“The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study”: comment from Liu et al.

We read with great interest the study by Driever et al. [1Driever E.G. Magaz M. Adelmeijer J. Turon F. Baiges A. Olivas P. Pérez-Campuzano V. Hernandez-Gea V. Blasi A. Garcia-Pagan J.C. Lisman T. The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study.J Thromb Haemost. 2022; 20: 2075-2082Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] exploring whether the portal vein (PV) in cirrhotic patients has particular proinflammatory or hypercoagulable characteristics that may contribute to portal vein thrombosis (PVT) development. They found no elevated levels of markers of endotoxemia, inflammation, and activation of hemostasis in the PV, which is in contrast to published studies [2Praktiknjo M. Trebicka J. Carnevale R. Pastori D. Queck A. Ettorre E. Violi F. Von Willebrand and factor VIII portosystemic circulation gradient in cirrhosis: implications for portal vein thrombosis.Clin Transl Gastroenterol. 2020; 11e00123Crossref PubMed Scopus (32) Google Scholar,3Kalambokis G.N. Oikonomou A. Christou L. Baltayiannis G. High von Willebrand factor antigen levels and procoagulant imbalance may be involved in both increasing severity of cirrhosis and portal vein thrombosis.Hepatology. 2016; 64: 1383-1385Crossref PubMed Scopus (19) Google Scholar]. In their study, we noticed that PVT was present in only 6 patients. Our study aimed to explore whether proinflammatory characteristics in either PVs or peripheral veins are associated with the presence of PVT. This was a retrospective case-control study, and we enrolled cirrhotic patients with PVT and portal hypertensive complications who underwent the transjugular intrahepatic portosystemic shunt (TIPS) procedure and consented to have their blood sample collected between November 2018 and September 2020. Cirrhotic patients undergoing TIPS without PVT were matched based on Child–Pugh class during the same period. Exclusion criteria were as follows: i) undergoing TIPS due to acute variceal bleeding, ii) blood-product transfusion before TIPS, iii) uncontrolled infection before TIPS, iv) presence of malignancies, and v) blood samples unavailable. Platelet-poor plasma was successfully collected from the PVs and jugular veins. Plasma levels of lipopolysaccharide (LPS), cell-free DNA, complexes of myeloperoxidase with DNA, and von Willebrand factor (VWF) were measured as described before [2Praktiknjo M. Trebicka J. Carnevale R. Pastori D. Queck A. Ettorre E. Violi F. Von Willebrand and factor VIII portosystemic circulation gradient in cirrhosis: implications for portal vein thrombosis.Clin Transl Gastroenterol. 2020; 11e00123Crossref PubMed Scopus (32) Google Scholar,4Blasi A. Patel V.C. Adelmeijer J. Azarian S. Aziz F. Fernández J. Bernal W. Lisman T. Plasma levels of circulating DNA are associated with outcome, but not with activation of coagulation in decompensated cirrhosis and ACLF.JHEP Rep. 2019; 1: 179-187Abstract Full Text Full Text PDF PubMed Scopus (27) Google Scholar]. A total of 15 patients with PVT who underwent TIPS due to portal hypertensive complications were included in this study. Hence, 15 patients undergoing TIPS without PVT during the same period were matched based on the Child–Pugh class. The baseline characteristics of the included patients are summarized in Supplementary Table S1. The entire study population had a median age of 53 years (IQR, 48-65 years) and was predominantly male (n = 24, 80%), with a median Child–Pugh score of 8 (IQR, 6-9). The most common etiology of cirrhosis was viral hepatitis B (n = 22, 73.3%), and most patients (83.3%) underwent TIPS for the prevention of variceal rebleeding. The median Child–Pugh scores were not significantly different between patients with PVT and those without. Patients with PVT had a higher portal-systemic pressure gradient before TIPS (P < .05). We compared the portal and peripheral levels of LPS, cell-free DNA, complexes of myeloperoxidase with DNA, and VWF between patients with PVT and those without. We found that plasma levels of these factors were similar between the 2 groups either in the PV or in the jugular vein (Figure). In addition, no significant differences were observed in the levels of these proinflammatory factors between the jugular vein and the PV in our cohort (Supplementary Figure S1). Previous studies reported that several proinflammatory factor levels were higher in the PV than in systemic circulation, and increased factors, such as LPS levels, were significantly correlated with the levels of VWF, the marker of endothelial damage. However, excessive local inflammation in the PV was not observed in the study by Driever et al. [1Driever E.G. Magaz M. Adelmeijer J. Turon F. Baiges A. Olivas P. Pérez-Campuzano V. Hernandez-Gea V. Blasi A. Garcia-Pagan J.C. Lisman T. The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study.J Thromb Haemost. 2022; 20: 2075-2082Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar] and our study. It might be explained by preexisting intrahepatic shunting, which was reported to be the predictor for hepatic encephalopathy after TIPS [5Dantas Machado A.C. Ramos S.F. Gauglitz J.M. Fassler A.M. Petras D. Aksenov A.A. Kim U.B. Lazarowicz M. Barnard Giustini A. Aryafar H. Vodkin I. Warren C. Dorrestein P.C. Zarrinpar A. Zarrinpar A. Portosystemic shunt placement reveals blood signatures for the development of hepatic encephalopathy through mass spectrometry.Nat Commun. 2023; 14: 5303Crossref PubMed Scopus (2) Google Scholar]. During chronic liver disease, vascular remodeling occurs in hepatic sinusoids due to local inflammation, oxidative stress, shear stress, and hypoxia, leading to portal toxins bypassing the hepatic cells and entering into systemic circulation [6Coulon S. Heindryckx F. Geerts A. Van Steenkiste C. Colle I. Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications.Liver Int. 2011; 31: 146-162Crossref PubMed Scopus (234) Google Scholar]. In addition, differences in the etiology of cirrhosis might have an influence on testing results. The major etiology of cirrhosis was viral hepatitis B in our study; moreover, our previous study revealed that patients with viral-induced cirrhosis displayed lower levels of proinflammatory cytokines than those displayed by patients with nonviral cirrhosis, which might be attributed to the difference in pathogenesis [7Liu G. Wang X. Yang T. Yan Y. Xiang T. Yang L. Luo X. High interleukin-8 levels associated with decreased survival in patients with cirrhosis following transjugular intrahepatic portosystemic shunt.Front Med (Lausanne). 2022; 9829245Google Scholar]. Disruption of gut permeability with consequent bacterial translocation may contribute to proinflammatory status, which has been reported to be associated with hypercoagulability in patients with cirrhosis [8Carnevale R. Raparelli V. Nocella C. Bartimoccia S. Novo M. Severino A. De Falco E. Cammisotto V. Pasquale C. Crescioli C. Scavalli A.S. Riggio O. Basili S. Violi F. Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. Implications for hypercoagulability in cirrhosis.J Hepatol. 2017; 67: 950-956Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar]. Huang et al. [9Huang X. Fan X. Zhang R. Jiang S. Yang K. Chen S. Systemic inflammation and portal vein thrombosis in cirrhotic patients with gastroesophageal varices.Eur J Gastroenterol Hepatol. 2020; 32: 401-405Crossref PubMed Scopus (44) Google Scholar] investigated the association between peripheral inflammatory biomarker levels and the presence of PVT, and they found that patients with PVT had elevated proinflammatory cytokine levels. Of note, higher Child–Pugh scores in the PVT group in their study might have an impact on inflammatory status itself [9Huang X. Fan X. Zhang R. Jiang S. Yang K. Chen S. Systemic inflammation and portal vein thrombosis in cirrhotic patients with gastroesophageal varices.Eur J Gastroenterol Hepatol. 2020; 32: 401-405Crossref PubMed Scopus (44) Google Scholar]. In our study, no increased inflammatory factor levels in the portal or peripheral blood were observed in patients with PVT when 2 groups were matched by the Child–Pugh class. Moreover, in a recent large prospective study, Turon et al. [10Turon F. Driever E.G. Baiges A. Cerda E. García-Criado Á. Gilabert R. Bru C. Berzigotti A. Nuñez I. Orts L. Reverter J.C. Magaz M. Camprecios G. Olivas P. Betancourt-Sanchez F. Perez-Campuzano V. Blasi A. Seijo S. Reverter E. Bosch J. et al.Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and hemostatic factors.J Hepatol. 2021; 75: 1367-1376Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar] found that only factors related to the severity of portal hypertension, instead of hemostatic disorders, and inflammatory status mainly predict the development of PVT in patients with cirrhosis. Although baseline inflammatory status seemed to not play a key role in the development of PVT, it cannot be excluded that acute inflammatory response may play a role in the formation of PVT, which needs to be elucidated in the future. Similar to the study by Driever et al. [1Driever E.G. Magaz M. Adelmeijer J. Turon F. Baiges A. Olivas P. Pérez-Campuzano V. Hernandez-Gea V. Blasi A. Garcia-Pagan J.C. Lisman T. The portal vein in patients with cirrhosis is not an excessively inflammatory or hypercoagulable vascular bed, a prospective cohort study.J Thromb Haemost. 2022; 20: 2075-2082Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar], compared with peripheral levels, we found no elevated inflammatory status in the PV. Additionally, when matched by the Child–Pugh class, no significant difference in portal and peripheral inflammatory status was observed between patients with PVT and patients without PVT in our study. However, relatively few patients were enrolled and only a few inflammatory factors were measured in our study. Hence, a large cohort and comprehensive procoagulant and inflammatory profiles are needed to assess the roles of inflammation and hypercoagulability in PVT. G.L. and X.W. performed experiments, analyzed data, discussed results, and wrote the manuscript. X.L. performed study concept and design. There are no competing interests to disclose. 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