Essential Thrombocytosis (Thrombocythemia)


ET defined as a platelet count of more than 450,000 mm³ is frequently encountered in clinical practice.

Most patients have a normal life expectancy while 5% to 10% may experience transformation into post-thrombocythemic myeloid metaplasia or acute leukemia.

6-7000 new cases diagnosed annually in the United States.

Incidence 1.2 to 3.0 per hundred thousand population.

Median age at diagnosis 58 years.

It also develops in adults younger than 40 years in 20% of cases.

Women are more often affected than men.

Median survival 19.8 years.

The most important determinant of survival among patients with essential thrombocythemia is age, with a median survival ranging from 8.1 years among patients older than 70 years of age, to 34.7 years among patients younger than 40 years of age.

Leukocytosis and history of thrombosis are key factors for survival.

Prevalence of essential thrombocytosis is 38-57 per 100,000.

Incidence estimated to be 1.2-3.0 per 100,000 population per year.

Predilection for females-up to 67%.

Fewer than 25% of patients have nonrandom chromosome abnormalities.

Medium platelet count at diagnosis 876,000/ cubicmm³.

The hallmark of ET is an elevated thrombocyte count in the peripheral blood, accompanied by excessive megakaryopoiesis in the bone marrow.

Splenomegaly, that is palpable, present in about 17% of patients at onset.

Leukocytosis is documented in about 26% of patients and diagnosis of an abnormal karyotype is detected in 9%.

A history of thrombosis at or before diagnosis is present in about 21% of cases.

Clinical features include headache, visual disturbances, lightheadedness, dysesthesia, and less frequently erythromelalgia.

In a Mayo clinic study Of 1076 patients median follow about 10 years was associated with a 43% death rate, leukemic transformation of 4%, myelofibrosis In 13%, new thrombosis in 21%, median survival rate of 18 years (Tefferi A).

In the above study the median survival was 26.7 years among patients with a low risk of thrombosis, a significantly shorter survival rate than that of age and sex match controls for the general population.

Thrombocytosis in ET maybe arterial or venous.
Arterial thrombosis is present before diagnosis in 14% of patients and venous  thrombosis was present and 8%.
And follow up of a median of 10 years about 15% of patients have arterial thrombosis and the nerve 8% and venous thrombosis.
The presence of JAK2 is associated with a significantly increased risk of thrombosis.

The diagnosis is established after four major criteria, were the first three major criteria and one minor criteria, have been met.

Major criteria- 1-platelet count greater than 450000, 2 – bone marrow biopsy showing proliferation mainly of megakaryocytes line with increased numbers of enlarged, mature megakaryocytes that have hyper lobulated nuclei, no significant increase or left shift in neutrophil granulopoiesis or erythropoiesis and very rarely minor increase in reticular fibers, 3 -not meeting the criteria for bcr-abl positive CML, PV, pmf, myelodysplastic syndromes or other myeloid neoplasms, and 4-presence of JAK2, CALR, or MPL mutation.

MPL myeloproliferative virus oncogene

Minor criteria-presence of a clonal marker or absence of evidence of reactive thrombocytosis.

Has no distinguishing clinical features from other myeloproliferative diseases and is a diagnosis of exclusion.

Patients have greater than 20% risk for thrombotic complications.

Polycythemia rubra vera and myelofibrosis can present as isolated thrombocytosis in a significant percentage of patients.

Bone marrow examination is necessary for proper diagnosis.

Characterized by abnormal megakaryocytic morphology.

Characterized by a persistent nonreactive thrombocytosis and increased risk of arterial and venous vascular events.

Higher platelet counts did not correlate well with thrombotic risk, but the association between thrombocytosis and bleeding is more clearly supported.

Bone marrow shows megakaryocytic proliferation and varying degrees of reticulin fibrosis.

Acquired von Willebrand disease is common among patients with essential thrombocytosis (11 to 17%).

Often has an indolent course.

50-60% of patients carry the JAK2 V617 F mutation.

5% carry mutated thrombopoietin receptor MPL.

Patients commonly have mutations in the calreticulum (CALR) gene-20%.

CALR mutations occur almost exclusively in patients  with thrombocytosis.

90% of patients with ET will have one of these three mutations and no mutations or detected in 10% of patients.

The calreticulin gene encodes for a chaperone protein that plays arole in cellular proliferation, differentiation, and a apoptosis.

10-20% of patients have none of the three driver mutations and are triple negative.

The incidence of thrombosis in ET is about 6.6% per year.

Leukocytes contribute to platelet activation in ET and are a stronger predictor of thrombosis than the platelet count: the risk of thrombosis is not correlated with the platelet count, per se.

Patients with JAK2 mutated ET tend to be older, have higher white blood cell counts and hemoglobin levels and have lower platelet counts, but are more likely to develop thrombosis.

Men are commonly affected by mutations, and the risk of thrombosis is lower in this sub group.

While a bone marrow examination is required for conclusive diagnosis, the presence of a drive a mutation, combined with appropriate clinical features strongly suggested diagnosis of essential thrombocythemia.

Up to 76% of patients experience arterial thrombosis, about 15% have venous thrombosis, about 63% experience hemorrhage, and about 69% encounter functional symptoms.

Next generation sequencing demonstrated 15% of patients harbor one or more non-driver mutations in SRSF2, U2AF1, SF3B1, or TP 53: these patients have lower rates of  myelofibrosis free and leukemia free survival.

Platelet thromboxane production is increased in these patients, as noted by increased excretion of a urinary metabolite Thromboxane A2.

A major goal of treatment is thrombosis prevention.

The main COX-1 mediated product of platelets which causes platelet aggregation, vascular proliferation and vasoconstriction.

Cyclooxygenase-one and cyclooxygenase-2 are isoenzymes that catalyze the conversion arachidonic acid to prostaglandin H2, the initial step in prostanoid synthesis that leads to the formation of thromboxane A2, PGI2, anf PGE2.

Under physiological conditions platelet thromboxane production is driven primarily by Cox-1, and fewer than 10% of normal platelets have Cox-2.

Cyclooxygenase-2 is expressed in young platelets and the megakaryocytes.

Estimated risk for thrombotic episodes is 6.6% per patient year and the risk increases to 15% per year for patients older than 60 years.

The presence of leukocytosis is significantly associated with an increased risk of arterial thrombosis.

Goals of treatment is to keep the platelet count less than 600,000, although the target platelet count for patients with high risk disease is less than 400,000 per cubic millimeter.

Much more common in women.

The International Prognostic Scoring System for essential thrombocytosis helps predict survival.

In the above system patients receive points for the following 1 -leukocyte count equal to or greater than 11 times 10 to the 9th/L, 2-age of 60 years or older, and 3 – history of thrombosis.

The above model is not used to estimate survival for low-risk patients.

Intermediate risk is associated with the median survival of approximately 25 years whereas high-risk carries a median overall survival of 15 years.

High-risk patients involve those over the age of 60 years, or have a history of thrombosis should be treated with hydroxyurea.

Hydroxyurea is associated with reduced incidence of thrombotic events and improved overall survival in older patients with ET.

Hydroxy urea is the most frequently prescribed first line drug for patients with essential thrombocytosis giving its ease of administration, good efficacy, modest side effects, and a low incidence of treatment resistance.
Hydroxyurea use in essential thrombocytosis is not associated with an increased risk of leukemia transformation unlike radioactive phosphorus, alkylating agents, particularly those receiving sequential therapy. Median age at diagnosis is 60 years.Process can occur at any age, including a rare childhood occurrence.For patients with low risk under the age of 60 years and have no history of thrombosis and a platelet count less than 1.5 million , and an absence of cardiovascular risk factors controlled studies have not shown a benefit to drug therapy.A large study revealed at 15 years that the cumulative risk of thrombosis, change into acute myelogenous leukemia or myelofibrosis with myeloid metaplasia was 17%, 2% and 4%, respectively.Incidence of acute leukemia is 1.2 x 1000 person years.10 year survival rates are approximately 89% and 15 year survival rates approximately 80% with leukemic transformation rates at 10 years 0.7% and 2.1% at 15 years, progression to overt myelofibrosis 0.8% at 10 years and 9.3% at 15 years (Barbui T et al).The risk of thrombosis and bleeding in patients with low-risk disease who do not receive cytoreductive therapy may not be different than age and sex matched control patients.

In a retrospective study of 891 patients with a median follow up time from diagnosis of 6.2 years, major bleeding at or before diagnosis was observed in 4%, and 6% at follow up.

In intermediate and high-risk patients cytoreductive therapy with hydroxyurea reveals superior antithrombotic effect compared the observation alone or anagrelide therapy.

Anagrelide reduces the platelet count and is approved for essential thrombocytosis but is in frequently use because of conflicting results from control trials.

And negative light is non-inferior to hydroxyurea in preventing vascular events.

In a large retrospective study the risk of developing AML and myelofibrosis with myeloid metaplasia, which were 2% and 4%, respectively, was not significantly influenced by single agent chemotherapy, including hydroxyurea.

Incidence of acute myocardial infarction in such patients is 9.4% (Rossi).

In the absence of cardiovascular risk factors very low risk disease may be managed with observation alone.
For patients with higher levels of risk, low-dose aspirin is the cornerstone of anti-thrombotic therapy especially in patients with JAK2 mutations.
However, once daily low-dose aspirin appears to be insufficient to produce 24 hours suppression of platelet thromboxane A2 synthesis owing to accelerated platelet turnover in essential thrombocytosis, but a twice daily aspirin does result in effective suppression.
For patients older than 60 years and not carriers of JAK2, or have no history of thrombosis, once-daily aspirin therapy is advised.
In patients with high-risk disease the combination of hydroxyurea therapy and once daily aspirin therapy is the standard of care.
Pegylated interferon does  not have genotoxic or leukemogeniv. effects, has high rates of complete hematologic responses and anti-clonal activity, with a minority of patients having a complete molecular response: follow up has shown a yearly discontinuation rate for 5-16% due to drug related toxicity, leukemic or fibrotic transformation, or loss of response.
Ruxolitinib compared with best available treatment with high risk essential thrombocytosis who did not have a response to hydtoxyurea or who has intolerable side effects: the complete response rate was similar in both groups.

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