Clinical manifestations, pathogenesis, and diagnosis of essential thrombocythemia

INTRODUCTION — Essential thrombocythemia (ET) is one of the chronic myeloproliferative neoplasms (MPN), which are collectively characterized by clonal proliferation of myeloid cells with variable morphologic maturity and hematopoietic efficiency. We consider the terms thrombocythemia and thrombocytosis equivalent; ET has also been called essential thrombocytosis and primary thrombocytosis. It is characterized by excessive, clonal platelet production with a tendency for thrombosis and hemorrhage. (See "Overview of the myeloproliferative neoplasms".)

The clinical manifestations and diagnosis of ET will be reviewed here. The prognosis and treatment of this disorder are presented separately as is the general approach to the patient with an elevated platelet count. (See "Approach to the patient with thrombocytosis" and "Essential thrombocythemia: Treatment and prognosis" and "Overview of the myeloproliferative neoplasms".)

PATHOGENESIS — The pathogenesis of ET is not completely understood. ET is a clonal stem cell disorder and the increased platelet counts are a result of excessive platelet production and not prolonged platelet survival in the peripheral blood.

Approximately 90 percent of cases have a somatically acquired driver mutation in JAK2, CALR, or MPL. These mutations result in the upregulation of JAK-STAT pathway genes, demonstrating the central importance of this pathway in the pathogenesis of ET. Ongoing investigations are aimed at determining the significance of these and other mutations in the genesis of ET and the other myeloproliferative neoplasms as well as their relative roles in determining disease phenotype, leukemic transformation, and the level of involvement of stem cells in these disorders. This is described in more detail separately. (See 'Genetic features' below and "Overview of the myeloproliferative neoplasms", section on 'Mutations in PV, ET, and PMF'.)

While most cases of ET appear to be sporadic, families with an increased incidence of ET have been described, with affected members having the same or different ET-defining mutations or even different myeloproliferative neoplasm type [1,2]. Familial cases are thought to be due to a genetic predisposition to acquire somatic mutations rather than to direct inheritance of germline mutations.

Neither thrombopoietin (TPO) nor its receptor (MPL) has been directly implicated in the pathogenesis of ET. Mutations involving the MPL gene are identified in ET in about 5 percent of subjects [3], and endogenous megakaryocyte colony growth does not appear to be dependent on an autocrine stimulation involving TPO [4,5]. This is in contrast to autosomal dominant familial ET where activating mutations in the genes for TPO or MPL, or mutations in the genes for other proteins are responsible for TPO-mediated thrombocytosis. (See "Biology and physiology of thrombopoietin", section on 'Familial thrombocythemia'.)

Serum TPO levels in ET have been reported to be inappropriately normal or elevated [6,7]. This unexpected finding may be a result of increased bone marrow stromal production of TPO [8] or decreased ligand clearance associated with reduced platelet MPL expression in patients with ET [9].

Increased sensitivity of circulating hematopoietic progenitor cells to TPO in vitro was found in 18 of 20 patients with ET, 1 of 8 patients with secondary thrombocytosis, and 0 of 22 healthy volunteers [10]. Similarly, endogenous megakaryocyte colony formation was found in 11 of 11 patients with ET and in none of 6 patients with reactive thrombocytosis or 7 healthy controls [11]. In contrast, endogenous megakaryocyte colony formation does not appear to distinguish ET (positive in 40 of 42 patients) from polycythemia vera (positive in 47 of 50 patients) [12].

EPIDEMIOLOGY — ET accounts for approximately one-third of cases of BCR-ABL-negative myeloproliferative neoplasms in the developed world [13-15]. Population-based epidemiologic studies have suggested an incidence rate for ET of 1 to 2.5 new cases/100,000 population per year [14-18]. Because life expectancy appears to be near normal in ET [19,20], the prevalence of the disease is much higher, and estimates have ranged from 9 to 24 total cases/100,000 population [15,21].

The incidence varies with race/ethnicity, sex, and age. In the United States, there is a higher incidence among Black Americans as compared with non-Hispanic White Americans and a lower incidence among Hispanic White Americans and Asians/Pacific Islanders [14]. There is a female preponderance with an approximate female to male incidence ratio of 2:1 [14,22-25]. The incidence increases with increasing age; the median age at diagnosis is 60 years, although as many as 20 percent may be younger than 40 years of age [25]. The prognosis of ET is discussed separately. (See "Essential thrombocythemia: Treatment and prognosis".)

Childhood ET — ET is rare in children, and little is known concerning its prognosis and treatment [26-29]. Population-based studies in Denmark and British Columbia have estimated an annual incidence of ET of 0.09 per million in children up to 14 years of age [27,30].

When ET does occur in children, it appears to be relatively benign. This was shown in a study of 64 consecutive patients <20 years of age being evaluated for a Philadelphia chromosome negative myeloproliferative neoplasm [31]. Of these, 50 were found to have sporadic or hereditary thrombocytosis, with the following observations:

●There were no prior episodes or thrombosis or bleeding. Symptoms were present in 16, and consisted of headaches in 13 and paresthesias in three. Splenomegaly was present in eight.

●Among the 34 children with sporadic thrombocythemia, 48 percent carried the JAK2 V617F mutation, while none had an MPL mutation. Among the 16 with hereditary thrombocythemia, none had the JAK2 mutation and 15 had an MPL mutation.

●After a median follow-up of approximately 11 years, no patient had developed acute leukemia or post-ET myelofibrosis, while three patients experienced a non-fatal thrombotic episode.

In two small studies, the percent of female children with a monoclonal pattern was 27 and 73 percent, while positivity for the JAK2 mutation was seen in 20 and 39 percent [32,33].

When ET is diagnosed in a child, it is reasonable to determine whether the disorder is acquired or familial by examining and testing the parents and other family members.

CLINICAL FEATURES

Overview — Up to one-half of patients with ET are discovered incidentally when thrombocytosis is noted on a complete blood count obtained for some other reason. Others present with disease-related symptoms (eg, headache, dizziness, visual changes) or complications (eg, thrombosis, bleeding, first trimester fetal loss). Unlike in polycythemia vera, pruritus is very uncommon in ET, occurring in less than 5 percent of patients.

There exists a wide range in the reported incidence rates of disease-related complications in ET because of inter-study differences in patient selection and the definition of what constitutes a "vasomotor symptom," "hemorrhage," or "thrombotic event."

In a single institution retrospective study of 150 patients with newly diagnosed ET, the median age at diagnosis was 50 years (range 17 to 98) and there was a female predominance (66 percent) [34]. Forty-five percent were asymptomatic. Among the group as a whole, the following clinical characteristics were noted (table 1):

●Median hemoglobin – 13.7 g/dL (range 9.1 to 16.8)

●Median leukocyte count – 9 x 10³/microL (range 4.1 to 25.2)

●Median platelet count – 1000 x 10³/microL (range 454 to 3460)

●Palpable splenomegaly – 35 percent

●History of thrombosis – 21 percent

●Vasomotor symptoms – 13 percent

●History of fetal loss – 11 percent (female patients only)

●History of bleeding – 9 percent

In various series, approximately 25 to 48 percent of patients present with palpable splenomegaly, usually only modest in degree [20,24,35]. Hepatomegaly and lymphadenopathy are uncommon. Patient questionnaires have also reported mild nonspecific complaints in approximately half of patients including fatigue, early satiety, abdominal discomfort, and difficulty concentrating [36,37]. Pulmonary hypertension, often asymptomatic, has been detected in patients with ET [38-40]. The clinical importance of this finding is unclear.

Vasomotor symptoms — In patients with ET, "vasomotor symptoms" refer to a constellation of symptoms that are thought to be related to microvascular disturbances. Retrospective case series have reported "vasomotor symptoms" in 13 to 40 percent of patients with ET [20,23,34,41].

Vasomotor manifestations include:

●Headache

●Lightheadedness

●Syncope

●Atypical chest pain

●Acral paresthesia

●Livedo reticularis

●Erythromelalgia (burning pain of the hands or feet associated with erythema and warmth) (picture 1) [42]

●Transient visual disturbances (eg, amaurosis fugax, scintillating scotomata, ophthalmic migraine) [43]

The causes of vasomotor symptoms are not well understood, but studies have correlated thromboxane-dependent platelet activation and subsequent arterial microvascular thrombosis with erythromelalgia [44,45]. These events are generally more bothersome than dangerous, and are usually controlled by treatment with low or standard doses of aspirin. (See "Essential thrombocythemia: Treatment and prognosis".)

Thrombosis and hemorrhage — Patients with ET have an increased risk of thrombosis (eg, cerebrovascular event, myocardial infarction, superficial thrombophlebitis, deep vein thrombosis, pulmonary embolus) and hemorrhage, likely due to qualitative and quantitative platelet alterations [46-48]. The risk of each is impacted by patient- and disease-related factors and by comorbidities. An assessment of thrombotic and hemorrhagic risk is an essential part of determining the appropriate management for an individual patient and is discussed in more detail separately. Importantly, some patients with platelet counts >1 million/microL will have bleeding associated with an acquired von Willebrand disease. (See "Essential thrombocythemia: Treatment and prognosis" and "Acquired von Willebrand syndrome".)

There has been a broad range of reported incidence rates of thrombosis (9 to 22 percent) and hemorrhage (3 to 37 percent) at the time of ET diagnosis [22-25,34,41,49]. As an example, in our series of 74 young women with ET, the respective incidences of thrombosis and hemorrhage, at diagnosis, were 18 percent and 26 percent [20]. However, the corresponding figures for "major" thrombotic or hemorrhagic events were 7 percent and 4 percent.

After diagnosis, reported rates for subsequent thrombosis and hemorrhage, over a median follow-up duration of 3 to 11 years, range from 7 to 31 percent and 8 to 14 percent, respectively [22-24,41,49]. In a series of 891 patients with World Health Organization-defined ET followed for a median of 6.2 years, the rate of fatal or nonfatal thrombotic events was 1.9 per 100 patient-years [50].

●Predictors of arterial thrombosis in this group included age >60, history of thrombosis, presence of cardiovascular risk factors (eg, tobacco use, hypertension, diabetes mellitus), white blood cell count >11,000/microL, and presence of the JAK2 V617F mutation.

●Of interest, the presence of a platelet count >1 million/microL was associated with a significantly decreased risk for arterial thrombosis (HR 0.42; 95% CI 0.22-0.78), presumably because of the occurrence of acquired von Willebrand disease in this group of patients. However, there was no correlation between extreme thrombocytosis and major bleeding in this study.

●Only male gender predicted for venous thrombosis.

Thrombotic events in ET have included stroke, transient ischemic attacks, retinal artery or venous occlusions, coronary artery ischemia, pulmonary embolism, hepatic or portal vein thrombosis, deep vein thrombosis, and digital ischemia [51]. Digital ischemia may start as the Raynaud phenomenon with pallor and/or cyanosis of the digits and dysesthesia, and may progress to ischemic necrosis of the terminal phalanges.

In our series of 305 female patients with ET, the use of estrogen-containing hormone therapy (hormone replacement therapy) was not associated with an increase in venous or arterial thrombotic events [52]. However, the use of oral contraceptives was associated with a threefold increased risk of venous thrombosis (23 versus 7 percent) and a fivefold increased risk of splanchnic thrombosis (15 versus 3 percent).

Bleeding manifestations at initial presentation of ET are relatively frequent; the risk is significantly associated with extreme thrombocytosis (platelet count >1 million/microL [24], >1.5 million/microL [20], and >2 million/microL [23]), the use of aspirin in doses >325 mg/day, or following treatment with nonsteroidal anti-inflammatory drugs [22,25,49,53]. However, the risk of major bleeding, as well as thrombosis may be high post-surgery even in patients with well-controlled disease, or who are receiving thromboprophylaxis [54].

Pregnancy loss — Patients with ET have an increased risk of first trimester pregnancy loss. In a review of the literature, the spontaneous abortion rate in 106 pregnancies in 57 women with ET was 43 percent, 36 percent of which occurred in the first trimester [55]. Similar rates were noted in an Italian study of 103 pregnancies in 62 women with ET [56]. Other complications included stillbirth (5 percent), premature delivery (8 percent), preeclampsia (4 percent), and fetal growth retardation (4 percent). In this and another report, the use of aspirin, with or without heparin therapy, was associated with a decreased incidence of spontaneous abortions [57]. However, these reports suffer from event selection bias stemming from underreporting of uneventful outcomes as well as early spontaneous abortions.

A report of 34 pregnancies in 18 patients with ET reported that 45 percent of the pregnancies ended in spontaneous abortions, primarily occurring in the first trimester [58]. The occurrence of abortions could not be predicted from the disease course, platelet count, or specific therapy. For those pregnancies carried to term, complications during delivery were infrequent, even in the absence of prophylactic platelet apheresis. The outcome of pregnancy was not different between patients who received no specific therapy and those treated with aspirin alone. Three pregnancies were carried to term, and resulted in deliveries of healthy babies, despite the use of radioactive ³²P or busulfan around the time of conception.

A decrease in platelet count in patients with ET during pregnancy is well documented; in a series of 43 pregnancies, the platelet count dropped from a median of 1.1 million/microL to 600,000/microL. In a separate study, this fall in platelet count was independent of the presence or absence of the V617F JAK2 mutation, although this mutation was an independent risk factor for the development of pregnancy complications (OR 2.0; 95% CI 1.1-3.8) [56].

PATHOLOGIC AND LABORATORY FEATURES

Peripheral blood smear — ET is characterized by marked thrombocytosis in the peripheral blood [59]. The platelets vary in size (platelet anisocytosis), ranging from very small to giant platelets. While agranular platelets and those with abnormal shapes may be seen, they are not common.

The red blood cells are usually normochromic and normocytic. Hypochromic, microcytic red cells may be present if there is concomitant iron deficiency. The white blood cell count is usually normal, but may be slightly elevated. The leukocyte differential is usually normal. Basophils are absent or minimal.

A leukoerythroblastic picture with teardrop-shaped red blood cells (dacryocytes), poikilocytosis, and circulating nucleated red cells suggests transformation to a post-ET myelofibrosis stage. (See "Clinical manifestations and diagnosis of primary myelofibrosis".)

Bone marrow aspiration and biopsy — Bone marrow biopsy classically shows normocellularity or moderate hypercellularity for age and trilineage growth with prominent large to giant megakaryocytes with abundant mature cytoplasm, and deeply lobulated and hyperlobulated nuclei [59]. The megakaryocytes are located throughout the bone marrow but may occur in loose clusters.

The following are not characteristic of ET and, if present, suggest an alternative diagnosis [60]:

●Megakaryocytes with highly atypical morphology

●Increased myeloblasts

●Myelodysplastic features

●Significant (>grade 1) reticulin fibrosis or collagen fibrosis

Genetic features — As with other myeloproliferative neoplasms, the vast majority of patients with ET demonstrate mutually exclusive mutations in JAK2, MPL, or CALR. Rough estimates for the frequency at which these genes are mutated in ET are as follows [61-66]:

●JAK2 mutation – 60 to 65 percent

●CALR mutation – 20 to 25 percent

●MPL mutation – 5 percent

●No JAK2, CALR, or MPL mutation ("triple negative") – 10 to 15 percent

A minority of "triple negative" ET has non-canonical mutations in JAK2, MPL, and other genes on whole exome sequencing [67,68]. Further study is needed to elucidate the function of these other gene mutations in the pathogenesis of disease. The role of gene mutations on the pathogenesis of myeloproliferative neoplasms is discussed in more detail separately. (See "Overview of the myeloproliferative neoplasms", section on 'Mutations in PV, ET, and PMF'.)

Presence of one of these mutations enables one to differentiate patients with myeloproliferative neoplasm-associated thrombocytosis from those with reactive thrombocytosis. However, it does not allow differentiation among ET, polycythemia vera, and primary myelofibrosis.

The clinical presentation of patients with ET may differ somewhat depending on the mutation present. As examples:

●JAK2 mutations – In several series, 50 to 64 percent of patients with ET had the JAK2 V617F mutation [46,63,64,69,70]. (See "Overview of the myeloproliferative neoplasms", section on 'JAK2 mutations'.)

•In one series, patients with ET and this mutation had higher total white blood cell counts and hemoglobin levels, lower platelet counts, and were more likely to transform into polycythemia vera than those without this mutation [34,71].

•Two other studies also found higher hemoglobin levels in patients with ET and the JAK2 mutation [72,73], while three studies found a higher incidence of thrombosis in those with the JAK2 mutation [72,74,75].

•A study of 82 patients with ET found higher total white blood cell counts and a higher incidence of thrombosis in those patients who demonstrated this mutation in both platelets and granulocytes as compared with those whose platelets and granulocytes were both negative for this mutation [74].

●CALR mutations – Mutations in the CALR gene have been reported in 15 to 25 percent of patients with ET [61-64,76]. Initial studies in patients with ET have indicated that those with CALR mutations are younger, more frequently male, have higher platelet counts, lower hemoglobin and leukocyte counts, and a lower risk of thrombosis than those with the JAK2 mutation, with no difference in the rate of transformation to post-ET myelofibrosis [62-64,77]. (See "Overview of the myeloproliferative neoplasms", section on 'Calreticulin (CALR) mutations'.)

●MPL mutations – In five large studies, MPL mutations were found in up to 4 percent of patients with ET [63,64,78-80]. MPL mutations lacked prognostic significance with respect to thrombosis, major hemorrhage, myelofibrotic transformation, or survival [79]. (See "Overview of the myeloproliferative neoplasms", section on 'MPL mutations'.)

DIAGNOSIS — ET should be suspected in patients with unexplained persistent thrombocytosis. (See "Approach to the patient with thrombocytosis", section on 'Hematologic malignancies'.)

Diagnostic evaluation — It is our practice to include the following in the evaluation of a patient with suspected ET:

●Clinical – Focused history including an assessment of constitutional symptoms, disease tempo (with prior blood counts when available), vasomotor symptoms, thrombotic/hemorrhagic events, and cardiovascular risk factors. Patients are queried about diseases or conditions that can be associated with thrombosis (eg, splenectomy, inflammatory bowel disease, malignancies, collagen vascular diseases) and whether the patient has relatives with thrombocytosis or other hematologic disorders. Physical examination should include an assessment of spleen size by palpation.

●Laboratory – Laboratory studies including a complete blood count with differential and review of the peripheral smear, chemistries with liver and renal function and electrolytes, lactate dehydrogenase (LDH), uric acid, and serum iron studies. Peripheral blood fluorescence in situ hybridization (FISH) or reverse transcription polymerase chain reaction (RT-PCR) for BCR::ABL1 is sent to exclude chronic myeloid leukemia. Patients with a platelet count >1 million/microL are also evaluated for acquired von Willebrand disease.

●Bone marrow examination – Unilateral bone marrow aspirate and biopsy is used to distinguish ET from other causes of persistent thrombocytosis and other MPNs (eg, primary myelofibrosis). This specimen should be sent for pathologic review with trichrome and reticulin stains, cytogenetics, and molecular testing for JAK2 mutations. If JAK2 testing is negative, molecular testing is performed for CALR and MPL mutations. If these are negative and the diagnosis is still suspected, identification of other gene mutations may offer proof of clonality (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or SR3B1 mutation).

Diagnostic criteria — Diagnosis of ET, according to the World Health Organization 5^th edition (WHO5) [81] and the International Consensus Classification [82], requires all four of the following major criteria or the first three major criteria plus the minor criterion (table 2):

●Major criteria:

•Platelet count ≥450 x 10⁹/L (≥450,000/microL)

•Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers.

•Criteria for BCR::ABL1-positive chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, myelodysplastic syndrome, or other myeloid neoplasm not met

•Demonstration of a JAK2, CALR, or MPL mutation

●Minor criterion:

•Demonstration of another clonal marker (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or SRF3B1 mutation) or no identifiable cause of thrombocytosis (eg, infection, inflammation, iron deficiency anemia)

DIFFERENTIAL DIAGNOSIS — Conditions which must be distinguished from ET include reactive thrombocytosis, chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, and myelodysplastic syndrome. They will be briefly described here, as more extensive discussion of their diagnosis can be found elsewhere in the program.

Reactive thrombocytosis — A variety of medical and surgical conditions can result in reactive thrombocytosis (table 3). These include iron deficiency anemia, surgical or functional asplenia, metastatic cancer, trauma (surgical or otherwise), acute bleeding or hemolysis, and a variety of infectious or inflammatory processes [83-85]. Unlike in ET, reactive thrombocytosis is not driven by a clonal process. (See "Approach to the patient with thrombocytosis", section on 'Other laboratory studies'.)

When a cause for reactive thrombocytosis is not readily apparent, the demonstration of elevated acute-phase reactants (C-reactive protein [CRP], fibrinogen, erythrocyte sedimentation rate, ferritin) may be used as evidence for the presence of an occult inflammatory process [86-89].

Chronic myeloid leukemia — Diagnosis of chronic myeloid leukemia (CML) requires demonstration of the BCR::ABL1 translocation, which is usually associated with chromosomal translocation t(9;22) (figure 1). This is particularly relevant to patients with CML who may present with either isolated thrombocytosis [90-92] or substantial bone marrow fibrosis, and who otherwise might have been diagnosed as having ET or primary myelofibrosis, respectively [93]. (See "Clinical manifestations and diagnosis of chronic myeloid leukemia", section on 'Other myeloproliferative neoplasms'.)

Polycythemia vera — A clonal JAK2 mutation positive chronic myeloproliferative disorder associated with an increased red cell mass defines polycythemia vera. A number of diagnostic criteria and algorithms are available for making this diagnosis (table 4). (See "Clinical manifestations and diagnosis of polycythemia vera".)

Primary myelofibrosis and prefibrotic myelofibrosis — Primary myelofibrosis (PMF) is characterized by bone marrow reticulin fibrosis along with a leukoerythroblastic blood picture with teardrop-shaped red blood cells (dacryocytes), poikilocytosis, and circulating nucleated red cells (picture 2). (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Evaluation and diagnosis'.)

However, bone marrow findings in ET show significant overlap with those seen in patients with prefibrotic myelofibrosis, such that this distinction may not be easily made [94-96]. The differentiation between PMF and ET is dependent primarily on the presence of megakaryocyte proliferation and atypia, degree of bone marrow fibrosis and splenomegaly, and the presence of peripheral blood leukoerythroblastosis in PMF. Distinguishing between these two conditions is important because of major differences in survival and complication rates between them [96-98]. Patients with prefibrotic myelofibrosis have a survival that is better than that of patients with overt PMF, but worse than that of patients with ET. (See "Clinical manifestations and diagnosis of primary myelofibrosis", section on 'Pre-PMF'.)

Myelodysplastic syndrome — Myelodysplastic syndromes (MDS) are a series of related diseases with varying degrees of disordered hematopoietic maturation. Although most are associated with thrombocytopenia, a few, such as the 5q– syndrome, the 3q21q26 syndrome, and myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis, are associated with thrombocytosis [99-102]. (See "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)", section on 'Complete blood count' and "Clinical manifestations, diagnosis, and classification of myelodysplastic syndromes (MDS)".)

Familial essential thrombocythemia — Familial ET, also called hereditary or inherited thrombocythemia or thrombocytosis, is an exceedingly rare disorder that may affect thrombopoietin (TPO) or MPL [103-109].

Thrombopoietin gene mutations — Analysis of affected members of one family revealed a single point mutation in the splice donor site of intron 3 of the TPO gene [104]. The mutant gene produced a new thrombopoietin mRNA with a normal protein coding region but with a shortened 5' untranslated region that was more efficiently translated than normal thrombopoietin transcripts. The net effect is more thrombopoietin protein synthesis, higher plasma thrombopoietin concentrations, and chronically elevated platelet counts. A similar mutation has been described in several other families [105]. However, mutations in the TPO gene do not appear to be commonly involved in sporadic cases of ET [108]. (See "Biology and physiology of thrombopoietin".)

Mutations in other genes — Other kindreds with familial ET have been described with mutations in genes also found to be affected in patients with sporadic ET. These include an activating mutation in the gene for the TPO receptor (MPL), several different JAK2 germline mutations [106,110-114], somatic mutations in the CALR gene [115], or without a mutation in any of these genes [107,116]. (See 'Childhood ET' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Myeloproliferative neoplasms".)

SUMMARY

●Description – Essential thrombocythemia (ET) is an uncommon myeloproliferative neoplasm (MPN) characterized by excessive, clonal platelet production with a tendency for thrombosis and hemorrhage. ET usually presents in middle aged and older adults. (See 'Epidemiology' above.)

●Pathogenesis – Approximately 90 percent of cases have a somatically-acquired driver mutation in JAK2, CALR, or MPL. These mutations result in the upregulation of genes in the JAK-STAT pathway. (See 'Pathogenesis' above.)

●Clinical presentation – Up to one-half of patients with ET are discovered incidentally when thrombocytosis is noted on a complete blood count. Others present with disease-related symptoms (eg, headache, dizziness, visual changes) or complications (eg, thrombosis, bleeding, first-trimester fetal loss) (table 1). (See 'Clinical features' above.)

●Evaluation – ET should be suspected in patients with unexplained persistent thrombocytosis and is evaluated with assessment of the disease tempo, review of a blood smear, and bone marrow examination with molecular testing (to confirm a clonal disorder and exclude chronic myeloid leukemia and other MPNs). (See 'Diagnostic evaluation' above.)

●Diagnostic criteria – The diagnosis of ET requires all four of the following major criteria or the first three major criteria plus the minor criterion (table 2) (see 'Diagnostic criteria' above):

•Major criteria:

-Platelet count ≥450 x 10⁹/L (≥450,000/microL)

-Bone marrow biopsy showing proliferation mainly of the megakaryocyte lineage with increased numbers of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor (grade 1) increase in reticulin fibers.

-Exclude other conditions – WHO criteria are not met for BCR::ABL1 positive chronic myeloid leukemia (CML), polycythemia vera (PV), primary myelofibrosis (PMF), myelodysplastic syndromes (MDS), or other myeloid neoplasm.

•Minor criterion:

-Molecular testing – Demonstration of a JAK2, CALR, or MPL mutation or demonstration of another clonal marker (ASXL1, EZH2, TET2, IDH1/IDH2, SRSF2, or SR3B1 mutation) or no identifiable cause of thrombocytosis (eg, infection, inflammation, iron deficiency anemia)

●Differential diagnosis – Reactive thrombocytosis is much more common than ET and may be related to various medical and surgical conditions; unlike ET, reactive thrombocytosis is not clonal. ET must also be distinguished from other causes of clonal thrombocytosis, including chronic myeloid leukemia, polycythemia vera, myelodysplastic syndrome, and different forms of familial thrombocythemia. (See 'Differential diagnosis' above.)

ACKNOWLEDGMENT — The editors of UpToDate acknowledge the contributions of Stanley L Schrier, MD as Section Editor on this topic, his tenure as the founding Editor-in-Chief for UpToDate in Hematology, and his dedicated and longstanding involvement with the UpToDate program.