Essential thrombocythemia (ET) is a rare blood condition involving the overproduction of platelets. As a myeloproliferative neoplasm (MPN), the bone marrow produces too many of one or more types of blood cells. The clinical course of ET is often slow but can be marked by complications from blood clotting or bleeding. Specific genetic mutations are central to understanding the disease, and mutations in the calreticulin (CALR) gene define a subtype with a distinct prognosis and management plan.
The Role of the CALR Gene Mutation
The calreticulin (CALR) gene provides instructions for making a protein with multiple functions. Its primary jobs are to ensure other proteins are folded correctly, a process known as protein chaperoning, and to help control calcium levels inside the cell.
In ET, CALR mutations are “driver” mutations that directly cause the uncontrolled production of platelets. These mutations are typically insertions or deletions of a small amount of DNA, which alters the final protein. This altered protein is believed to activate signaling pathways in hematopoietic stem cells, instructing them to produce an excess of megakaryocytes, the cells that make platelets.
The most common CALR mutations are Type 1 (a 52-base pair deletion) and Type 2 (a 5-base pair insertion). These mutations are almost always mutually exclusive with the other primary driver mutations in ET: JAK2 and MPL. A patient will have a mutation in only one of these three genes, and the specific one present helps define the disease’s characteristics.
Diagnosis and Clinical Features
Diagnosis of essential thrombocythemia often begins with a routine blood test that reveals a persistently high platelet count of 450 × 10^9/L or higher. Genetic testing is then performed on the blood to look for the main driver mutations associated with MPNs. This testing identifies the presence of a CALR, JAK2, or MPL mutation.
To confirm the diagnosis and rule out other blood disorders, a bone marrow biopsy is usually performed. This procedure involves taking a small sample of bone marrow for microscopic examination. In ET, the marrow shows a significant increase in large, mature megakaryocytes that may be clustered, which helps distinguish ET from conditions like prefibrotic myelofibrosis.
Patients with a CALR mutation often present with a distinct clinical profile. Compared to individuals with the more common JAK2 mutation, those with CALR-mutated ET are often younger and may have a higher platelet count at diagnosis. Conversely, their hemoglobin levels and white blood cell counts tend to be lower.
Prognosis and Risk Stratification
The specific genetic mutation an ET patient carries has a significant bearing on their long-term outlook. A CALR mutation is generally associated with a more favorable prognosis when compared to the JAK2 mutation. This difference is linked to the risk of thrombosis (blood clots), a primary complication of the disease.
The most notable prognostic advantage for patients with a CALR mutation is a significantly lower risk of thrombosis. For instance, one study estimated the 20-year thrombosis-free survival to be 100% for CALR-mutated patients, compared to 71% for those with a JAK2 mutation. The type of CALR mutation may also play a role, with some research suggesting the Type 2 mutation offers more protection against thrombosis than the Type 1 mutation.
While the clotting risk is lower, some studies suggest that patients with CALR-mutated ET may have a higher long-term risk of the disease transforming into myelofibrosis (MF), a more serious condition involving bone marrow scarring. The risk of transformation to acute myeloid leukemia (AML), a rare but serious outcome, is low for all ET patients but appears less frequent in those with CALR mutations.
Treatment and Management
The primary goal of treating essential thrombocythemia is to prevent complications from blood clots, such as heart attacks and strokes. Treatment is individualized based on a patient’s risk category, which is determined by their age, history of blood clots, and specific driver mutation (CALR, JAK2, or MPL).
For patients classified as low-risk, often younger individuals (under 60) with a CALR mutation and no prior thrombosis, management may be observation combined with daily low-dose aspirin. Aspirin helps make platelets less “sticky,” reducing their ability to form clots without lowering the overall platelet count. This approach acknowledges the lower clotting risk associated with the CALR mutation.
For patients in a high-risk category, typically defined by being over 60 or having a previous blood clot, more direct intervention is required. In these cases, cytoreductive therapies are prescribed to lower the number of platelets in the blood. Common first-line medications include hydroxyurea and pegylated interferon-alpha, with the choice depending on the patient’s age and health to minimize the risk of clotting or bleeding.