Effects of thrombopoietin pre-treatment on peri-liver transplantation thrombocytopenia in a mouse model of cirrhosis with hypersplenism

ARTICLE HIGHLIGHTS

Research background

During cirrhosis, the liver undergoes significant impairment, leading to various complications, including thrombocytopenia and bleeding tendency. Thrombopoietin (TPO) is a hormone produced by the liver that plays a crucial role in regulating platelet production and clearance. However, in cirrhotic patients, the liver’s ability to synthesize and clear TPO is compromised. The impaired liver function in cirrhosis results in reduced TPO synthesis. TPO is primarily produced in the liver sinusoidal endothelial cells, and when the liver is damaged, the production of TPO is significantly decreased. This reduction in TPO levels leads to a decrease in the production of new platelets in the bone marrow, contributing to thrombocytopenia.

Research motivation

It is important to manage thrombocytopenia and bleeding tendency in cirrhotic patients. Treatment options may include platelet transfusions, medications that stimulate platelet production (such as TPO receptor agonists), and interventions to address the underlying liver dysfunction. Close monitoring and collaboration with a healthcare provider are crucial in managing these complications in cirrhotic patients.

Research objectives

To evaluate the clinical effectiveness of recombinant human TPO (rhTPO) in managing perioperative thrombocytopenia during liver transplantation in cirrhotic mice with hypersplenism. We aimed to assess whether rhTPO administration could effectively increase platelet count and reduce bleeding complications in this specific population.

Research methods

To achieve this objective, we conducted a controlled experiment using a cirrhotic mouse model with hypersplenism. The mice were divided into two groups: A treatment group receiving rhTPO and a control group receiving a placebo or standard care. We monitored the platelet counts of the mice before and after liver transplantation, as well as during the perioperative period.

Research results

The results of our study demonstrated that preoperative administration of rhTPO effectively improved perioperative thrombocytopenia in mice with cirrhosis and hypersplenism undergoing liver transplantation (OLT). This finding suggests that rhTPO may have potential clinical efficacy in managing thrombocytopenia in cirrhotic patients undergoing liver transplantation. Furthermore, we found that blocking the expression of TPO receptors exacerbated peri-OLT thrombocytopenia, indicating the importance of the TPO/c-Mpl pathway in platelet regulation during liver transplantation in cirrhotic mice with hypersplenism. In our study, we observed a decrease in TPO concentration in the mouse model of cirrhosis with hypersplenism, while the concentration of c-Mpl increased in compensation. However, pre-treatment with TPO significantly increased the postoperative TPO concentration in mice, leading to a decrease in the c-Mpl concentration. This suggests that TPO administration can regulate the TPO/c-Mpl pathway and potentially improve platelet production and function. Additionally, TPO pre-treatment significantly enhanced the protein expressions of the Janus kinase (Jak)/signal transducers and activators of transcription (STAT) pathway in bone marrow stem cells of the mice. The Jak/STAT pathway is involved in regulating various cellular processes, including cell proliferation and differentiation, and plays a role in platelet production. The enhancement of this pathway may contribute to the increased platelet production observed with TPO administration. Moreover, the administration of TPO, both before and after surgery, was found to regulate the levels of biochemical indicators, such as alanine aminotransferase (ALT), alkaline phosphatase (ALP), and aspartate aminotransferase (AST) in the mice. This suggests that TPO administration may have additional beneficial effects on liver function and overall liver health in cirrhotic mice undergoing liver transplantation.

Research conclusions

Pre-treatment with TPO not only exhibited therapeutic effects on perioperative thrombocytopenia in the mice with cirrhosis and hypersplenism, who underwent liver transplantation but also significantly enhanced the perioperative liver function.

Research perspectives

Overall, our study provides evidence supporting the clinical efficacy of rhTPO in managing perioperative thrombocytopenia during liver transplantation in cirrhotic mice with hypersplenism. These findings may have implications for the development of potential therapeutic strategies for managing thrombocytopenia in cirrhotic patients undergoing liver transplantation.