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GPIbα is required for platelet-mediated hepatic thrombopoietin generation

Miao Xu, June Li, Miguel Antonio Dias Neves, Guangheng Zhu, Naadiya Carrim, Ruoying Yu, Sahil Gupta, John Marshall, Ori Rotstein, Jun Peng, Ming Hou, Shinji Kunishima, Jerry Ware, Donald R. Branch, Alan H. Lazarus, Zaverio M. Ruggeri, John Freedman and Heyu Ni

Key Points

  • Platelet GPIbα induces hepatic TPO generation and maintains TPO levels in blood.

  • Antiextracellular GPIbα antibodies decrease TPO generation and may affect TPO levels in immune-mediated thrombocytopenias.

Publisher's Note: There is a Blood Commentary on this article in this issue.

Abstract

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 recapitulated in interleukin-4/GPIbα–transgenic mice, as well as with antibodies targeting the extracellular portion of GPIbα, demonstrating that the N terminus of GPIbα is required for platelet-mediated hepatic TPO generation. These findings reveal a novel nonredundant regulatory role for platelets in hepatic TPO homeostasis, which improves our understanding of constitutive TPO regulation and has important implications in diseases related to GPIbα, such as BSS and auto- and alloimmune-mediated thrombocytopenias.

  • Submitted December 8, 2017.
  • Accepted May 18, 2018.
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