Ligand for Mpl receptor expressed in platelets and megakaryocytes and can induce growth and maturation of megakaryocytes and results in increased platelet counts in healthy volunteers.

Thrombopoietin (TPO) is a hormone constitutively produced by the liver which regulates platelet production by binding to and activating TPO receptors on the megakaryocyte cell surface, thereby inducing intracellular signalling cascades that lead to increased platelet production.

Binds to its ligand Mpl on the surface of platelets and megakaryocytes and in their absence results in higher levels. 

Experimental evidence suggests it helps the regulate the survival and proliferation of hematopoietic stem cells.

The humeral regulator of platelet production, and it is produced mainly in the liver, binds and activates specific thrombopoietin receptors on the membrane of the megakaryocyte and induces cytoplasmic signaling for platelet production.

A megakaryocyte growth and differentiation factor made in the liver, kidneys and bone marrow stroma.

Principal cytokine initiator of thrombopoiesis, interacting with hematopoietic stem cells in the bone marrow sinusoids and promotes their differentiation into megakaryocytic precursor cells.

Stimulates the proliferation and maturation of stem cells into megakaryocytes that act as incubators of platelets.

Other cytokines that play roles in thrombopoiesis includes interleukins 1, 3, 6 and 11.

Cleared from peripheral blood by binding the platelets and megakaryocytes.

As the number of platelets in the blood increases thrombopoietin binds to the thrombopoietin receptor on circulating platelets causing a reduction in free thrombopoietin to stimulate platelet production.

Plasma levels of TPO are regulated by binding of TPO to circulating platelets which results in its removal from circulation and subsequent degradation.

As the number of platelets falls the amount of free thrombopoietin increases to stimulate platelet production.

In patients with ITP, TPO plasma levels are inappropriately low as compared with individuals with hypoproliferative thrombocytopenias, an observation which led to the development of recombinant thrombopoietins, the first generation of exogenous thrombopoiesis-stimulating agents.

Megakaryopoiesis regulated by circulating platelet count and by megakaryocyte content of the bone marrow.

levels increase when thrombocytopenia occurs or when marrow megakaryocyte count decreases, as occurs following chemotherapy, with a reduction in the clearance of thrombopoietin.

Endogenous levels of plasma from thrombopoietin and are typically high in the presence of bone marrow failure syndromes.

In many patients with idiopathic thrombocytopenic purpura (ITP) serum levels are with in normal levels despite thrombocytopenia.

AMG531 an immunoglobulin Fc domain fragment linked to two identical peptide chains that bind and activate the Mpl receptor.

AMG 531 has a 68% response rate in chronic ITP.

AMG 531 side affects include mild to moderate headaches, and transient decrease in platelet counts after discontinuation of the drug.

AMG 531, a thrombopoietic effusion protein for low or intermediate risk of myelodysplastic syndrome, demonstrating an increase of platelet counts and durability in about one third of patients.

AMG 531, 5% of patients get grade ¾ treatment related adverse events.

AMG 531 not associated with neutralizing antibodies.

AMG 531 maximum tolerated dose 1500 mcg.

Eltrombopag a small molecule, nonpeptide, thrombopoietin receptor agonist that initiates thrombopoietin receptor signaling by interacting with the transmembrane domain of the receptor increasing megakaryocytic differentiation and proliferation.

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