Essential Thrombocythemia
Essential Thrombocythemia-BM
Essential thrombocythemia (ET) is a myeloproliferative neoplasm (MPN) characterized by megakaryocyte hyperplasia and thrombocytosis due to a multipotent hematopoietic stem cell clonal abnormality.
From the genetic perspective, ET patients harbour mutations in JAK2 (50–60%), CALR (15–30%) and MPL (1–5%) genes.
Platelet survival is normal in ET.
Approximately one-third of patients with ET are asymptomatic at diagnosis.
ET usually occurs with bimodal peaks between ages 50 and 70 years and a separate peak among young females.
Patients particularly suffer from combined bleeding and clotting tendency, as well as the general features of myeloproliferative disorders such as anemia, headaches, and malaise.
Bleeding is usually mild and manifests as epistaxis, easy bruising, or GI bleeding. However, thrombosis is a major cause of morbidity and mortality in ET.
Recent studies indicate an elevated leukocyte count is a major independent risk factor for thromboses.
Erythromelalgia (burning pain in hands and feet, with warmth, erythema, and sometimes digital ischemia) may occur. 
Mild splenomegaly occurs in < 50% of patients. Hepatomegaly may rarely occur.
Myelofibrosis is common.
Transformation to Acute Myeloid Leukemia (AML) occurs in 0.6-5% of patients with ET; the risk may be comparable to that of the healthy population.
Diagnosis:
The diagnosis can be difficult to differentiate from secondary (reactive) thrombocytosis and is partly a diagnosis of exclusion*.
Platelets are acute-phase reactants; therefore, they increase in response to various stimuli, including systemic infections, inflammatory conditions, bleeding, and tumors.
There is current diagnostic controversy, including heterogeneity within ET and the phenotypic overlap between ET, polycythemia rubra vera, and primary myelofibrosis.
*FBC and peripheral blood smear. The platelet count can be >1,000,000/μL but may be as low as 450,000/μL. The peripheral smear may show platelet aggregates, giant platelets, and megakaryocyte fragments.
Essential Thrombocythemia-Blood Film
*Exclusion of causes of secondary thrombocytosis, e.g. Chronic inflammatory disorders, hemorrhage, acute infection, iron deficiency, splenectomy, and cancer.
*Cytogenetic studies, including Philadelphia chromosome or BCR-ABL assay, should be done.
*JAK2 mutation by PCR. The JAK2 V617F mutation occurs in about 50-60% of patients and, if present, helps distinguish ET from other causes of thrombocytosis.
Polycythemia vera is mainly related to JAK2 mutations, whereas a wider mutational spectrum is detected in ET with mutations in JAK2, the thrombopoietin (TPO) receptor (MPL), and the calreticulin (CALR) genes.
Overall, there is general agreement that 10–30% of all ET patients are wild-type for JAK2, CALR, and MPL mutations when the molecular analyses are performed with DNA from isolated granulocytes or peripheral blood. This subgroup of patients, called ‘triple-negative‘ (TN), has not been extensively studied regarding the presence of JAK2, CALR, and MPL mutations in platelets and RNA from granulocytes.
*Possibly bone marrow aspirate and trephine biopsy. The bone marrow shows increased megakaryocyte numbers and drifts of platelets. Megakaryocytes display a spectrum of morphology with predominant large megakaryocytes with hyperlobated nuclei and abundant cytoplasm. The bone marrow iron is present and reticulin is generally not increased.
Atypical megakaryocytes are evident on the bone marrow aspirate smear, including quite large forms with abundant cytoplasm, and deeply lobulated nuclei.
To distinguish ET from other myeloproliferative disorders that cause thrombocytosis, the diagnosis of ET requires a normal Hct, MCV, and iron studies to outrule PRV; the absence of the Philadelphia chromosome and BCR-ABL translocation to outrule CML; and absence of teardrop-shaped RBCs to out rule idiopathic myelofibrosis, although there may be significant increase in bone marrow fibrosis.
Treatment:
Treatment in patients with ET should be individualized based on risk factors for thrombo-hemorrhagic complications. Risk factors include the following:
- Age 60 years or older.
- History of thrombosis or transient ischemic attack.
- Platelet count >1.5 million/µL.
- Obesity.
- Cardiovascular risk factors such as smoking, hypertension, and hypercholesterolemia.
- Markers of hypercoagulability such as factor V Leiden and antiphospholipid antibodies.
Treatment includes the following:
- Observation may be appropriate for low-risk patients (ie, those lacking any of the above risk factors).
- Low-dose Aspirin.
- Platelet-lowering drugs i.e. cytoreductive agents (eg, hydroxyurea, anagrelide).
- Plateletpheresis is rarely used in emergencies to achieve a rapid decrease in platelet counts in the setting of acute thrombosis and/or marked thrombocytosis.
- Rarely cytotoxic agents.
- Rarely interferon.
- Rarely stem cell transplantation.
Conclusion:
Essential thrombocythemia (ET) is a myeloproliferative neoplasm characterized by the overproduction of platelets in the bone marrow. It can lead to an increased risk of blood clotting and other complications.
JAK2, CALR, and MPL are genes that play a role in regulating blood cell production. Mutations in these genes are known to contribute to the development of essential thrombocythemia. The JAK2 mutation is the most common, occurring in around 50-60% of ET cases. CALR mutations are found in 15-30% of cases, and MPL mutations are rare, occurring in around 1-5% of cases.
When a patient with essential thrombocythemia does not have any of these three mutations, it is classified as triple negative ET. This subtype of ET is less common and may have distinct clinical characteristics compared to patients with JAK2, CALR, or MPL mutations.
Diagnosing triple negative ET requires excluding the presence of these common mutations through genetic testing. Other tests and criteria for diagnosing essential thrombocythemia, such as elevated platelet count and bone marrow examination, may still be applicable.
References:
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Elizabeth L. Courville. Essential Thrombocythemia. https://imagebank.hematology.org/reference-case/16/essential-thrombocythemia
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Rumi E, Pietra D, Ferretti V, Casetti I, Bellini M, Milanesi C, Severgnini M, Astori C, Roncoroni E, Cazzola M, Vannucchi AM. JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes. Blood. 2014 Mar 20;123(12):1544-51. doi: 10.1182/blood-2013-11-539098.
well organized topic.