The biology of thrombopoietin and thrombopoietin receptor agonists

Abstract

Thrombopoietin (TPO) is the major physiological regulator of platelet production. TPO binds the TPO receptor, activates JAK and STAT pathways, thus stimulating megakaryocyte growth and platelet production. There is no ''sensor'' of the platelet count; rather TPO is produced in the liver at a constant rate and cleared by TPO receptors on platelets. TPO levels are inversely proportional to the rate of platelet production. Early recombinant TPO molecules were potent stimulators of platelet production and increased platelets in patients with immune thrombocytopenia, chemotherapy-induced thrombocytopenia, myelodysplastic syndromes and platelet apheresis donors. Neutralizing antibodies formed against one recombinant protein and ended their development. A second generation of TPO receptor agonists, romiplostim and eltrombopag, has been developed. Romiplostim is an IgG heavy chain into which four TPO agonist peptides have been inserted. Eltrombopag is an oral small molecule. These activate the TPO receptor by different mechanisms to increase megakaryocyte growth and platelet production. After administration of either to healthy volunteers, there is a delay of 5 days before the platelet count rises and subsequently reaches a peak after 12-14 days. Both have been highly effective in treating ITP and hepatitis C thrombocytopenia. Studies in a wide variety of other thrombocytopenic conditions are underway.

Clinical heterogeneity and predictors of outcome in primary autoimmune hemolytic anemia: a GIMEMA study of 308 patients

“…45 Altogether, our results showed that one-fourth of primary AIHA patients require at least 2 lines of therapy, about 13% require 3, and a small fraction (4%) require $4 lines; the most severe cases and the mixed and atypical forms had a 3-fold increased risk of relapse or unresponsiveness to therapy. Younger age was also associated with a severe clinical presentation and an increased risk of relapse and refractoriness, probably due to a more aggressive immune reactivity.…”

Revealing eltrombopags promotion of human megakaryopoiesis through AKT/ERK-dependent pathway activation

“…9 Among the small, non-peptide c-Mpl agonists, 10,11 eltrombopag has been successfully employed to stimulate platelet production in patients suffering from IT caused by mutations of the MYH9 gene, immune thrombocytopenia (ITP), and thrombocytopenia due to hepatitis C infection. [12][13][14] Moreover, improvement of thrombocytopenia has been obtained in patients with acute myeloid leukemia (AML) and MDS.…”

Thrombopoietin Treatment of One Graft in a Double Cord Blood Transplant Provides Early Platelet Recovery While Contributing to Long-Term Engraftment in NSG Mice

“…Thrombopoietin (TPO) is known to be critical for both HSC maintenance and platelet production [34][35][36][37][38][39][40]. SanjuanPla et al [41] have recently identified, in the mouse, a TPOdependent platelet-biased HSC expressing Sca-1, c-kit, CD150, and von Willebrand factor (vWF), which exists at the apex of the hematopoietic hierarchy and which not only generates platelets over the short and longer term, but also can give rise to both myeloid-and lymphoid-biased HSCs.…”