Faculty Collaboration Database

Efficiently Restored Thrombopoietin Production by Ashwell-Morell Receptor and IL-6R Induced Janus Kinase 2/Signal Transducer and Activator of Transcription Signaling Early After Partial Hepatectomy. Hepatology 2021 Jul;74(1):411-427

Date

12/29/2020

Pubmed ID

33369745

Pubmed Central ID

PMC8236498

DOI

10.1002/hep.31698

Scopus ID

2-s2.0-85107131623 (requires institutional sign-in at Scopus site)   12 Citations

Abstract

BACKGROUND AND AIMS: Thrombocytopenia has been described in most patients with acute and chronic liver failure. Decreased platelet production and decreased half-life of platelets might be a consequence of low levels of thrombopoietin (TPO) in these patients. Platelet production is tightly regulated to avoid bleeding complications after vessel injury and can be enhanced under elevated platelet destruction as observed in liver disease. Thrombopoietin (TPO) is the primary regulator of platelet biogenesis and supports proliferation and differentiation of megakaryocytes.

APPROACH AND RESULTS: Recent work provided evidence for the control of TPO mRNA expression in liver and bone marrow (BM) by scanning circulating platelets. The Ashwell-Morell receptor (AMR) was identified to bind desialylated platelets to regulate hepatic thrombopoietin (TPO) production by Janus kinase (JAK2)/signal transducer and activator of transcription (STAT3) activation. Two-thirds partial hepatectomy (PHx) was performed in mice. Platelet activation and clearance by AMR/JAK2/STAT3 signaling and TPO production were analyzed at different time points after PHx. Here, we demonstrate that PHx in mice led to thrombocytopenia and platelet activation defects leading to bleeding complications, but unaltered arterial thrombosis, in these mice. Platelet counts were rapidly restored by up-regulation and crosstalk of the AMR and the IL-6 receptor (IL-6R) to induce JAK2-STAT3-TPO activation in the liver, accompanied by an increased number of megakaryocytes in spleen and BM before liver was completely regenerated.

CONCLUSIONS: The AMR/IL-6R-STAT3-TPO signaling pathway is an acute-phase response to liver injury to reconstitute hemostasis. Bleeding complications were attributable to thrombocytopenia and platelet defects induced by elevated PGI₂ , NO, and bile acid plasma levels early after PHx that might also be causative for the high mortality in patients with liver disease.

Author List

Reusswig F, Fazel Modares N, Brechtenkamp M, Wienands L, Krüger I, Behnke K, Lee-Sundlov MM, Herebian D, Scheller J, Hoffmeister KM, Häussinger D, Elvers M

Author

Karin Hoffmeister MD Professor in the Biochemistry department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Asialoglycoprotein Receptor
Disease Models, Animal
Hepatectomy
Humans
Janus Kinase 2
Mice
Mice, Knockout
Platelet Count
Receptors, Interleukin-6
STAT3 Transcription Factor
Specific Pathogen-Free Organisms
Thrombocytopenia
Thrombopoietin