Thrombopoietin (TPO) is a naturally occurring protein that functions like a hormone in the body. Its primary role involves regulating the production of platelets, which are tiny blood cells that play a part in stopping bleeding.
The Role of Thrombopoietin in the Body
Thrombopoietin is mainly produced in the liver and kidneys, with smaller amounts in striated muscle and bone marrow. Once produced, TPO travels through the bloodstream to the bone marrow.
In the bone marrow, TPO specifically interacts with large cells known as megakaryocytes. It binds to a receptor on their surface called c-Mpl. This binding triggers a series of internal signals within the megakaryocytes, prompting their growth and maturation.
As megakaryocytes mature, they undergo a unique process where they fragment into thousands of small, anucleated cellular pieces, which are the circulating platelets. Each megakaryocyte can produce a number of platelets. These platelets are then released into the bloodstream.
Platelets circulate for approximately 7 to 10 days. Their main job is to form a plug at the site of blood vessel damage, stopping blood loss. This process, known as hemostasis, stops blood loss.
Regulation of Thrombopoietin Levels
The body maintains a steady supply of platelets through a self-regulating feedback system involving thrombopoietin. The concentration of TPO in the blood is inversely related to the total mass of circulating platelets and megakaryocytes.
When platelet counts are high, these abundant platelets in the bloodstream bind to TPO through their c-Mpl receptors. This binding leads to the internalization and subsequent destruction of TPO. With less free TPO available, the signal to the bone marrow for new platelet production diminishes.
Conversely, if platelet counts drop due to bleeding or other factors, fewer platelets are available to bind and clear TPO. This leaves more TPO free to travel to the bone marrow. The increased availability of TPO then stimulates megakaryocytes to accelerate their maturation and platelet release, thereby restoring platelet levels.
This intricate control mechanism ensures that the body’s platelet count remains within a healthy range, typically between 150,000 and 450,000 platelets per microliter of blood. The liver’s production of TPO appears to be relatively constant, with changes in circulating TPO levels largely driven by this platelet-mediated clearance.
Clinical Significance of Abnormal Levels
Disruptions in thrombopoietin production or its regulatory pathway can lead to abnormal platelet counts. When TPO levels are too low, or its signaling is ineffective, the body produces an insufficient number of platelets, a condition called thrombocytopenia. Platelet counts below 150,000 per microliter are generally considered low.
Thrombocytopenia can result from reduced TPO production, as seen in severe liver disease, where the liver’s capacity to synthesize the hormone is impaired. Bone marrow disorders, such as aplastic anemia, leukemia, or myelodysplastic syndrome, also lead to low platelet production. Certain viral infections, like HIV or hepatitis C, and specific medications can similarly suppress platelet formation or increase their destruction.
Individuals with thrombocytopenia are at an increased risk of bleeding and bruising, even from minor injuries. Symptoms can range from easy bruising and nosebleeds to more severe internal bleeding, such as gastrointestinal or intracranial hemorrhage.
On the other hand, excessively high platelet counts, known as thrombocytosis, can also arise from TPO dysregulation. This condition is often “reactive” or “secondary,” meaning it occurs in response to an underlying medical issue. Inflammatory conditions, such as rheumatoid arthritis or inflammatory bowel disease, and acute or chronic infections can trigger increased TPO production.
Certain malignancies, including lymphomas and solid tumors, can also lead to thrombocytosis by stimulating TPO synthesis. Iron deficiency anemia and the removal of the spleen (splenectomy), which normally filters old platelets, are additional causes of elevated platelet levels. While reactive thrombocytosis is typically temporary, it can still increase the risk of dangerous blood clots forming in vessels, known as thrombosis.
Therapeutic Uses of Thrombopoietin Analogs
Given thrombopoietin’s role in platelet production, scientists have developed medications that mimic its action to treat conditions of low platelet counts. These therapeutic agents are known as thrombopoietin receptor agonists (TPO-RAs). TPO-RAs are designed to activate the c-Mpl receptor on megakaryocytes and hematopoietic stem cells, stimulating the body’s own platelet production machinery.
These drugs, which include medications like romiplostim, eltrombopag, avatrombopag, and lusutrombopag, bind to the TPO receptor, initiating the same intracellular signaling pathways that natural TPO would. This activation leads to increased proliferation, differentiation, and maturation of megakaryocytes within the bone marrow, ultimately resulting in a higher number of circulating platelets.
TPO-RAs are used to manage several medical conditions characterized by persistently low platelet counts. A primary application is in chronic immune thrombocytopenia (ITP), an autoimmune disorder where the immune system mistakenly destroys platelets. They provide a targeted approach to boost platelet levels when other treatments have not been successful.
These medications are also used in patients with severe aplastic anemia, a rare disorder where the bone marrow fails to produce enough blood cells, including platelets. Furthermore, TPO-RAs can address thrombocytopenia associated with chronic liver disease, where impaired liver function reduces natural TPO production, and in cases of chemotherapy-induced thrombocytopenia to help patients continue their cancer treatments.