A Review of Romiplostim Mechanism of Action and Clinical Applicability

Abstract

Thrombocytopenia results from a variety of conditions, including radiation, chemotherapy, autoimmune disease, bone marrow disorders, pathologic conditions associated with surgical procedures, hematopoietic stem cell transplant (HSCT), and hematologic disorders associated with severe aplastic anemia. Immune thrombocytopenia (ITP) is caused by immune reactions that accelerate destruction and reduce production of platelets. Thrombopoietin (TPO) is a critical component of platelet production pathways, and TPO receptor agonists (TPO-RAs) are important for the management of ITP by increasing platelet production and reducing the need for other treatments. Romiplostim is a TPO-RA approved for use in patients with ITP in the United States, European Union, Australia, and several countries in Africa and Asia, as well as for use in patients with refractory aplastic anemia in Japan and Korea. Romiplostim binds to and activates the TPO receptor on megakaryocyte precursors, thus promoting cell proliferation and viability, resulting in increased platelet production. Through this mechanism, romiplostim reduces the need for other treatments and decreases bleeding events in patients with thrombocytopenia. In addition to its efficacy in ITP, studies have shown that romiplostim is effective in improving platelet counts in various settings, thereby highlighting the versatility of romiplostim. The efficacy of romiplostim in such disorders is currently under investigation. Here, we review the structure, mechanism, pharmacokinetics, and pharmacodynamics of romiplostim. We also summarize the clinical evidence supporting its use in ITP and other disorders that involve thrombocytopenia, including chemotherapy-induced thrombocytopenia, aplastic anemia, acute radiation syndrome, perisurgical thrombocytopenia, post-HSCT thrombocytopenia, and liver disease.

Keywords: immune thrombocytopenia; pharmacodynamics; pharmacokinetics; structure; thrombopoietin receptor agonist.

Figure 1

Structure of thrombopoietin, and TPO-MPL signaling. Thrombopoietin is synthesized in the liver and kidney as a single 353-amino acid precursor protein. Plasma concentrations of TPO increase in response to reduced platelet mass. Conversely, TPO binds to MPL receptors on circulating platelets in the blood when platelet levels are high. Upon exogenous TPO stimulation, HSCs differentiate to megakaryocytes. Local TPO production by stromal cells in the bone marrow also stimulates megakaryocyte maturation.

Figure 2

Pathophysiology of immune thrombocytopenia. Production of antiplatelet autoantibodies appears to be a key event in the pathophysiology of ITP. These autoantibodies target platelets for destruction by macrophages in the spleen or liver through activation of Fcγ receptors, a process controlled by spleen Syk. Autoantibodies may also destroy platelets through other mechanisms and inhibit platelet production by megakaryocytes. Antigens from phagocytosed platelets are thought to be presented by the MHCII to TCRs, stimulating autoreactive T cells. Pathogenic T-cell changes seen in ITP include skewing of T-helper cells toward a type 1 T-helper (Th1) and type 17 T-helper (Th17) phenotype, reduction of regulatory T-cell activity, and an increase in cytotoxic T cells. From N Engl J Med, Cooper N, Ghanima W. Immune Thrombocytopenia. 381(10):945–955. Copyright ©(2019) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.

Figure 3

Chemical structure of romiplostim. Romiplostim (molecular weight ≈60 kDa) is a peptibody composed of four identical thrombopoietin peptides of 14 amino acids each that are chemically coupled by glycine spacer domains to the carboxy-terminus of the Fc carrier domain. These 14 amino acid peptides have no sequence homology with native thrombopoietin.

Figure 4

Cellular mechanism of action of thrombopoietin receptor agonists. Binding of the ligand (TPO/TPO-RA) to the c-MPL receptor on the megakaryocyte causes conformational change in the receptor, resulting in downstream activation of the various signaling pathways, including JAK2/STAT5, PI3K/Akt, MEK/ERK, and p38, ultimately resulting in increased platelet production. Various pathways can be activated by the different substances. Romiplostim activates the extracellular domain of the TPO-R and eltrombopag and avatrombopag activate the transmembrane portion of the TPO-R.