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Cited by 28Platelet Disorders and TreatmentsLiver physiology and pathologyBlood Coagulation and Thrombosis Mechanisms

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

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Reusswig, Friedrich, Fazel Modares, Nastaran, Brechtenkamp, Marius, Wienands, Leonard, Krüger, Irena, Behnke, Kristina, Lee‐Sundlov, Melissa M., Herebian, Diran +4 more·2021·Hepatology
DOI 10.1002/hep.31698PMC PMC8236498
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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 PGI 2, NO, and bile acid plasma levels early after PHx that might also be causative for the high mortality in patients with liver disease.

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  • IL-6 is involved in thrombopoietin homeostasis and platelet count restoration pathways as well as angiotensinogen gene expression during liver regeneration.

    “It is involved in thrombopoietin homeostasis and platelet count restoration pathways as well as angiotensinogen gene expression during liver regeneration [36,37].”

    From The Role of Perioperative Interleukin-6 Serum Levels on Liver Dysfunction and Infectious Complications After Hepatectomy—A Systematic Review (2025) · cites this paper as [36]

    The Discussion and Abstract Conclusions link IL-6R signaling to thrombopoietin homeostasis and platelet-count regulation after partial hepatectomy in mice. The paper does not address angiotensinogen gene expression; a search for “angiotensinogen” found no matching passage. The Results also report that recombinant hyper-IL-6 did not itself increase platelet counts. (LLM, conf=0.88)

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Authors
Reusswig, F., Fazel Modares, N., Brechtenkamp, M., Wienands, L., Krüger, I., Behnke, K., Lee‐Sundlov, M. M., Herebian, D., Scheller, J., Hoffmeister, K. M., Häussinger, D., & Elvers, M.
Affiliations
  • Düsseldorf University Hospital (DE)
  • Institute of Biochemistry and Molecular Biology II, Medical Faculty,Heinrich‐Heine University,Düsseldorf,Germany
  • Heinrich Heine University Düsseldorf (DE)
  • Versiti Blood Center of Wisconsin (US)
Corresponding author
Elvers, Margitta
ORCID
Venue
Hepatology
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2021-06-04
Volume
74
Issue
1
Pages
411-427
ISSN
  • 0270-9139 (ISSN-L)
  • 1527-3350
DOI
10.1002/hep.31698
PMC
PMC8236498
OpenAlex
W3116927555
Cited by
28
References
5
Citations by year
2026: 3 · 2025: 7 · 2024: 6 · 2023: 6 · 2022: 4 · 2021: 2
FWCI
1.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Hepatology (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
  • Deutsche Forschungsgemeinschaft (project A16, CRC974)
  • National Heart, Lung, and Blood Institute (K12HL141954, R01HL089224)
Topics
  • Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
  • Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
Keywords
thrombopoietin, IL-6 receptor, JAK2/STAT3 signaling, partial hepatectomy, thrombocytopenia, platelet activation, megakaryocytes, liver regeneration, platelet clearance, liver failure, bleeding complications, bile acids, nitric oxide
MeSH terms
Animals, Disease Models, Animal, Hepatectomy, Humans, Platelet Count, Specific Pathogen-Free Organisms, Thrombocytopenia, Thrombopoietin, Mice, Knockout, Receptors, Interleukin-6, Asialoglycoprotein Receptor, STAT3 Transcription Factor, Mice, Janus Kinase 2

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