4.7 Article

GPIb alpha is required for platelet-mediated hepatic thrombopoietin generation

Journal

BLOOD
Volume 132, Issue 6, Pages 622-634

Publisher

AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2017-12-820779

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Funding

  1. Canadian Institutes of Health Research [MOP 97918, MOP 119540]
  2. Heart and Stroke Foundation of Canada (Ontario)
  3. Canadian Foundation for Innovation
  4. China Scholarship Council
  5. Ontario Trillium Scholarship
  6. Canadian Blood Services
  7. Canadian Blood Services in Cardiovascular Studies
  8. Canadian Blood Services Postdoctoral Fellowship

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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 GPIb alpha(-/-) mice compared with wild-type (WT) controls, which was consistent in GPlba-deficient human Bernard-Soulier syndrome (BSS) patients. We showed that lower TPO levels in GPIb alpha-deficient conditions were not due to increased TPO clearance by GPIb alpha(-/-) platelets but rather to decreased hepatic TPO mRNA transcription and production. We found that WT, but not GPIb alpha(-/)(-), platelet transfusions rescued hepatic TPO mRNA and circulating TPO levels in GPIb alpha(-/-) mice. In vitro hepatocyte cocultures with platelets or GPIb alpha-coupled beads further confirm the disruption of platelet-mediated hepatic TPO generation in the absence of GPIb alpha. Treatment of GPIb alpha(-/-) platelets with neuraminidase caused significant desialylation; however, strikingly, desialylated GPIb alpha(-/-) platelets could not rescue impaired hepatic TPO production in vivo or in vitro, suggesting that GPIb alpha, independent of platelet desialylation, is a prerequisite for hepatic TPO generation. Additionally, impaired hepatic TPO production was recapitulated in interleukin-4/GPIb alpha-transgenic mice, as well as with antibodies targeting the extracellular portion of GPIb alpha, demonstrating that the N terminus of GPIb alpha 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 GPIb alpha, such as BSS and auto- and alloimmune-mediated thrombocytopenias.

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