Overview

Essential Thrombocythemia (ET) is a genetic disorder that causes the bone marrow to produce too many platelets, blood cells involved in blood clotting. ET is a myeloproliferative neoplasm (MPN) that develops through the process of clonal expansion (production of clones of a single cell) of defective blood stem cells. An abnormal amount of platelets can disturb the physiological processes of thrombosis, leading to various blood-related complications. 

Generally, ET patients exhibit a near-normal life expectancy. However, individuals categorised as high risk are exposed to many transient and uninvited vascular events, ranging from stroke and myocardial infarction (heart attack) to acute myeloid leukaemia and gradual progression to myelofibrosis (MF).^1,2

Thus, individuals categorised as high risk need prompt therapeutic decisions and implementation to immediately reduce platelet count and prevent any risk of thrombosis and bleeding. The strategies involve the formation of curated approaches that involve careful risk factor stratifications based on age, history of thrombosis, platelet counts, and mutation status to create targeted therapies.^2,3,4

This article highlights the two major cytoreductive treatment plans curated for high-risk ET patients: hydroxyurea and anagrelide.

Understanding high-risk essential thrombocythemia

What is the criterion for high-risk in ET? 

The following are the benchmark features to characterise a patient in a high-risk category:⁵

1. Patient is aged 60 years or above
2. Any history of thrombotic episodes (blood clotting) in venous or arterial circulation
3. Extremely high levels of platelets^6,7
4. Presence of any other comorbid cardiovascular disorder, such as diabetes or hypertension
5. Somatic mutations, especially JAK2 V617F and MPL genes, are associated with several myeloproliferative neoplasms (MPNs)^8,9

Why high-risk ET needs treatment 

If left untreated, high-risk ET can impose serious consequences, such as:

• A high percentage of platelets in the circulating blood can cause sudden medical emergencies, such as stroke, heart attack, and deep vein thrombosis (DVT)^10,11
• Greater chances of developing bleeding complications due to dysfunctional platelets or neoplasm-related acquired Von Willebrand disease¹²
• Risk of developing MF (bone marrow fibrosis), the replacement of healthy cell-producing cells of bone marrow with dead scar-like tissue and disease advancement to acute myeloid leukaemia^13,14
• Increased morbidity and mortality, mostly due to vascular complications
• Severe acute complications like cardiogenic shock, if high-risk ET is left untreated¹⁵
• Morbidity driven by thrombotic events highlights the urgent need for early treatment and risk reduction¹⁶

The role of cytoreductive therapy in managing essential thrombocythemia

Cytoreductive therapy involves direct targeting of abnormal or cancerous cells to inhibit their growth. This is the first line of treatment for managing high-risk essential thrombocythemia.^17,18,19

Hydroxyurea: the first-line treatment for high-risk ET individuals

Hydroxyurea is an oral chemotherapy drug commonly prescribed to minimise the elevated platelet count and increased red blood cells in myeloproliferative neoplasms such as ET, polycythemia (PV), and sickle cell disease.²⁰ 

Hydroxyurea can selectively inhibit the activity of the ribonucleotide reductase (RNR) enzyme and prevent DNA replication in abnormal or cancerous cells. This mechanism slows down the overproduction of blood cells, specifically platelets, in ET.¹⁷

How does hydroxyurea work?

Inhibition of ribonucleotide reductase (RNR)

Hydroxyurea blocks RNR, the enzyme necessary for the conversion of ribonucleotides to DNA. 

Cell cycle arrest

By obstructing DNA production, hydroxyurea creates S-phase cell cycle arrest in rapidly dividing haematopoietic progenitor cells in the bone marrow.

Inhibiting the production of platelets

This mechanism reduces the growth of megakaryocyte precursor cells that produce platelets. This leads to lower platelet counts in the blood.

Lower risk of thrombosis

By actively controlling platelet counts, hydroxyurea can prevent hypercoagulability (excess blood clotting) and the risk of acute thrombotic events (like intracranial haemorrhage and myocardial infarction) in ET patients.

Additional effects

An additional feature of hydroxyurea is its potential to lower leukocyte levels and its anti-inflammatory effects that enhance its overall ability to reduce vascular risk.²¹

Anagrelide as a targeted approach for ET 

Anagrelide is an ingestible drug that helps in lowering platelet count. It works by targeting the bone marrow cells responsible for platelet production, the megakaryocytes. It inhibits the maturation (growth) and differentiation (specialised cell formation) of megakaryocytes into platelets without putting a major impact on white and red blood cells. Anagrelide also inhibits phosphodiesterase III (PDE3), thus decreasing platelet aggregation. 

This selective targeting and mode of action set anagrelide apart from hydroxyurea and other cytoreductive drugs that influence the growth of various blood cell types. Direct regulation of megakaryocytes can restrict platelet excess in ET and lower thrombotic risk while minimally affecting other cell types.²²

How anagrelide works

Terminating the development of megakaryocytes

Anagrelide selectively targets megakaryocyte progenitor cells, a specialised stem cells that develop into megakaryocytes in the bone marrow. Thus, block maturation and prevent them from developing into platelet-producing cells.

Suppression of proplatelet formation

It disrupts the development and progression of proplatelets, the cellular extensions that facilitate the release of platelets into the bloodstream.

Phosphodiesterase III inhibition

Anagrelide inhibits phosphodiesterase III (PDE3), an enzyme responsible for degrading cyclic AMP (cAMP) levels needed to activate platelets. When cAMP remains intact, platelets are unable to alter their shape and clump together. Thus, it reduces platelet clumping and maintains blood vessel function.

Selective platelet reduction

Anagrelide reduces platelet counts without harming other blood cells. It focuses on inhibiting megakaryocyte differentiation without causing suppression of red and white blood cell production. 

Reduction of thrombotic risk

A generalised decrease in the number of circulating platelets can lower the risk of abnormal clot formation (thrombosis) in ET.

However, regular platelet count and clinical assessments are recommended to avoid cytopenia or side effects such as headache, palpitations, or gastrointestinal symptoms.^22,23,24,25

Key benefits and side effects of hydroxyurea vs. anagrelide

Summary

Essential Thrombocytopenia is a myeloproliferative neoplasm (cancer), characterised by higher concentrations of platelets in systemic blood flow that can cause serious thrombotic accidents. Patients who fall under the category of high-risk ET are usually more complex and hard to manage due to accompanying underlying health conditions. Hydroxyurea and anagrelide are most commonly used cytoreductive drugs. Hydroxyurea is a chemotherapeutic drug that lowers the number of cells in the blood by directly impacting the haemopoietic stem cells (Stem cells that produce all types of blood cells) in bone marrow. Anagleride is not a chemotherapeutic drug as it selectively inhibits the production of platelet-forming cells (megakaryocytes) in bone marrow without lowering other cell types. Both of these drugs have proven evidence for reducing the platelet concentration in the blood. However, anagrelide is a better and more selective drug for treating essential thrombocytopenia, but due to its cardiovascular side effects, close monitoring is required when treating high-risk ET patients.