The heart-liver axis controls platelet turnover by hepatic STAT3 phosphorylation and TPO regulation after acute myocardial infarction

Authors

Reusswig, F., Tajdar, B., Gorressen, S., Fischer, J. W., Elvers, M.

Abstract

Background: Platelets play a critical role in thrombo-inflammation following acute myocardial infarction (AMI). Objectives: Their impact on hepatic thrombopoietin (TPO) regulation after AMI remains poorly understood to date. Methods: Wildtype, thrombocytopenic or GPVI deficient mice underwent ischemia/reperfusion (I/R) injury. Platelet activation and turnover, and hepatic expression of different receptors involved in TPO regulation were analyzed. Results: Here, we identify a heart-liver axis that dynamically regulates platelet production post AMI. An elevated platelet turnover with increased reticulated as well as desialylated platelets early after AMI was detected. This was accompanied by the upregulation of specific receptors such as Asgr1/2 and IL-6R and increased phosphorylation of STAT3 in the liver and elevated numbers of megakaryocytes in spleen tissue. Consequently, increased TPO plasma levels at 24h post AMI were detected and platelet counts were rapidly restored after AMI. Platelet depletion induces a compensatory increase in hepatic TPO expression and plasma TPO levels, accompanied by dysregulated STAT3 signaling. This response contrasts with GPVI-deficient (Gp6-/-) mice, which exhibit no major alterations in TPO regulation, suggesting distinct mechanisms between acute thrombocytopenia and chronic platelet receptor deficiency in platelet homeostasis after AMI. These findings provide the first evidence of a direct heart-liver axis regulating platelet homeostasis after AMI, driven by inflammatory and hepatic signaling pathways. Conclusions: Our study highlights a previously unrecognized role of the heart-liver axis in controlling platelet turnover, with hepatic STAT3 signaling as a key mediator. These insights enhance our understanding of post AMI platelet homeostasis and may be critical for future therapeutic strategies.

Preprint server: bioRxiv
The authors list and abstract were imported from bioRxiv on 22 Sep 2026.

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