Efficiently restored thrombopoietin production via AMR and IL-6R induced JAK2-STAT3 signaling early after partial hepatectomy.

Thrombocytopenia has been described in most of patients with acute and chronic liver failure. Decreased platelet production and decreased half-life of platelets might be a consequence of low levels of 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. Recent work provided evidence for the control of TPO mRNA expression in liver and bone marrow by scanning circulating platelets. The Ashwell-Morell receptor (AMR) was identified to bind desialylated platelets to regulate hepatic thrombopoietin (TPO) production via JAK2-STAT3 activation. 2/3 partial hepatectomy (PHx) was performed in mice. Platelet activation and clearance by AMR/JAK2/STAT3 signaling and TPO production was 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 via up-regulation and crosstalk of the AMR and the IL-6 receptor to induce JAK2-STAT3-TPO activation in the liver accompanied by an increased number of megakaryocytes in spleen and bone marrow before liver was completely regenerated. Conclusion: The AMR/IL-6R-STAT3-TPO signaling pathway is an acute phase response to liver injury to reconstitute hemostasis. Bleeding complications were due to thrombocytopenia and platelet defects induced by elevated PGI2 , NO and bile acid plasma levels early after PHx that might be also causative for the high mortality in patients with liver disease.