Project 457545

Thrombopoietin (TPO) is a hormone required for platelet generation; thus cessation bleeding (hemostasis). Prevailing theory posits that liver hepatocytes constitutively produce TPO, and levels are fine-tuned by platelet uptake. Therefore, TPO levels should be inversely proportional to platelet count. However, immune thrombocytopenia (ITP) patients, an autoimmune disorder characterized by platelet destruction, have relatively unchanged TPO levels despite proportionally lower platelet counts, suggesting an additional mechanism of TPO regulation. Since then, it has been reported that aged platelets can stimulate TPO through the hepatocyte Ashwell-Morell Receptor. Our lab has additionally shown that platelet glycoprotein (GP) Iba is indispensable for platelet-mediated TPO generation; however, the mechanism of this interaction and the GPIba cognate receptor is not known. Emerging reports have shown that liver resident macrophages that reside along and within this endothelium are required for platelet clearance; however, whether they are a required intermediary for TPO generation has never been explored. My preliminary data show that liver resident macrophages are required for platelet-mediated and constitutive hepatocellular TPO generation. Future experiments will elucidate the mechanism of Kupffer cell contribution to platelet-mediated TPO generation and extent of contribution to baseline TPO production. Understanding the mechanism of TPO regulation in its entirety is crucial for platelet generation and, therefore, hemostasis. Moreover, treatment for patients suffering from dangerously low platelet count, as seen in leukemia or ITP, for example, is currently lacking; sustained response is rarely achieved, and there lacks a gold standard efficacious across all patients. Comprehensive understanding of TPO regulation will allow for clinical investigation of novel receptor agonist therapies providing alternative therapeutic avenues for refractory thrombocytopenic patients.