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Thrombocytopenia is a common hematological abnormality in patients with cirrhotic hypersplenism. Splenectomy with paraesophagogastric devascularization (SPD) is a conventional surgical therapy which can reverse pancytopenia in these patients. Platelets are traditionally recognized for their central role in hemostasis. However, the status of platelet aggregation in chronic hepatitis B patients with cirrhotic hypersplenism before and after SPD has not been reported yet. A total of 41 cirrhotic patients and 31 healthy controls were included in this study. Platelet aggregation was detected by AggRAM® Advanced Modular System (Helena Laboratories, USA). ELISA was used to detect the cytokines closely related to platelet aggregation. Expressions of platelet membrane glycoproteins (GPs) were evaluated by flow cytometric analysis. Platelet aggregation was found to be decreased distinctly in the cirrhotic patients, and to be restored to normal level after SPD. The cirrhotic patients showed higher plasma levels of the cytokines HMGB1, PEDF, vWF, cAMP and cGMP, which also improved partially after SPD. Moreover, the cirrhotic patients had much lower expression of GPIIb/IIIa, GPIbα and P -selectin than either the healthy controls or SPD patients at basal or activated level. Generally, SPD benefits cirrhotic patients with bleeding tendencies by improving platelet counts and aggregation. GPIIb/IIIa may be the key membrane protein responsible for the change in platelet aggregation before and after SPD.

• Splenectomy alleviates the liver inflammation and fibrosis. • Splenectomy promotes the phenotype switch of infiltrating macrophages to Ly6Clow. • Splenectomy activates the ERK1/2 pathway in hepatic macrophages in fibrotic liver. • Inhibitor of ERK1/2 rescues the phenotype switch of macrophages after splenectomy. Background and aim: Splenectomy has been reported to attenuate liver fibrosis. In addition, phenotype transitions of infiltrating macrophages, including Ly6Chigh and Ly6Clow, play an essential role in the liver fibrosis. However, whether the spleen can regulate the phenotype switch of macrophages and the underlying mechanism still remain unclear. Methods: Chronic liver fibrosis in mice was induced by intraperitoneal injection with carbon tetrachloride. Splenectomy or sham operation was performed with or without depletion of macrophages during liver fibrosis. Liver fibrosis and the proportion of Ly6Chigh and Ly6Clow macrophages were analyzed. Western blotting of ERK1/2 signals was performed in isolated macrophages to investigate the underlying mechanism of phenotype transition. RAW264.7 cells were stimulated by liver total cells conditioned medium with or without preincubation of SCH772984, the ERK1/2 inhibitor, and the phenotype switch of RAW264.7 cells was examined. In vivo , intraperitoneal injection of SCH772984 was performed on the splenectomy mice and the phenotype switch of liver infiltrating macrophages was tested. Results: Splenectomy alleviated the liver inflammation and fibrosis and also promoted the phenotypic switch of infiltrating macrophages to a Ly6Clow phenotype in fibrotic liver. The p-ERK1/2 expression was upregulated in macrophages at the same time. Furthermore, splenectomy increased the percentage of Ly6Clow macrophages and decreased the percentage of Ly6Chigh macrophages both in vivo and in vitro , which was reversed by SCH772984. Conclusions: Splenectomy attenuates both the liver fibrosis and inflammation, and promotes the phenotype switch of infiltrating macrophages to an anti-inflammatory Ly6Clow phenotype by activating the ERK1/2 pathway during liver fibrosis. [ABSTRACT FROM AUTHOR]