Essential Thrombocythemia

At a Glance

Essential thrombocythemia (ET) is a chronic myeloproliferative neoplasm (CMPN) characterized by a clonal proliferation of megakaryocytes that typically leads to a marked thrombocytosis. Approximately one-half of patients are asymptomatic at diagnosis, whereas the other half presents with thrombosis or bleeding. Of note, many chronic myeloproliferative neoplasia (CMPN) may present with thrombocytosis, and primary myelofibrosis (PMF) in particular may present with similar peripheral blood findings. Over time, any chronic myeloproliferative neoplasm may present with symptoms and signs of bone marrow failure.

World Health Organization (WHO) 2008 Criteria for ET (all four must be met)

sustained platelet count of at least 450,000 per microliter

increased numbers of large megakaryocytes in the bone marrow without an associated left-shift in myelopoiesis or myeloid hyperplasia or erythroid hyperplasia

no evidence that the thrombosis is reactive (e.g., not in response to tumor, autoimmune disease, infection/inflammation, splenomegaly, iron deficiency) OR evidence of a clonal disorder by cytogenetics, OR demonstration of JAK2 V617F mutation

does not meet criteria for any other chronic myeloproliferative disorder or myelodysplastic disorder

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Karyotype is required to rule out other myeloproliferative diseases with thrombocytosis.

Bone marrow biopsy is required to confirm that the proliferation is limited to the megakaryocytic lineage and the megakaryocytes show the appropriate morphology (i.e., large size, abundant cytoplasm, hyperlobated nuclei, low nuclear, cytoplasmic ratio, and minimal atypia).

Although the megakaryocyte morphology of chronic myeloid leukemia (CML) (dwarf megakaryocytes) and of ET (giant megakaryocytes) should be straightforward to distinguish, fluorescent in situ hybridization (FISH) for cryptic BCRABL rearrangements can be useful for the definitive exclusion of CML if there is any clinical concern.

JAK2V617F mutation analysis is not specific for ET but is seen in 40-50% of cases.

What other diseases should be considered in the differential? How do I distinguish between them?

There can be significant overlap between ET and any of the other chronic myeloproliferative neoplasia (CMPN). Key in the distinction is the lack of BCRABL rearrangement as detected by FISH and no increase in red cell mass with marked thrombocytosis and normal or near normal leukocyte numbers. The presence of JAK2V617F is not specific for ET but does help classify the disease as a CMPN.

ET and prefibrotic PMF can both present with markedly increased platelets, mild anemia, and mild leukocytosis, although PMF is more likely to present with a leukocytosis. ET can be distinguished from PMF in the bone marrow biopsy. PMF bone marrow, typically, shows hypercellularity that is rare in ET bone marrows. PMF also shows myeloid hyperplasia and left-shifting, clustered megakaryocytes with atypical morphology and, even in early stage, is more likely to show WHO grade 1 of 3 fibrosis. ET bone marrows, typically, show normocellularity or only mild hypercellularity with an intact myeloid to erythroid ratio and a marked increase in megakaryocytes, particularly large megakaryocytes with hyperlobation.

Notwithstanding these differences, the pathologic distinction between early prefibrotic PMF and ET and early polycythemia vera (PV) can be very challenging with intraobserver concordance between experts of 80-90% in some series.

PV, typically, presents with an increased hematocrit and hemoglobin. There is, typically, a panmyelosis in the bone marrow biopsy, as opposed to solely a megakaryocytic hyperplasia, as is seen in ET.

CML must be excluded before a diagnosis of ET is made. FISH for BCRABL is typically sufficient to diagnose CML. Of course, the small megakaryocytes with monolobated nuclei in CML are quite distinct from the large, hyperlobated megakaryocytes seen in ET. Also, CML, typically, presents with a leukocytosis with left-shifted granulocytosis.

What Lab Results Are Absolutely Confirmatory?

No laboratory test is absolutely confirmatory. Patients require complete blood count (CBC), bone marrow biopsy, cytogenetics, and JAK2 mutation studies.

Patients must display a sustained thrombocytosis with characteristic bone marrow histomorphology. If a Jak2 mutation or a cytogenetic abnormality is not found, a thorough work-up for reactive causes of thrombocytosis must be performed. Once that is complete, if the bone marrow shows no other features of other CMPNs, the patient may be diagnosed with ET.

What are the long-term sequelae in patients?

The prognosis in ET patients is good if thrombosis and hemorrhage can be controlled. In several studies, the risk of thrombosis or bleeding is approximately 2% per patient-year. High risk factors include male sex, presence of a JAK2 mutation, history of thrombosis, age greater than 60 years, and presence of cardiovascular risk factors (i.e., hypertension, smoking history, diabetes mellitus). Even in high-risk patients, extreme thrombocytosis (Plt >1,000/microliter) is not associated with thrombocytosis. Low-risk patients can be followed or placed on low-doses of aspirin. High-risk patients may need more aggressive therapy, such as aspirin, anagrelide, or hydroxyure,a or more rarely interferon and/or busulfan.

The risk of leukemic transformation in ET is very low (<1%), as is the risk of progressive marrow fibrosis (1%) if a strict WHO definition is used to separate prefibrotic PMF from ET.

Mean overall survival in ET patients is estimated at least 20 years.

What other reactive causes should I rule out?

Thrombocytosis is a common reactive response. In the physiologic state, the liver produces thrombopoietin, 1 of the main megakaryocytic growth factors, at a constant rate. Platelets and megakaryocytes consume thrombopoietin (TPO) at a constant rate, maintaining a steady-state, constant TPO level in the blood. Increased TPO production occurs in the liver as an acute phase reactant leading to an increase in platelet production and megakaryocytic proliferative drive.

Infection/inflammation leads to thrombocytosis, as it triggers the acute phase reactant condition in the liver. Connective tissue diseases can similarly lead to thrombocytosis. Metastatic cancer and lymphoproliferative disorders are also associated with reactive thrombocyosis. Iron deficiency anemia leads to increased erythropoietin production, which has some crosstalk on the TPO receptor, leading, therefore, also to a thrombocytosis. Splenectomy leads to an increase in circulating platelets, since a large proportion of the body’s platelets are sequestered in the spleen.