Current Opinion in Hematology:
Essential thrombocythemia: scientific advances and current practice
Division of Hematology, Department of Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
Correspondence to Ayalew Tefferi MD, Division of Hematology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Tel: +1 507 284 3159; fax: +1 507 266 4972; e-mail: firstname.lastname@example.org
Purpose of review: Median survival in essential thrombocythemia exceeds 20 years and clinical course is usually indolent with a minority of patients experiencing thrombohemorrhagic complications. Leukemic, polycythemic, or fibrotic disease transformation in essential thrombocythemia is an infrequent occurrence with a 15-year cumulative risk of approximately 5% or less in each instance. The major incentives for this review have been the recent description of an activating JAK2 tyrosine kinase mutation (JAK2V617F) in essential thrombocythemia, related myeloproliferative disorders, and the impact on clinical practice from the publication of a major treatment trial.
Recent findings: Several studies have reported on the occurrence of JAK2V617F in approximately 50% of patients with essential thrombocythemia and its presence has been associated with advanced age at diagnosis, higher hemoglobin and leukocyte levels, and increased rate of polycythemic transformation. In contrast, the mutation did not appear to affect the incidence of thrombotic, leukemic, or fibrotic events. There is increasing evidence regarding the thrombogenic role of neutrophils in essential thrombocythemia and this might partly explain the superior overall performance by hydroxyurea, compared with anagrelide, in a recent randomized study.
Summary: Although it is in vogue to consider essential thrombocythemia as more than one disease in terms of both molecular phenotype (presence or absence of JAK2V617F) and putative pattern of myelopoiesis (monoclonal versus polyclonal), it is yet to be shown that such differences influence either the natural history of the disease or current therapy. From a treatment standpoint, hydroxyurea is now confirmed to be the drug of choice for high-risk patients with essential thrombocythemia.
Abbreviations AvWS: acquired von Willebrand syndrome; MDS: myelodysplastic syndrome; MMM: myelofibrosis with myeloid metaplasia; MPD: myeloproliferative disorder.
Essential thrombocythemia is currently defined as a persistent thrombocythemic state that is neither reactive nor associated with an otherwise defined chronic myeloid disorder. Essential thrombocythemia was first described by Epstein and Goedel in 1934 , classified as a myeloproliferative disorder (MPD) by Dameshek in 1951 , and acknowledged as a distinct clinicopathologic entity that is separate from polycythemia vera in 1960 . In most cases, essential thrombocythemia is believed to represent a stem cell-derived clonal myeloproliferation but the primary clonogenic mutation remains elusive . As such, current diagnosis is based on a clinicopathologic profile and not attached to a specific molecular marker (Table 1). Strict diagnostic criteria for essential thrombocythemia were first established in the 1970s by the polycythemia vera study group and have since been revised by the World Health Organization-sponsored cooperative group (Table 1) . The utilization, by these criteria, of a platelet count threshold (600 × 109/l) that is biologically unsound, however, has resulted in gross underestimation of disease incidence (0.2–2.5/100 000) as well as a potentially detrimental oversight of phenotypically classic essential thrombocythemia cases with platelet counts between 400 and 600 × 109/l [6–8].
In 1981, Fialkow and colleagues  established essential thrombocythemia as a stem cell-derived clonal myeloproliferation by employing a clonality assay that is based on glucose-6-phosphate dehydrogenase isoenzyme analysis. This seminal observation was subsequently confirmed by modern clonality studies that are based on DNA methylation and expression patterns of X-linked polymorphic genes in females. X-linked clonal assays have also suggested the presence of ‘polyclonal’ hematopoiesis in a substantial minority of patients with essential thrombocythemia . The particular phenomenon, however, probably reflects the insensitivity of the specific assay in detecting minor populations of clonal cells in a background of polyclonal hematopoiesis since a recent study has demonstrated the presence of JAK2V617F in the majority of patients with ‘polyclonal’ essential thrombocythemia [10••].
The year 2005 was marked by a major molecular event with potential pathogenetic relevance in essential thrombocythemia as well as other MPDs [11••]. An activating somatic point mutation (a guanine-to-thymine transversion at nucleotide 1849), in exon 12 of JAK2, resulting in a valine-to-phenylalanine amino acid substitution at codon 617 (JAK2V617F), was described in 65–97% of patients with polycythemia vera (homozygous in 25–33%), 35–57% with myelofibrosis with myeloid metaplasia (MMM) (homozygous in 9–29%), and 23–57% with essential thrombocythemia (homozygous in 0–7%) . JAK2 is structurally characterized by the presence of two homologous kinase domains: JAK homology 1 (JH1), which is functional, and JH2, which lacks kinase activity (i.e. pseudo-kinase domain). The JAK2V617F mutation resides in the JH2 domain, which normally interacts with the JH1 domain to inhibit kinase activity .
The presence of the same functional mutation among essential thrombocythemia, PV, and MMM might explain the sharing between these disorders of several biological features including in-vitro growth factor independence/hypersensitivity of both erythroid and megakaryocyte progenitor cells and increased neutrophil polycythemia rubra vera-1 (PRV-1) expression [14•,15]. By contrast, the specific pathogenetic role of JAK2V617F is further confounded by its infrequent occurrence in other myeloid disorders including the myelodysplastic syndrome (MDS) and atypical MPD [16•,17•]. Regardless, the mutation appears to be both myeloid lineage and myeloid disorder-specific [18•,19,20]. In essential thrombocythemia, the presence of JAK2V617F has been associated with advanced age at diagnosis, higher hemoglobin and leukocyte levels, and increased rate of polycythemic transformation [10••,21••]. In contrast, the mutation did not appear to affect either thrombosis risk or the transformation rate into either acute myeloid leukemia (AML) or myelofibrosis [21••].
Conventional cytogenetics reveals microscopic abnormalities in less than 5% of patients with essential thrombocythemia and application of fluorescent in-situ hybridization (FISH) might disclose additional karyotypically occult numerical abnormalities of chromosomes 8 and 9 . Other structural abnormalities include long arm deletions of chromosomes 5, 7, 13, 17, and 20. None, however, has enough specificity to be particularly useful in either diagnosis or providing pathogenetic insight . In the past, there had been some discussion regarding the occurrence of the BCR/ABL mutation in essential thrombocythemia, but this was later discarded as being an atypical presentation of true chronic myeloid leukemia (CML) . Such cases do not display peripheral blood features of CML but bone marrow examination discloses CML-characteristic, small hypo-lobulated megakaryocytes . Application of reverse transcriptase polymerase chain reaction (RT-PCR) in FISH-negative essential thrombocythemia has revealed the presence of BCR/ABL transcripts in some patients and both the prevalence of the particular phenomenon and its clinical relevance remain controversial .
Pathogenesis of vascular events
Approximately 20% of patients with essential thrombocythemia experience major thrombotic events either at diagnosis or during their clinical course . In this regard, neither thrombocytosis nor qualitative platelet defects has been correlated with thrombosis risk in essential thrombocythemia . By contrast, the demonstration of altered neutrophil activation parameters as well as circulating platelet–leukocyte aggregates in essential thrombocythemia implicates a thrombogenic role for neutrophils, thus providing an explanation for the antithrombotic property of hydroxyurea that is not shared by anagrelide [27•,28,29••]. Abnormal thromboxane A2 (TX A2) generation might play a role in the pathogenesis of microvascular symptoms, including headaches and erythromelalgia . The particular possibility is consistent with the efficacy of aspirin in alleviating such symptoms that are believed to be linked to small vessel-based abnormal platelet–endothelial interactions .
Bleeding diathesis in essential thrombocythemia is currently believed to involve an acquired von Willebrand syndrome (AvWS) that becomes apparent in the presence of extreme thrombocytosis . The mechanism of AvWS in essential thrombocythemia is currently believed to involve a platelet count-dependent increased proteolysis of high molecular weight von Willebrand protein by the ADAMTS13 cleaving protease . Other qualitative platelet defects in essential thrombocythemia are believed to play a minor role in disease-associated hemorrhage and include defects in epinephrine, collagen, and ADP-induced platelet aggregation, decreased ATP secretion, and acquired storage pool deficiency that results from abnormal in-vivo platelet activation .
Median age at diagnosis in essential thrombocythemia is estimated at 55 years [33•]. Thrombohemorrhagic complications cap the clinical course and major thrombosis, which is mostly arterial, occurs in 11–25% of patients at diagnosis and in 11–22% during follow-up . In contrast, the incidence of major hemorrhage is only 2–5% at diagnosis and 1–7% during follow-up . Similarly, hemorrhage is a rare cause of death in essential thrombocythemia whereas thrombosis might account for 13–27% of deaths . Abdominal large vessel thrombosis is particularly prevalent in both essential thrombocythemia and polycythemia vera, affecting approximately 10% of patients . Non-life-threatening complications in essential thrombocythemia include microvascular disturbances (headaches, acral paresthesia, erythromelalgia) and first trimester miscarriages. The former are relatively frequent but easily managed by low-dose aspirin therapy. The latter occur in 30–40% of pregnant women with essential thrombocythemia and do not appear to be influenced by either platelet count or aspirin therapy .
The normal platelet count in both sexes as well as across different ethnic backgrounds is estimated to be less than 400 × 109/l . Therefore, essential thrombocythemia must be considered in the presence of a platelet count above 400 × 109/l. During the evaluation of thrombocytosis, one must first rule out the possibility of reactive thrombocytosis (Fig. 1). In this regard, one is strongly advised to review old records in order to determine the duration of thrombocytosis. The complete blood count and the peripheral blood smear might provide information that is useful in distinguishing essential thrombocythemia from reactive thrombocytosis. For example, a diagnosis of reactive thrombocytosis is preferred over that of essential thrombocythemia in the presence of either microcytosis (iron deficiency anemia) or Howell-Jolly bodies (surgical or functional asplenia). Additional laboratory tests that help in this regard are serum ferritin and C-reactive protein (CRP) levels. A normal serum ferritin level excludes the possibility of iron deficiency anemia-associated reactive thrombocytosis. An increased CRP value suggests the presence of inflammatory or malignant process. Neither a low serum ferritin level nor an increased CRP, however, excludes the possibility of essential thrombocythemia.
If neither the history nor the aforementioned initial laboratory test profile suggests reactive thrombocytosis, a bone marrow examination is recommended (Fig. 1). Peripheral blood screening for JAK2V617F cannot substitute for bone marrow examination because it is neither adequately sensitive (∼50% of patients with essential thrombocythemia do not carry the mutation) nor specific to essential thrombocythemia (the mutation also occurs in MMM and other MPDs) . Furthermore, the role of bone marrow examination is not only to confirm the diagnosis of essential thrombocytosis but also to exclude other causes of clonal thrombocythemia: CML , myelodysplastic syndrome , or cellular phase of agnogenic myeloid metaplasia (AMM)  can all present with isolated thrombocytosis that might not be easily distinguished from essential thrombocythemia.
Bone marrow histological features of MPDs include bone marrow hypercellularity, abnormal megakaryocyte morphology and pattern of distribution (e.g. presence of megakaryocyte clusters), and reticulin fibrosis . The possibility of MDS should be considered in the presence of dyserythropoiesis, ringed sideroblasts, macrocytosis, monocytosis, and pseudo Pelger-Huet anomaly . In addition to bone marrow morphological assessment, it is generally advised to obtain FISH for BCR/ABL (in order to exclude the possibility of CML) and mutation screening for JAK2V617F (in order to complement histological diagnosis of either essential thrombocythemia or another MPD) (Fig. 1). In this regard, although the presence of JAK2V617F does not distinguish one MPD from another, it makes the diagnosis of MDS less likely, and when present in a homozygous state, the diagnosis of polycythemia vera more likely. Finally, one must always keep ‘cellular phase’ MMM in the differential diagnosis of thrombocytosis and the presence of either elevated levels of serum lactate dehydrogenase level or a leukoerythroblastic peripheral blood smear favors this particular diagnosis over essential thrombocythemia.
The majority of patients with essential thrombocythemia can expect a normal life expectancy in the first 15 years of the disease . Thereafter, survival is shortened because of increased attrition from disease transformation into AML, which occurs in less than 5% and 20% of the cases in the first and second decades of the disease, respectively [33•,39]. A similar percentage of patients experience either polycythemic or fibrotic disease transformation [33•,39]. Leukemic transformation in essential thrombocythemia is considered a natural progression of the disease and not a result of drug therapy.
Both antiplatelet (e.g. aspirin) and cytoreductive (e.g. hydroxyurea) agents are used in essential thrombocythemia to either alleviate microvascular symptoms  or prevent thrombohemorrhagic complications , respectively. Cytoreductive therapy does not benefit all patients and is indicated primarily for high-risk patients (Table 2) [28,40]. Most investigators agree on what constitutes ‘high-risk’ and ‘low-risk’ disease in essential thrombocythemia (Table 2) [25,26,41]. There is controversy, however, regarding the disease-specific thrombogenic potential of either extreme thrombocytosis (i.e. platelet count > 1 million/μl) or cardiovascular risk factors. By contrast, extreme thrombocytosis in essential thrombocythemia is associated with AvWS . In order to attract attention to this particular bleeding diathesis, especially in view of the frequent use of aspirin in essential thrombocythemia, such patients are considered to have ‘intermediate-risk’ disease (Table 2).
It is currently not clear if the presence of cardiovascular risk factors (smoking, hypertension, diabetes, and hypercholesterolemia) increases risk of thrombosis more than expected from the control population without essential thrombocythemia [25,26,41]. Furthermore, because aspirin therapy is recommended for most patients with essential thrombocythemia, regardless of risk category, it might not be therapeutically relevant to continue listing cardiovascular risk factors in risk stratification models for essential thrombocythemia. Similarly, controlled prospective studies are needed before assigning essential thrombocythemia-related thrombogenic relevance to hereditary and acquired causes of thrombophilia , ‘monoclonal’ as opposed to ‘polyclonal’ X chromosome inactivation pattern of myelopoiesis [9,42–44], and altered PRV-1, platelet Mpl, or endogenous erythroid colony expression .
Cytoreductive therapy with hydroxyurea has been shown to significantly reduce the risk of thrombosis in high-risk essential thrombocythemia [28,29••,45]. In contrast, the therapeutic value of other platelet-lowering agents remains dubious. In this regard, a large randomized study compared hydroxyurea with anagrelide, both in combination with aspirin, in high-risk patients with essential thrombocythemia and demonstrated an overall superiority of hydroxyurea over anagrelide [29••]. Hydroxyurea was better tolerated and associated with significantly less risk of arterial thrombosis, major hemorrhage, and fibrotic transformation. In contrast, anagrelide displayed better activity against venous thrombosis. Accordingly, high-risk patients with essential thrombocythemia are currently offered treatment with a combination of hydroxyurea and low-dose aspirin (81 mg/day) whereas low-risk patients are treated with aspirin alone (Table 2) [28,29••,40].
In high-risk disease, based on retrospective studies, the therapeutic platelet target is set at 400 000/μl or less [46,47]. In hydroxyurea-intolerant patients, interferon (IFN)-α is a reasonable alternative and is the drug of choice during pregnancy . Incidentally, the low-risk pregnant patient is generally managed the same way as her nonpregnant counterpart . When both hydroxyurea and IFN-α are not tolerated, other drugs including anagrelide and pipobroman (not available in the US) might be considered [26,41].
Treatment for the intermediate-risk patient should be individualized and should take into consideration the presence or absence of clinically significant AvWS (e.g. ristocetin cofactor activity < 20%). Accordingly, one must be careful when using aspirin in the presence of extreme thrombocytosis without confirming a comfortable level of ristocetin cofactor activity (e.g. > 50%). The utilization of cytoreductive therapy for the intermediate-risk patient with essential thrombocythemia is highly controversial. In general, I avoid using cytoreductive therapy in patients with a platelet count of less than 1.5 million/μl whereas I consider it reasonable but not evidence based to use such treatment in the presence of a higher platelet count. In this regard, there is the factor of anxiety that comes into play when managing a patient with extreme thrombocytosis and one has to temper the temptation to use cytoreductive agents in asymptomatic patients with the awareness that long-term use of such drugs could be detrimental to patients.
Recent developments in both laboratory investigations and treatment trials in essential thrombocythemia have already impacted routine clinical practice. Diagnostic algorithms are now beginning to incorporate mutation screening for JAK2V617F, although the particular mutation might not possess therapeutically relevant information [12,21••]. Hydroxyurea has now been confirmed to be the initial drug of choice for the treatment of high-risk patients with essential thrombocythemia [29••]. Long-term, natural history studies are revealing shortened life expectancy in essential thrombocythemia after the first decade of the disease and fundamental pathogenetic information is crucial if this is to be altered .
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 115–116).
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