Neutrophil Extracellular Traps And Systemic Inflammatory Markers Are Associated With Enhanced Procoagulant Activity In Liver Cirrhosis Patients With Portal Vein Thrombosis

Objective:Immunothrombosis has recently been used to describe the responses/mechanisms in thrombosis.Systemic inflammatory markers and Neutrophil extracellular traps(NETs)are associated with a variety of thrombotic conditions,but their possible value in portal vein thrombosis(PVT)is not known.We aimed to establish an easy-to-use nomogram to predict portal vein thrombosis and assess whether NETs promote thrombosis and contribute to the procoagulant state in patients with liver cirrhosis.Methods:This retrospective study included patients with liver cirrhosis from January 2013 to January 2021 in the Affiliated Hospital of Qingdao University.Reputed systemic inflammatory markers(systemic immune-inflammation index [SII],neutrophil-to-lymphocyte ratio [NLR],monocyte-to-lymphocyte ratio [MLR],and platelet-to-lymphocyte ratio [PLR])were measured,and clinical data were recorded.The independent risk factors of PVT were determined with univariate analyses and multivariate logistic regression analyses,and a nomogram to predict the occurrence of PVT was established.The concordance index,receiver operating characteristic curves,and calibration plots were used to evaluate model performance.At the same time,the circulating levels of NETs markers(myeloperoxidase,neutrophil elastase,citrullinated histone H3)were measured in patients with liver cirrhosis from September 2020 to February 2021 in the Affiliated Hospital of Qingdao University.Then they were divided into two groups: patients with or without PVT.NETs procoagulant activity was assessed based on thrombin–antithrombin complex(TAT complex)and Factor X.The levels of plasma markers were determined by ELISA.Correlation analysis of coagulation indicators and NETs was performed to assess the procoagulant activity of NETs.Results:1.239 patients with PVT and 239 patients without PVT were selected.In the univariate analysis,high SII,NLR,PLR,MLR,APTT,TT,splenic vein diameter and splenic vein velocity were significantly associated with PVT.NLR ≥3.14,PLR ≥103.35,endoscopic ligation,D-dimer,splenectomy,splenic vein diameter and absence of autoimmune liver disease were independently associated with PVT by multivariate analysis(p<0.05).The nomogram had good predictive efficiency for predicting PVT in patients with cirrhosis,with concordance index of 0.891 and an area under the receiver operating characteristic(AUROC)curves of 0.891(95% CI 0.862–0.919).The calibration curves fit was well.2.There were 72 patients with liver cirrhosis were selected at all.28 patients with PVT and 44 patients without PVT.The levels of NETs markers(myeloperoxidase,neutrophil elastase,citrullinated histone H3),hypercoagulability markers(TAT complex and Factor X)and infectious markers(endotoxin and tissue factor)in the plasma of liver cirrhosis patients with PVT were significantly higher than those of without PVT(p<0.05).Additionally,the levels of the NETs markers correlated with TAT complex and Factor X(Spearman correlation rho > 0.73,p<0.0001).Conclusions:PVT in cirrhotic patients is associated with increased systemic inflammatory marker.We successfully developed a practical nomogram based on NLR and PLR to accurately predicted PVT.Additionally,NETs enhance procoagulant activity in liver cirrhosis patients with PVT;thus,they may be a practical predictor of PVT as well as a rapid and easy-to-use diagnostic and treatment guide for PVT in patients with cirrhosis.