Journal of Hematology & Thromboembolic Diseases
Open Access

Clinical Applications of Thrombopoietin Receptor Agonists for Immune Thrombocytopenia

Peter de Mouzon^{* *}Correspondence: Peter de Mouzon, Department of Hematopathology, Paris Descartes University, Paris, France, Email:

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Description

Immune Thrombocytopenia (ITP) is an autoimmune disorder characterized by low platelet counts due to the immune system attacking and destroying platelets. The disease can be either primary (idiopathic) or secondary to other conditions, such as Systemic Lupus Erythematosus (SLE) or Human Immunodeficiency Viruses (HIV). The sign of ITP is a platelet count below 100,000 per microliter, which can lead to bleeding complications. The management of ITP has evolved considerably over the past decades, with advancements in understanding its pathophysiology and developing more targeted therapies. Thrombopoietin Receptor Agonists (TPO-RAs) represent a optimistic class of drugs that have shown efficacy in increasing platelet counts in patients with ITP. This article investigates the use of TPO-RAs in ITP, exploring their mechanism of action, clinical applications, benefits, challenges, and future directions.

Pathophysiology of immune thrombocytopenia

In ITP, the immune system produces antibodies against platelet antigens, leading to the premature destruction of platelets by macrophages in the spleen and liver. The production of platelets in the bone marrow is also impaired due to the interaction of these autoantibodies with megakaryocytes, the precursor cells of platelets. Consequently, patients with ITP often present with thrombocytopenia, which can lead to symptoms ranging from petechiae and bruising to life-threatening hemorrhages.

Thrombopoietin (TPO), a glycoprotein hormone, plays an important role in the regulation of platelet production. It is primarily produced by the liver and kidneys and acts through its receptor, the TPO receptor Myeloproliferative Leukaemia Gene (MPL), which is expressed on megakaryocytes and hematopoietic stem cells. TPO stimulates megakaryocyte proliferation and maturation, thereby increasing platelet production. In ITP, platelet counts are reduced due to both accelerated destruction and insufficient platelet production. Thus, therapies aimed at enhancing platelet production by boosting the action of TPO for managing the disease.

Mechanism of action of TPO-RAs

TPO-RAs are synthetic agents designed to impersonate the action of TPO and activate the MPL receptor. These agents stimulate the production of megakaryocytes and platelets by binding to MPL receptors on hematopoietic stem cells and megakaryocytes, leading to increased megakaryocyte proliferation and differentiation. This results in enhanced platelet production, which helps to restore platelet counts in patients with ITP.

The key difference between TPO-RAs and endogenous TPO is that TPO-RAs are not subject to the negative feedback regulation that governs natural TPO production. As a result, TPO-RAs can directly stimulate platelet production without being limited by the body’s normal regulatory mechanisms, offering an advantage in the treatment of ITP where platelet production is often inadequate.

Approved TPO-RAs for ITP

Several TPO-RAs have been developed and approved for use in ITP. The two most widely studied and used agents are romiplostim and eltrombopag.

Romiplostim: Romiplostim is a peptibody (a fusion of a peptide and an antibody) that binds to the MPL receptor and mimics TPO activity. It is administered subcutaneously, typically once a week. Romiplostim has demonstrated efficacy in increasing platelet counts and reducing bleeding events in patients with chronic ITP who have failed first-line treatments, such as corticosteroids and Intravenous Immunoglobulin (IVIG). In clinical trials, romiplostim has been shown to significantly improve platelet counts in approximately 60–80% of patients.

Eltrombopag: Eltrombopag is a small molecule, oral TPO-RA that also stimulates the MPL receptor. It is typically used in patients with chronic ITP who have not responded to corticosteroids or splenectomy. Eltrombopag has been shown to effectively raise platelet counts in these patients and reduce the need for rescue treatments. It has the advantage of being orally administered, which provides a more convenient treatment option compared to romiplostim, which requires subcutaneous injection. Clinical trials have demonstrated that eltrombopag can increase platelet counts in up to 70% of patients with chronic ITP.

Both drugs have been approved by regulatory agencies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) for the treatment of ITP in patients who have not responded to other treatments. However, their use is not without challenges and requires careful monitoring for side effects and complications.

Conclusion

TPO receptor agonists represent a significant advancement in the treatment of immune thrombocytopenia. These agents effectively increase platelet counts and reduce bleeding risk in patients with chronic ITP, offering a valuable alternative to conventional therapies. While they have shown remarkable clinical benefits, careful monitoring and consideration of potential risks, including thrombosis, are essential for their safe use. As our understanding of the pathophysiology of ITP continues to evolve, the role of TPO-RAs will likely expand, further improving outcomes for patients with this challenging condition.