GPIb{alpha} is required for platelet-mediated hepatic thrombopoietin generation

Thrombopoietin (TPO), a hematopoietic growth factor produced predominantly by the liver, is essential for thrombopoiesis. Prevailing theory posits that circulating TPO levels are maintained through its clearance by platelets and megakaryocytes via surface c-Mpl receptor internalization. Interestingly, we found a two- to threefold decrease in circulating TPO in GPIbα–/– mice compared with wild-type (WT) controls, which was consistent in GPIbα-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIbα-deficient conditions were not due to increased TPO clearance by GPIbα–/– platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIbα–/–, platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIbα–/– mice. In vitro hepatocyte cocultures with platelets or GPIbα-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIbα. Treatment of GPIbα–/– platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIbα–/– platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIbα, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was r...

Source: Blood - August 9, 2018 Category: Hematology Authors: Xu, M., Li, J., Neves, M. A. D., Zhu, G., Carrim, N., Yu, R., Gupta, S., Marshall, J., Rotstein, O., Peng, J., Hou, M., Kunishima, S., Ware, J., Branch, D. R., Lazarus, A. H., Ruggeri, Z. M., Freedman, J., Ni, H. Tags: Platelets and Thrombopoiesis, Thrombosis and Hemostasis Source Type: research