despite the similarities in their molecular basis. The pathogenesis of the thrombosis seen in ET is not fully understood. However, three prospective studies [10],[11],[12] come in level II-2 or (level B), which revealed that in brief, although the results of most such studies tend to support a contributory role of higher leukocyte counts and JAK 2 mutation status and allele burden in thrombosis, agreement is not universal. The role of leukocyte and platelet activation is better established. Moreover, two cohort studies [4],[6] come in the second level regarding the pyramid of EBM. We found that the link between leukocyte and platelet activation and thrombosis in ET has been reinforced by the finding of increased concentrations of markers of coagulation and endothelial activation in patients with increased blood cell activation [Table 1]. Concerning, prognostic factors and risk stratification, three prospective studies [10],[13],[14] come in level II-2 or (level B) and reported that survival of patients with ET does not seem to differ substantially from that of the general population. Evolution to myelofibrosis is seen in 3.9–8.3% of patients at 10 years and in more than 15% at 15 years. Moreover, two cohort analyses [15],[16] come in the second level regarding the pyramid of EBM and found that acute myeloid leukemia and myelodysplasia can occur in treatment-naive patients, but they are more frequently seen in those having received radioactive phosphorus or pipobroman. Vascular events represent by far the most frequent complication of ET, but they affect the patients' quality of life more than their survival. However, three randomized case–control studies [8],[12],[17] come in level I or (level A) and found that it must be pointed out that attempts to consider an intermediate-risk group, which would include patients from 40 to 60 years of age with no high-risk factors and patients younger than 60 years with cardiovascular risk factors, have not gained general acceptance [Table 2]. In addition, three cohort studies [18],[19],[20] come in the second level regarding the pyramid of EBM and reported that antiplatelet therapy reduced the risk of venous thrombosis in JAK2-positive patients and the risk of arterial thrombosis in those with cardiovascular risk factors, whereas it was associated with an excess of bleeding episodes in patients with platelet counts above 1000 × 109/l. Moreover, three randomized case–control studies [17],[21],[22] come to level I or (level A). These reported that antiplatelet therapy was based on the physician's best judgement and pose some limitations to the results of the aforementioned study. However, the high number of patients analyzed and the long follow-up make its conclusions of value. On the contrary, four prospective studies [23],[24],[25],[26] come in level II-2 or (level B) and indicated that recombinant IFN-α can control platelet counts but is associated with frequent adverse effects, which makes its long-term administration difficult, especially as the patient's age increases [Table 3].
Table 1: The pathogenesis of the thrombosis

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Table 2: Prognostic factors and risk stratification

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Table 3: Management of essential thrombocythemia

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  Discussion Top


ET is one of the classical clonal MPNs that constitute a clinical entity distinct from the other MPNs such as polycythemia vera and primary myelofibrosis despite the similarities in their molecular basis [7]. Other host factors, such as coexistent vascular risk factors and occasional thrombophilia, may also contribute to the thrombotic risk [8]. In recent years, the possible importance in MPN thrombosis of leukocytes and JAK2 mutational status and allele burden has been a field of intense investigation [9]. In brief, although the results of most such studies tend to support a contributory role of higher leukocyte counts and JAK2 mutation status and allele burden in thrombosis, agreement is not universal [10]. Indeed, leukocytes of patients with ET have an activated phenotype, with increased phagocytosis, overexpression of the membrane CD11b antigen and leukocyte alkaline phosphatase, and increased plasmatic and cellular elastase content [11]. Overexpression of monocyte tissue factor, currently considered as the main trigger of the coagulation cascade in vivo, has been demonstrated in patients with ET with thrombosis, and an increased number of platelets expressing P-selectin has also been found [12]. Evolution to myelofibrosis is seen in 3.9–8.3% of patients at 10 years and in more than 15% at 15 years [13]. In one study, the use of anagrelide was associated with an increased frequency of evolution to myelofibrosis [14]. Transition to PV is occasionally observed. Acute myeloid leukemia and myelodysplasia can occur in treatment-naive patients, but they are more frequently seen in those having received radioactive phosphorus or pipobroman [15]. Vascular events represent by far the most frequent complication of ET, but they affect the patients' quality of life more than their survival. Because of this, prognostic stratification of ET must be dictated by the patients' risk of developing such complications, and therefore the treatment goal should be to prevent thrombosis and bleeding without increasing the risk of transformation of the disease [16]. The results of an ongoing PT-1 trial comparing hydroxyurea plus low-dose aspirin with low-dose aspirin alone in this ET subpopulation will hopefully provide evidence to help answer this question [17]. A recent study has provided some guidance for indications for low-dose aspirin in low-risk ET [18]. There are currently four drugs to consider as second-line therapy in ET: pegylated IFN-α, busulfan, anagrelide, and pipobroman [18]. Hydroxyurea became the first-line drug of choice after a randomized trial, which showed that it produced a significant reduction in thrombotic events [21]. This observation was further supported by the results of the PT-1 trial, a randomized study that demonstrated the superiority of hydroxyurea plus low-dose aspirin in preventing vascular events overall and transformation to myelofibrosis, although anagrelide proved to be superior in preventing venous thrombosis [22]. For high-risk ET patients resistant or intolerant to hydroxyurea, anagrelide, an imidazoquinazoline derivative, is considered as the second-line therapy. The drug selectively reduces the platelet counts by inhibiting megakaryocytic differentiation and has also some effect on platelet aggregation [19]. Although the preliminary results of the ANAHYDRET Study, which prospectively compared hydroxyurea and anagrelide in ET, failed to show inferiority of anagrelide to hydroxyurea, it must be noted that the number of patients in that study was small and the follow-up relatively short [20]. Other drugs occasionally used in ET are radioactive phosphorus, pipobroman, and busulfan. Given their leukemogenic potential, they should be restricted to patients with reduced life expectancy, usually those over the age of 75 years who cannot tolerate hydroxyurea [23]. In an attempt to minimize IFN toxicity, a study from the Anderson group provided the pegylated isoform of IFN-α2a to 39 patients with ET who had previously received at least one cytoreductive drug [24]. A retrospective study from the French Intergroup on Myeloproliferative Disorders that included 59 patients with high-risk ET treated for a median of 16 months reported 92% hematologic responses, which were complete in 76% of cases, with 81% of patients remaining on treatment at last follow-up [25]. However, toxicity of pegylated IFN is not negligible and its effects in the long run are not yet known [26].


  Conclusion Top


ET is a chronic disease that has no cure. It may not need treatment in a mild condition, whereas in severe condition, it may need medicine that lowers platelet count, blood thinners, or both. Treatment is controversial but may include aspirin. Patients older than 60 years and those with previous thromboses and transient ischemic attacks are at higher risk for subsequent thromboembolic events. Data suggest that risk of thrombosis is not proportional to platelet count.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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    Tables

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