Essential thrombocytosis overview

# Overview
Essential thrombocytosis (ET) or primary thrombocytosis is a rare hematologic disorder which arises from hematopoietic stem cells that give rise to megakaryocytes which in turn produce platelets (thrombocytes), that are normally involved in blood clotting. Essential thrombocytosis is characterized by overproduction of platelets in the absence of an underlying disease. Essential thrombocytosis was first defined by Emil Epstein and Alfred Goedel, two Austrian pathologists, in the year 1934 and was initially called hemorrhagic thrombocythemia. Subsequently, essential thrombocytosis was classified as a myeloproliferative disorder along with chronic myelogenous leukemia (CML), polycythemia vera (PV), and chronic idiopathic myelofibrosis (CIMF). The incidence of essential thrombocytosis is approximately 0.6-2.5 cases per 100,000 individuals worldwide annually. The prevalence of essential thrombocytosis is about 30 for every 100,000 people worldwide. Females are more commonly affected with essential thrombocytosis than males. The female to male ratio is approximately 2 to 1. Symptoms of essential thrombocytosis include vision disturbances, transient loss of consciousness, chest pain, intense burning pain in hands or feet (erythromelalgia), numbness and tingling of hands and feet, persistent and painful erection of the penis (priapism). Bone marrow biopsy may be helpful in the diagnosis of essential thrombocytosis, in addition to ruling out other secondary causes of thrombocytosis. The majority of cases of essential thrombocytosis only require supportive care. Pharmacologic medical therapies for essential thrombocytosis include aspirin therapy for low risk patients and platelet lowering drugs such as (hydroxyurea, interferon-, and anagrelide) for high risk patients.

# Historical Perspective
Essential thrombocytosis was first defined by Emil Epstein and Alfred Goedel, two Austrian pathologists, in the year 1934 and was initially called hemorrhagic thrombocythemia.

# Classification
There is no classification system established for essential thrombocytosis. However, essential thrombocytosis may be broadly classified into sporadic and familial forms.

# Pathophysiology
Essential thrombocytosis arises from hematopoietic stem cells which give rise to megakaryocytes which give rise to platelets (thrombocytes), that are normally involved in blood clotting. Development of essential thrombocytosis is the result of a genetic mutation in the janus kinase 2 (JAK2) gene in 50% of the patients. Other genes that may be involved in the pathogenesis of essential thrombocytosis are CALR, MPL, and THPO genes. On microscopic histopathological analysis, thrombocytosis and bone marrow hyperplasia with hyperlobated megakaryotic nuclei evident of thrombopoiesis are characteristic findings of essential thrombocytosis.

# Epidemiology and Demographics
The incidence of essential thrombocytosis is approximately 0.6-2.5 cases per 100,000 individuals worldwide annually. The prevalence of essential thrombocytosis is approximately 30 per 100,000 individuals worldwide. The incidence of essential thrombocytosis increases with age; the median age at diagnosis is 65-70 years. Patients of all age groups may develop essential thrombocytosis. However, essential thrombocytosis commonly affects individuals older than 60 years of age. Females are more commonly affected with essential thrombocytosis than males. The female to male ratio is approximately 2 to 1.

# Risk Factors
Common risk factor in the development of essential thrombocytosis is female sex. Common risk factors in the development of thrombotic complications in patients with essential thrombocytosis are previous history of thrombotic events and age greater than 60 years.

# Screening
Screening for essential thrombocytosis by cell-based quantitative assays for  JAK2V617F mutation  is recommended among individuals with a positive family history for the disease (autosomal dominant inheritance) and in patients who present with thrombocytosis, erythrocytosis, and monocytosis.

# Causes
Essential thrombocytosis may be caused by a mutation in the janus kinase 2 (JAK2) gene (in 50% of the patients), CALR, MPL, or THPO genes.

# Differential Diagnosis
Essential thrombocytosis  must be differentiated from other causes of thrombocytosis, such as chronic myelogenous leukemia (CML), myelodysplastic syndrome, polycythemia vera, primary myelofibrosis, secondary thrombocytosis.

# Natural History, Complications and Prognosis
If left untreated, patients with essential thrombocytosis  may progress to develop symptoms like headache, dizziness, vision disturbances, chest pain, intense burning pain in hands and/or feet (erythromelalgia), numbness and tingling of hands and feet, priapism (persistent and painful erection of the penis) and so on depending on the vessel occluded with the thrombus. Common complications of essential thrombocytosis include thrombotic events (DVT, cerebrovascular accidents,etc), bleeding (bruises, gum bleeds, epistaxis, etc), acute leukemia and myelofibrosis. Prognosis is generally good, and the survival rate of patients is usually normal with  regular medical supervision. However, the disease may rarely undergo a leukemic conversion or develop myelofibrosis.

# Diagnosis

## Diagnostic Criteria
The diagnosis of essential thrombocytosis is made when all four of the following diagnostic criteria are met:
- Sustained elevation of platelet counts > 450,000,000  103/L, AND
- Bone marrow biopsy specimen showing proliferation, mainly of the megakaryocytic lineage with increased numbers of enlarged, mature megakaryocytes and no significant increase or left-shift of neutrophil granulopoiesis or erythropoiesis, AND
- Not meeting WHO criteria for polycythemia vera (PV), PMF, CML, MDS, or other myeloid neoplasm, AND
- Demonstration of JAK2 617VF or other clonal marker, or in the absence of a clonal marker, no evidence for reactive thrombocytosis

## History and Symptoms
People with essential thrombocytosis are usually asymptomatic. Symptoms of essential thrombocytosis include vision disturbances, transient loss of consciousness, chest pain, intense burning pain in hands or feet (erythromelalgia), numbness and tingling of hands and feet, persistent and painful erection of the penis (priapism). Neurologic symptoms like headache may occur but the pathophysiology is not completely understood. A positive family history of  may be present in those with familial essential thrombocytosis.

## Laboratory Findings
Laboratory findings consistent with the diagnosis of essential thrombocytosis include abnormal complete blood count (CBC), elevated platelet count, peripheral blood smear showing large platelets, megakaryocyte fragments and platelet aggregates, presence of JAK2 mutation and absence of BCR-ABL or Philadelphia chromosome. Leukocytosis, erythrocytosis, and mild anemia may be present. Bone marrow biopsy is an important test and needed to make a diagnosis of essential thrombocytosis as per WHO definition.

## Electrocardiogram
There are no EKG findings associated with essential thrombocytosis. However, EKG should always be ordered in essential thrombocytosis patients who present with chest pain to rule out other dangerous causes of chest pain like myocardial infarction (MI).

## Chest X Ray
A chest x-ray is not diagnostic of essential thrombocytosis. However, a chest x-ray may be a helpful test in the management of complications that develop due to essential thrombocytosis, such as pulmonary thromboembolism.

## CT Scan
CT scan is not diagnostic of essential thrombocytosis. Findings on abdominal CT suggestive of essential thrombocytosis include splenomegaly. A spiral chest CT  may be helpful in the diagnosis of complications from essential thrombocytosis like pulmonary thromboembolism in patients with suggestive symptoms.

## MRI
There are no MRI findings associated with essential thrombocytosis.

## Ultrasound
Abdominal ultrasound may be helpful in the diagnosis of Essential thrombocytosis. Findings on abdominal ultrasound suggestive of essential thrombocytosis include Splenomegaly. There are no electrocardiogram findings associated with essential thrombocytosis.

## Other Imaging Findings
There are no other imaging studies associated with essential thrombocytosis.

## Bone Marrow Biopsy Findings
Bone marrow biopsy is an important test and needed to make a diagnosis of essential thrombocytosis as per WHO definition. The bone marrow biopsy shows hypercellularity with clusters of megakaryocytes that stain positive for iron. There may be increased reticulin but no collagen fibrosis.

# Treatment

## Medical Therapy
The majority of cases of essential thrombocytosis only require supportive care. Pharmacologic medical therapies for essential thrombocytosis  include aspirin therapy for patients at low risk and platelet lowering drugs (Hydroxyurea, interferon- and anagrelide) for patients at high risk for thrombosis.

## Surgery
Surgical intervention is not recommended for the management of essential thrombocytosis.

## Primary Prevention
There is no established method for primary prevention of Essential thrombocytosis.

## Secondary Prevention
Secondary prevention strategy following essential thrombocytosis include low dose aspirin therapy.