Increased Factor VIII Activity Is Predictive of the Occurrence of Portal Vein Thrombosis in Cirrhosis.

BACKGROUND: The aim of this study was to identify the role of factor VIII (FVIII) in portal vein thrombosis (PVT) occurrence in cirrhotic patients with gastroesophageal variceal bleeding. METHODS: A total of 453 cirrhotic patients with gastroesophageal varices were enrolled. Computed tomography was performed at baseline and patients were divided into PVT and non-PVT groups (n = 131 vs. 322). Individuals without PVT at baseline were followed up for the development of PVT. Time-dependent receiver operating characteristic analysis of FVIII for PVT development was performed. The Kaplan-Meier methodology was used to analyze the predictive ability of FVIII for PVT incidence at 1 year. RESULTS: FVIII activity (177.00 vs. 153.70, p = 0.001) was significantly increased in the PVT group compared with the non-PVT group in cirrhotic patients with gastroesophageal varices. FVIII activity was positively correlated with the severity of PVT (161.50 vs. 171.07 vs. 187.05%, p = 0.001). Furthermore, FVIII activity (hazard ratio [HR]: 3.48, 95% confidence interval [CI]: 1.14-10.68, p = 0.029 in model 1; HR: 3.29, 95% CI: 1.03-10.51, p = 0.045 in model 2) was an independent risk factor of 1-year PVT development in patients without PVT at baseline, which was confirmed by two separate Cox regression analysis and competing risk models. Patients with elevated FVIII activity exhibit a higher incidence of PVT in the non-PVT group at 1 year (15.17 vs. 3.16%, p < 0.001). The predictive value of FVIII remains significant in individuals who have never received splenectomy (14.76 vs. 3.04%, p = 0.002). CONCLUSION: Elevated FVIII activity was potentially associated with the occurrence and the severity of PVT. It might be helpful to identify cirrhotic patients at risk of PVT.

Platelet-derived TGF-ß1 is related to portal vein thrombosis in cirrhosis by promoting hypercoagulability and endothelial dysfunction.

Background: Portal vein thrombosis (PVT) is a serious complication of cirrhosis accompanied by unclear pathogenesis. Transforming growth factor-beta (TGF-ß) has been implicated in atherosclerosis and venous thrombosis whereas study regarding its part in PVT is lacking. The aim of this study was to explore the role of cytokine TGF-ß1 in PVT and the potential mechanism. Materials and methods: We included patients with cirrhotic gastroesophageal varices and divided them into two groups according to the presence of PVT. Serum levels of TGF-ß1 were detected using Cytometric Bead Array kit and compared between two groups. Coagulation status was assessed using thromboelastography (TEG). Primary liver sinusoidal endothelial cells were treated with TGF-ß1 and evaluated for endothelial dysfunction by RT-PCR. Results: Our results uncovered that TGF-ß1 (6,866.55 vs. 3,840.60 pg/ml, P = 0.015) significantly increased in the PVT group. Splenectomy might promote PVT by increasing platelet-derived TGF-ß1 levels. Other cytokines showed no difference between PVT and non-PVT groups. Besides, TGF-ß1 was correlated with platelet, fibrinogen, TEG-CI, TEG-MA, and TEG-α (coef = 0.733, 0.494, 0.604, 0.608, and 0.511; P < 0.001, 0.027, 0.004, 0.004, and 0.021, respectively), which indicated a hypercoagulable state in PVT patients. RT-PCR of liver sinusoidal endothelial cells showed a markable increment of von Willebrand Factor (vWF), thrombomodulin(TM), intercellular adhesion moleclar-1(ICAM-1), and vascular endothelial growth factor(VEGF) after TGF-ß1 treatment, suggesting the involvement of endothelial dysfunction. Conclusion: Elevated platelet-derived TGF-ß1 exhibited association with hypercoagulability and promoting effect on endothelial dysfunction, closely related with PVT in cirrhotic patients.

Endoscopic Treatment as the Rescue Therapy for Recurrent Bleeding after Transjugular Intrahepatic Portosystemic Shunt (TIPS).

BACKGROUND: Transjugular intrahepatic portosystemic shunt (TIPS) is suggested as the salvage therapy for gastroesophageal variceal bleeding in cirrhosis. However, rebleeding might occur in some patients after TIPS. Currently, there is a lack of evidence in the endoscopic management of recurrent bleeding in these patients. AIMS: To evaluate the efficacy of endoscopic treatment in cirrhotic patients with recurrent bleeding after TIPS. METHODS: Cirrhotic patients with gastroesophageal varices who received endoscopic treatment for recurrent bleeding after TIPS were included. RESULTS: 6 patients were enrolled in this study. The median age of the patients was 47 years (range 27 to 65 years), and the duration of follow-up time was 346 (17-773) days. Stent stenosis or occlusion was found in 5 out of 6 patients after TIPS. Salvage endoscopic treatment, including esophageal variceal ligation (EVL), gastric variceal cyanoacrylate injection, esophageal variceal sclerotherapy, and balloon-occluded retrograde transvenous obliteration- (BRTO-) assisted endoscopic cyanoacrylate injection. Among included patients, 2 died shortly after EVL (14 and 19 days) due to variceal bleeding. Among other 4 patients, 2 had rebleeding episodes at 422 and 789 days, respectively. CONCLUSION: Endoscopic treatment may be an option for recurrent bleeding after TIPS in selected patients. Further studies are needed to carefully define the indication and efficacy of this option.

Positive consequences of splenectomy for patients with schistosomiasis-induced variceal bleeding.

BACKGROUND: Patients with hepatic schistosomiasis are at high risk of gastroesophageal variceal bleeding, which is highly torrential and life threatening. This study aimed to assess the effects of splenectomy on patients with schistosomiasis-induced variceal bleeding, especially those influences related to overall survival (OS) rate. METHODS: From January 2005 to December 2018, 112 patients with schistosomiasis-induced varices were enrolled. In that period, all the patients with hepatic schistosomiasis who received endoscopic treatment for primary and secondary prophylaxis of gastroesophageal variceal bleeding were found eligible. The patients were divided into splenectomized group (n = 44, 39.3%) and control group (n = 68, 60.7%). RESULTS: Multivariate regression analysis of OS showed that splenectomy, hepatic carcinoma, and times of endoscopic treatment were independent prognostic factors for OS. Kaplan-Meier analysis revealed that the 5-year OS rate was 82.7% in splenectomized group versus 53.2% in control group (P = 0.037). The rate of no recurrence of variceal bleeding during 5-year (56.8% vs. 47.7%, P = 0.449) indicated that there was no significant difference between the two groups. Patients who received splenectomy had increased risk of portal vein thrombosis (52.3% vs. 29.4%, P = 0.012) and decreased proportion of severe ascites (20.5% vs 50.0%, P = 0.002). CONCLUSION: Splenectomy prior to endoscopic treatment provides a superior long-term survival for patients with schistosomiasis-induced variceal bleeding.

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer.

Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration, and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings. Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates, and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with ß-cyclodextrin (ß-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo, knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of ß-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

Endoscopic treatment of gastroesophageal variceal bleeding after oxaliplatin-based chemotherapy in patients with colorectal cancer.

BACKGROUND : Oxaliplatin, used as first-choice treatment for colorectal cancer (CRC), induces sinusoidal endothelial injury and portal hypertension. This study investigated the characteristics of oxaliplatin-induced portal hypertension and evaluated the efficacy of endoscopic management of gastroesophageal variceal bleeding. METHODS : We performed a retrospective, multicenter, case-control study between January 2010 and December 2018. Patients who received oxaliplatin-based chemotherapy after CRC surgery and presented with portal hypertension and gastroesophageal varices were compared with consecutive patients with hepatitis B-related cirrhotic portal hypertension receiving endoscopic treatment for variceal bleeding. RESULTS : 39 patients with oxaliplatin-induced portal hypertension were identified, 35 of whom had a history of variceal bleeding. The median period between start of oxaliplatin-based chemotherapy and the occurrence of varices was 50.4 months (n = 39). A total of 26 patients with oxaliplatin-related portal hypertension and 230 patients with hepatitis B-related portal hypertension underwent endoscopic treatment. Kaplan-Meier analysis revealed that the 1-year rebleeding rate was significantly higher in the oxaliplatin group than in the hepatitis B group (43.3 % vs. 19.0 %, P = 0.001). Multivariable Cox regression analysis showed that oxaliplatin-based chemotherapy was an independent factor for 3-year rebleeding (hazard ratio [HR] 2.46, 95 % confidence interval [CI] 1.24-4.87; P = 0.01) and 3-year overall mortality (HR 9.43, 95 %CI 2.32-38.31; P = 0.002). CONCLUSIONS : Oxaliplatin-related portal hypertension was characterized by massive ascites, splenomegaly, gastric varices, concomitant arterioportal fistula, and relatively normal liver function. Endoscopic treatment to prevent variceal rebleeding in these patients was unsatisfactory compared with endoscopic treatment for hepatitis B-related portal hypertension.

Simvastatin Mitigates Apoptosis and Transforming Growth Factor-Beta Upregulation in Stretch-Induced Endothelial Cells.

Portal hypertension is a common clinical symptom of digestive disorders. With an increase in portal pressure, the portal vein will continue to dilate. We aimed to determine whether continuous stretch induced by portal hypertension may impair the function of endothelial cells (ECs) in the portal vein and aggravate the progress of portal hypertension and explore its mechanism. ECs were cultured on an elastic silicone membrane and subjected to continuous uniaxial stretch. Apoptosis and expression of TGF-ß in ECs under stretch were measured. We found that sustained stretch induced the apoptosis of ECs in a stretch length-dependent manner. Compared with the control, continuous stretch increased the nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression and damaged the mitochondria, resulting in an evident increase in reactive oxygen species (ROS) levels; pretreatment with gp91ds-tat or MitoTEMPO decreased the ROS level in the intracellular levels. N-acetyl-cysteine (NAC) treatment before stretch not only reduced ROS levels but also mitigated the apoptosis of ECs; simvastatin had similar effects through targeting NOX2 and mitochondria. During the stretch, the phosphorylation of p38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), and nuclear factor-kappa B (NF-κB) was obviously increased; pretreatment with P38MAPK or JNK inhibitors decreased the phosphorylation of NF-κB and TGF-ß expression. Pyrrolidine dithiocarbamate (PDTC) treatment before stretch also reduced TGF-ß expression. After pretreatment with NAC, the phosphorylation of P38MAPK, JNK, and NF-κB and TGF-ß expressions in ECs under stretch was suppressed; similar results were observed in simvastatin-treated ECs. This study demonstrated that simvastatin could mitigate EC apoptosis and TGF-ß upregulation induced by continuous stretch by reducing the level of ROS.