Clinic of Vascular and Endovascular Surgery, Medical Faculty and University Hospital, Düsseldorf, Germany.
Institute of Biochemistry and Molecular Biology II, Medical Faculty, Heinrich-Heine University, Düsseldorf, Germany.
Hepatology. 2021 Jul;74(1):411-427. doi: 10.1002/hep.31698. Epub 2021 Jun 4.
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.
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.
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 , NO, and bile acid plasma levels early after PHx that might also be causative for the high mortality in patients with liver disease.
血小板减少症已在大多数急性和慢性肝功能衰竭患者中被描述。血小板生成减少和血小板半衰期缩短可能是这些患者中血小板生成素 (TPO) 水平降低的结果。血小板生成受到严格调控，以避免血管损伤后的出血并发症，并且可以在像肝病中观察到的血小板破坏增加的情况下增强。血小板生成素 (TPO) 是血小板生成的主要调节剂，支持巨核细胞的增殖和分化。
最近的工作提供了证据，表明循环血小板的扫描可控制肝脏和骨髓 (BM) 中的 TPO mRNA 表达。阿什韦尔-莫雷尔受体 (AMR) 被鉴定为结合去唾液酸化的血小板，以通过 Janus 激酶 (JAK2)/信号转导和转录激活因子 3 (STAT3) 激活来调节肝脏中的血小板生成素 (TPO) 产生。在小鼠中进行了三分之二部分肝切除术 (PHx)。在 PHx 后不同时间点分析 AMR/JAK2/STAT3 信号转导的血小板激活和清除以及 TPO 产生。在这里，我们证明 PHx 导致血小板减少和血小板激活缺陷导致出血并发症，但这些小鼠的动脉血栓形成没有改变。通过上调和 AMR 和白细胞介素 6 受体 (IL-6R) 的串扰诱导肝脏中 JAK2-STAT3-TPO 激活，迅速恢复血小板计数，同时在肝脏完全再生之前，脾脏和 BM 中的巨核细胞数量增加。
AMR/IL-6R-STAT3-TPO 信号通路是肝脏损伤的急性期反应，以重建止血。出血并发症归因于 PHx 后早期升高的 PGI、NO 和胆汁酸血浆水平诱导的血小板减少症和血小板缺陷，这也可能是肝病患者高死亡率的原因。
