Essential Thrombocytosis

Etiology

The primary cause of ET is the overproduction of hematopoietic cells resulting from mutations in the JAK2, CALR, or MPL genes. These genes are known as "driver mutations" due to their role in developing MPNs.[5] Though 90% of adults have JAK2, CALR, or MPL mutations, it is not unusual for children to exhibit a trip-negative (wild-type) molecular profile.[6][7]

The JAK2 V617F mutation (Janus kinase 2, located at 9p24) is present in approximately 50% to 60% of patients with essential thrombocythemia. Exon 12 mutations of JAK2 are not associated with ET but with polycythemia vera. Homozygous JAK2 mutations present with more severe complications, such as increased thrombotic risk and a higher likelihood of progression to myelofibrosis.[8][9]

The CALR mutation (calreticulin, located at 19p13.2) is found in approximately 20% to 30% of patients with essential thrombocythemia. CALR encodes a calcium-binding chaperone involved in endoplasmic reticulum function. These variants are more frequently associated with younger age, higher platelet counts, and a lower thrombotic risk relative to JAK2-mutant ET.[6][10] The MPL mutation (located at 1p34) is found in approximately 5% to 10% of patients with essential thrombocythemia. These mutations are primarily located in exon 10, particularly in the MPL W515LK variant.[6] MPL is also known as the gene encoding the thrombopoietin receptor.[11]

Other harmful mutations and variants have been identified in ET, including the following: 

• SH2B3, SRSF2 (associated with fibrosis) [12]
• U2AF1 (associated with fibrosis and platelet counts >1.5 × 106/µL) [12][10]
• TP53 (predicts leukemic transformation)
• IDH2, EZH2 (associated with platelet counts >1.5 × 106/µL) [10]
• 20q- (found in about 5% of patients)
• The loss of the Y chromosome (-Y; associated with a decrease in median survival)
  • These abnormalities are frequently seen in advanced disease phases, such as post-ET myelofibrosis or leukemic transformation. Mutations of the GSN (gelsolin) and JAK2 V617I genes have been implicated in hereditary forms.[13][14] A highly aggressive form carrying the MPL Ser505Asn mutation has been found among Italian families.[15] Familial clusters of thrombocytosis exist and are underdiagnosed.[16]   

Epidemiology

ET is one of the most common Philadelphia chromosome–negative myeloproliferative neoplasms. The annual incidence of ET is estimated to be 1.0 to 2.5 cases per 100,000 individuals.[17] The prevalence was reported to be 38 to 57 per 100,000 persons between 2008 and 2010, with a higher incidence in women.[18] The incidence of essential thrombocytosis increases with age, and most patients present between the ages of 50 and 60. Notably, transient thrombocytosis can occur in neonates and infants, particularly in those with low birth weight or underlying illness. In such cases, platelet counts exceeding 600 × 10³/µL may be observed and are often benign, though they remain above the typical reference range for healthy term neonates.[7]

Pathophysiology

The driver genes JAK2, CALR, and MPL have specific physiological functions that, when mutated, lead to MPNs. In 2005, research results demonstrated that a single point mutation of the JAK2 leads to a myeloproliferative neoplasm.[19] The point mutation causes a change in the amino acid from valine to phenylalanine at codon 617, hence, the abbreviation JAK2 V617F.[20] JAK2 is a nonreceptor tyrosine kinase located in the cytoplasm and plays a pivotal role in hematopoiesis. This mutation causes the constitutive activation of the JAK2 tyrosine kinase, promoting uncontrolled intracellular signaling via pathways downstream of hematopoietic cytokine receptors, including those for erythropoietin, thrombopoietin, and granulocyte colony-stimulating factor.[5] Approximately 50% of patients with ET have a JAK2 mutation.[5]

CALR mutations result from insertions or deletions that shift the amino acid reading frame, forming a novel C terminus.[5] CALR functions typically as a calcium-binding chaperone in the endoplasmic reticulum and is involved in protein folding and calcium homeostasis. Mutant CALR aberrantly activates the thrombopoietin receptor (MPL), driving clonal proliferation.[20] The MPL gene is mutated via point mutations, primarily at exon 10, with the MPL W515LK mutation occurring more frequently. These mutations occur in approximately 3% to 5% of patients with essential thrombocythemia.[20] 

ET bleeding episodes are often associated with extreme thrombocytosis (eg, platelet counts exceeding 1 to 1.5 × 10^6/µL) and may be attributed to acquired von Willebrand syndrome.[11] The mechanism involves the adsorption of large von Willebrand factor (VWF) multimers onto the surfaces of the abundant platelets, reducing plasma VWF activity and impairing its ability to stabilize coagulation factor VIII. The decreased circulating VWF contributes to bleeding diathesis despite thrombocytosis. This pathophysiology supports the clinical use of cytoreductive therapy to lower platelet counts and reduce the risk of bleeding.

Histopathology

Bone marrow examination is an important component of the diagnosis of essential thrombocythemia. In ET, bone marrow cellularity is usually normal or mildly increased. Microscopic evaluation typically reveals large, mature megakaryocytes with abundant cytoplasm and hyperlobulated (eg, “staghorn”) nuclei. These megakaryocytes often form loose clusters without significant cytologic atypia or fibrosis.[3] 

History and Physical

Patients with ET present with a wide range of symptoms. In asymptomatic individuals, thrombocytosis is typically an incidental finding on a complete blood count. For symptomatic individuals, the most common symptoms are fatigue (in 90% of patients), insomnia, migraines, headache, and dizziness.[11][17] Patients can also present with various manifestations of thrombosis, including hepatic vein thrombosis, which is a hallmark of the disease, or with transient ischemic attack, erythromelalgia, and easy bruising.[17] The most common physical finding in ETis is that splenomegaly is typically mild compared to other MPNs.[17]  

Evaluation

The World Health Organization diagnostic criteria for ET are established if all 4 major or 3 major and 1 minor criteria are met.[7] 

Major Criteria

• The platelet count is greater than or equal to 450 × 10³/µL.
• The bone marrow biopsy shows proliferation, mainly of the megakaryocytic lineage, with an increase in the number of enlarged, mature megakaryocytes with hyperlobulated nuclei. No significant increase or left shift in neutrophil granulopoiesis or erythropoiesis is present, and there is very rarely a minor increase in reticulin fibers. 
• Not meeting World Health Organization criteria for BCR-ABL1–positive chronic myeloid leukemia, polycythemia vera, primary myelofibrosis, myelodysplastic syndromes, or other myeloid neoplasms.
• A JAK2, CALR, or MPL mutation is present.

Minor Criteria

• There is a clonal marker or absence of evidence for reactive thrombocytosis.

As stated above, evaluating patients with essential thrombocytosis includes obtaining a complete blood cell count, performing a bone marrow biopsy, and genetic testing. The bone marrow biopsy often reveals evidence of increased proliferation of megakaryocytic cell lines, characterized by an increased number of enlarged, mature megakaryocytes. Because the symptoms of MPNs overlap, it is essential to rule out other causes of thrombocytosis, including clonal and reactive, before diagnosing ET.[21] Acute-phase reactants and an iron panel can differentiate reactive thrombocytosis from ET. Acute-phase reactants, such as C-reactive protein or erythrocyte sedimentation rate, are elevated during an inflammatory process.[22] Once the inflammation has resolved, thrombocytosis improves. Similarly, iron deficiency-induced thrombocytosis resolves with iron replacement.  

Pediatric ET differs from the adult form.[7] Many children are asymptomatic, splenomegaly is observed in nearly 50% of patients, and hepatomegaly in 25%.[23] The JAK2 V617F mutation is detected in approximately 40% to 50% of pediatric ET cases. Diagnosing children requires careful integration of clinical, laboratory, and especially bone marrow histologic findings, because thrombocytosis is frequently reactive.[7] Platelets are also acute-phase reactants, increasing in response to elevated thrombopoietin receptor expression and inflammatory cytokines, such as interleukin-6.[24]  

Genetic mutations, such as JAK2, CALR, or MPL, determine the clinical features, complications, and prognosis of MPNs.[20] For example, patients with ET and CALR mutations generally have a lower risk of thrombosis and more favorable outcomes than those with JAK2 mutations.[25] Approximately 85% to 90% of patients with ET carry 1 of these driver mutations, underscoring the diagnostic significance of molecular testing.[25]

Treatment / Management

The primary goal of the treatment of ET is to prevent vascular complications such as thrombotic and hemorrhagic events, the leading causes of morbidity and mortality.[26] The International Prognostic Score for Essential Thrombocythemia (IPSET-thrombosis) stratifies patients based on risk factors, including those aged 60 years or older, prior thrombosis, cardiovascular risk factors (eg, diabetes, tobacco use, hypertension), and presence of the JAK2 V617F mutation.[27][28] Leukocytosis is recognized as an additional risk factor in some models but is not part of the classical IPSET-thrombosis score. Risk stratification guides therapy, dividing patients into low- and high-risk groups. 

Generally, low-risk individuals are younger than 60 with no history of thrombosis, whereas high-risk individuals are aged 60 years or older or have a prior thrombotic event.[22] For those at low risk, treatment with aspirin is recommended if there are no major contraindications. If platelets exceed 1000 × 10^9/µL, acquired von Willebrand syndrome should be considered. Aspirin should be avoided if abnormal von Willebrand laboratory parameters and/or bleeding are present. For high-risk individuals, antiplatelet (low-dose aspirin) and cytoreductive therapy are preferred treatments. 

Hydroxyurea is the most commonly used cytoreductive agent, with anagrelide and pegylated interferon used secondarily. Hydroxyurea reduces both platelets and leukocytes, resulting in decreased thrombosis and myelofibrosis.[1] Anagrelide is a second-line therapy used to reduce the platelet count.[29] Anagrelide inhibits the differentiation of megakaryocytes and platelet aggregation.[1] Compared to hydroxyurea, anagrelide is superior in preventing venous thrombosis, but it increases the risk of hemorrhage when combined with aspirin.

Data from the United Kingdom support the use of interferon, with an overall response rate of 81%.[28] Pegylated forms are reportedly superior to anagrelide, but flu-like toxicity still occurs.[30][31] Many clinical trials' results have demonstrated the benefits of cytoreductive therapy in reducing the number of thrombotic events. Cortelazzo et al followed high-risk individuals taking either hydroxyurea or a placebo for 6 months. They found that 3.6% of patients receiving hydroxyurea suffered from thrombotic events, compared to 24% of those in the placebo group.[32] (A1)

Pregnancies complicated by ET have an increased risk of first-trimester fetal loss as well as placental complications.[11] For pregnant individuals with ET, low molecular weight heparin used concurrently with low-dose aspirin is recommended; the latter should be withdrawn if bleeding occurs. Low-molecular-weight heparin should be continued for 6 weeks postpartum. Additionally, cytoreduction with pegylated interferon can improve live birth rates.[1][28][33] Pregnant individuals with extremely high platelet counts (eg, >1.5 × 10^6/µL) may experience a slow reduction in platelet count with interferon; plateletpheresis is also an option for reducing platelet levels.[34] Hydroxyurea and anagrelide are contraindicated in pregnant patients with ET.[28] Hydroxyurea is potentially teratogenic, and anagrelide can cross the placenta, leading to fetal thrombocytopenia. 

Other agents have been considered, but they have their shortcomings.[28] Busulfan has demonstrated some activity in ET but is limited by its hematologic toxicity, including high rates of transformation into myelodysplastic syndromes and acute leukemia. Histone deacetylase inhibitors (eg, vorinostat, givinostat) have modest efficacy, while telomerase inhibitors like imetelstat carry significant toxicities, including neutropenia and liver abnormalities.

Ruxolitinib, a JAK1/2 inhibitor, has limited benefit in ET and is generally reserved for patients intolerant or refractory to standard therapies. Erythromelalgia, characterized by painful burning and erythema of the extremities due to abnormal interactions between small vessels and platelets, is effectively treated with aspirin.[6] However, aspirin use in pediatric ET requires caution due to the risk of Reye syndrome, a rare but potentially fatal condition involving cerebral edema and hepatic injury, with an average mortality rate of approximately 21%.[24](B3)

Differential Diagnosis

The differential diagnosis of ET is broad and includes other causes of clonal neoplasms and 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 overlaps considerably, and the only way to confirm the diagnosis is to rule out other myeloproliferative disorders.[17] ET is characterized by sustained thrombocytosis with normal to mildly increased bone marrow fibrosis, in contrast to primary myelofibrosis, in which moderate to severe fibrosis is typical.

Reactive thrombocytosis may occur due to various causes, including infection, inflammation (eg, Kawasaki disease), tissue injury (surgery or trauma), hyposplenism, iron deficiency anemia, malignancy, certain medications (eg, vincristine), allergic reactions, and hemolysis. Recent studies’ results have shown that COVID-19 infection creates a hyperinflammatory and procoagulant state, which can exacerbate thrombosis risk, particularly in patients with underlying myeloproliferative neoplasms such as ET.[35][36] Reactive thrombocytosis is typically transient and lacks clonal genetic mutations or megakaryocyte atypia.

Spurious thrombocytosis results from a laboratory artifact when automated counters mistakenly classify nonplatelet structures—such as cryoglobulin crystals, cytoplasmic fragments from leukemic cells, or bacteria—as platelets, leading to falsely elevated platelet counts.[22] Hereditary or familial thrombocytosis is a rare, autosomal dominant disease with variable penetrance, caused by germline mutations that affect thrombopoietin or its receptor, MPL.[7][24][37] Unlike ET, hereditary thrombocytosis is generally nonclonal (polyclonal) and associated with mild thrombocytosis, sometimes hepatosplenomegaly. Bone marrow findings include megakaryocytosis without the marked atypia typically seen in ET. Platelet activation may be increased, but thrombosis risk is usually lower than in clonal myeloproliferative neoplasms.

Prognosis

ET is an indolent disease, with a median survival of 18 to 20 years.[6] The reported life expectancy of patients with essential thrombocytosis was as high as 33 years in patients younger than 60.[38] Compared to patients with polycythemia vera, those with essential thrombocytosis have a superior life expectancy.[38] Despite its relatively indolent course, ET is associated with a reduced life expectancy compared to the general population, largely attributable to complications from thrombotic events such as arterial and venous thromboses.[20] These vascular complications remain the leading cause of morbidity and mortality in patients with ET, underscoring the importance of appropriate risk stratification and treatment.

Complications

The most common causes of morbidity and mortality in patients with ET are thrombotic events. Thrombosis occurs in approximately 20% of patients, followed by hemorrhagic complications occurring in about 10% of patients; the risk of leukemic transformation is estimated at less than 1% annually, cumulatively reaching around 2% to 3% at 10 years and 5% at 15 years.[17][39] Thrombosis may affect various vascular territories, including cerebral vessels, causing transient ischemic attacks or strokes; coronary arteries, leading to acute coronary syndromes; and hepatic veins, resulting in Budd-Chiari syndrome.

Other common sites include deep veins of the legs and pulmonary arteries. Older patients (eg, those 60 and older) and those with a history of thrombosis have the highest risk of recurrent thrombotic events.[20] In pediatric ET, thrombotic and hemorrhagic complications are rare.[7] Essential thrombocytosis is also associated with pregnancy complications, including eclampsia, placental abruption, intrauterine growth retardation, and stillbirth.[1]