TPO agonists are medications that address low platelet counts by mimicking the body’s natural platelet-producing hormone, thrombopoietin (TPO). Produced mainly in the liver, TPO regulates platelet generation. These drugs act as agonists by stimulating the bone marrow to create more platelets, just like the natural hormone.
Platelets are small cell fragments in our blood that form clots to stop or prevent bleeding. When platelet levels are insufficient, a condition known as thrombocytopenia, the risk of significant bleeding increases. TPO agonists were developed to provide a targeted way to boost platelet numbers, thereby reducing bleeding risks associated with certain medical conditions.
The Biological Mechanism of TPO Agonists
TPO agonists function by binding to and activating the thrombopoietin receptor (c-Mpl) on the surface of bone marrow cells. These receptors are found on megakaryocytes—the large precursor cells that produce platelets—and the stem cells that develop into them. This binding initiates a cascade of signals inside the cell.
When the c-Mpl receptor is activated, it triggers internal pathways that instruct megakaryocyte progenitor cells to multiply and mature. As these large cells develop, they break apart into thousands of smaller fragments. These fragments are then released into the bloodstream as new, functional platelets.
Different TPO agonists interact with the c-Mpl receptor in slightly different ways. Some bind to the same external part of the receptor as natural TPO, while others bind to the portion of the receptor within the cell membrane. Despite these differences in attachment points, all agonists successfully activate the receptor to increase platelet production.
Medical Uses for TPO Agonists
The most common use for TPO agonists is managing chronic Immune Thrombocytopenia (ITP), an autoimmune disorder. In ITP, the immune system mistakenly creates antibodies that attack and destroy platelets. TPO agonists help by stimulating the bone marrow to produce platelets at a faster rate, which offsets their rapid destruction.
TPO agonists are also used for patients with chronic liver disease (CLD) who need a medical or surgical procedure. Advanced liver disease often causes thrombocytopenia due to decreased TPO production. Administering a TPO agonist before a procedure can temporarily raise the platelet count to a safer level, reducing bleeding risks.
These drugs are also approved for severe aplastic anemia, a condition where the bone marrow fails to produce enough new blood cells. For patients who have not responded to other treatments, TPO agonists can stimulate the bone marrow to increase production of platelets and sometimes other blood cells. This treatment aims to improve overall blood counts and reduce the need for transfusions.
Common TPO Agonist Medications
Several TPO agonist medications are available in both injectable and oral forms. Romiplostim (Nplate) is a peptide-based agonist administered as a weekly subcutaneous injection. As a protein-based drug, it cannot be taken orally because it would be broken down by the digestive system.
Eltrombopag (Promacta, Revolade) is a small-molecule agonist available as a daily oral tablet. It activates the TPO receptor by binding to its transmembrane domain. Eltrombopag has specific dietary restrictions and must be taken on an empty stomach, separate from calcium-rich foods or supplements that can interfere with its absorption.
Newer oral TPO agonists include avatrombopag (Doptelet) and lusutrombopag (Mulpleta). These small-molecule drugs are primarily approved for patients with chronic liver disease before a procedure. A major advantage of these agents, especially avatrombopag, is that they can be taken with food and lack the strict dietary restrictions of eltrombopag.
Potential Side Effects and Risks
TPO agonists are associated with side effects that require medical monitoring. Common side effects include headaches, muscle aches, nausea, and fatigue. Eltrombopag specifically carries a risk of liver toxicity, requiring regular liver function tests during treatment.
A more serious risk is the development of blood clots (thrombosis). Because these medications increase platelet counts, excessively high levels can lead to unwanted clots in veins or arteries. This risk is particularly noted in patients with chronic liver disease, who may develop portal vein thrombosis.
Long-term use carries a risk of bone marrow changes, specifically an increase in reticulin fibers that can lead to fibrosis. Although this is monitored, severe fibrosis is uncommon and the changes are often reversible if the drug is stopped. Abruptly discontinuing a TPO agonist can also cause rebound thrombocytopenia, where platelet counts drop sharply, sometimes to levels lower than before treatment.