Download PDF
Thromb Haemost 2023; 123(07): 714-722
DOI: 10.1055/a-2052-9381
Stroke, Systemic or Venous Thromboembolism

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

Siyu Jiang   *
1   Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
,
Yingjie Ai   *
1   Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
,
Xiaowen Fan   *
2   Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Florida, Gainesville, Florida, United States
,
Xiaoquan Huang
1   Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
,
Ling Wu
1   Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
,
Liyuan Ni
1   Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
,
Feng Li
1   Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
,
Shiyao Chen
1   Department of Gastroenterology and Hepatology, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
3   Endoscopy Center and Endoscopy Research Institute, Zhongshan Hospital, Fudan University, Shanghai, P. R. China
› Author Affiliations Funding This study was supported by Shanghai Sailing Program (No. 19YF1406500), the National Natural Science Foundation of China (No. 81900511), and Zhongshan Hospital Foundation (No. 2021ZSYQ03). The funders played no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.
› Further Information
    Permissions and Reprints


Abstract

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.

Keywords

cirrhosis - portal vein thrombosis - coagulation FVIII - portal hypertension - prognosis

Ethical Statement

Ethics Committee of Zhongshan Hospital of Fudan University approved the study protocol (B2015–133R). The study was conducted in accordance with the Helsinki Declaration as revised in 2013. Informed consent was obtained from all participants.


Data Availability Statement

All data included in this study are available upon request by contact with the corresponding author.


Authors' Contribution

S.J. analyzed, interpreted the data, and drafted the manuscript. Y.A. and X.F. undertook data analysis and revised the manuscript. X.H. conceived the study, collected and interpreted the data, and revised the manuscript. L.W. and L.N. helped with the data collection and analysis. F.L. helped with data interpretation and the revision of the manuscript. S.C. conceived the study and performed the critical revision of the manuscript. All authors were involved in the critical revision of the manuscript for important intellectual content.


* Siyu Jiang, Yingjie Ai, and Xiaowen Fan contributed equally to this manuscript.


Supplementary Material



Publication History

Received: 04 December 2022

Accepted: 01 March 2023

Accepted Manuscript online:
13 March 2023

Article published online:
04 April 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Nery F, Chevret S, Condat B. et al; Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. Causes and consequences of portal vein thrombosis in 1,243 patients with cirrhosis: results of a longitudinal study. Hepatology 2015; 61 (02) 660-667
    CrossrefPubMedGoogle Scholar
  • 2 Violi F, Corazza GR, Caldwell SH. et al; PRO-LIVER Collaborative Group. Incidence and recurrence of portal vein thrombosis in cirrhotic patients. Thromb Haemost 2019; 119 (03) 496-499
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Senzolo M, Garcia-Tsao G, García-Pagán JC. Current knowledge and management of portal vein thrombosis in cirrhosis. J Hepatol 2021; 75 (02) 442-453
    CrossrefPubMedGoogle Scholar
  • 4 Intagliata NM, Caldwell SH, Tripodi A. Diagnosis, development, and treatment of portal vein thrombosis in patients with and without cirrhosis. Gastroenterology 2019; 156 (06) 1582.e1-1599.e1
    CrossrefPubMedGoogle Scholar
  • 5 Qi XS, Dai JN, Yang M, Ren WR, Jia J, Guo XZ. Association between portal vein thrombosis and survival in non-liver-transplant patients with liver cirrhosis: a systematic review of the literature. Gastroent Res Pract 2015; 2015: 480842
    PubMedGoogle Scholar
  • 6 Violi F, Ferro D, Basili S. et al. Ongoing prothrombotic state in the portal circulation of cirrhotic patients. Thromb Haemost 1997; 77 (01) 44-47
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Praktiknjo M, Trebicka J, Carnevale R. et al. Von Willebrand and factor VIII portosystemic circulation gradient in cirrhosis: implications for portal vein thrombosis. Clin Transl Gastroenterol 2020; 11 (02) e00123
    CrossrefPubMedGoogle Scholar
  • 8 Stine JG, Wang J, Shah PM. et al. Decreased portal vein velocity is predictive of the development of portal vein thrombosis: a matched case-control study. Liver Int 2018; 38 (01) 94-101
    CrossrefPubMedGoogle Scholar
  • 9 Xu X, Guo X, De Stefano V. et al. Nonselective beta-blockers and development of portal vein thrombosis in liver cirrhosis: a systematic review and meta-analysis. Hepatol Int 2019; 13 (04) 468-481
    CrossrefPubMedGoogle Scholar
  • 10 Mannully ST, L NR, Pulicherla KK. Perspectives on progressive strategies and recent trends in the production of recombinant human factor VIII. Int J Biol Macromol 2018; 119: 496-504
    CrossrefPubMedGoogle Scholar
  • 11 Tripodi A, Mannucci PM. The coagulopathy of chronic liver disease. N Engl J Med 2011; 365 (02) 147-156
    CrossrefPubMedGoogle Scholar
  • 12 Martinelli I, Primignani M, Aghemo A. et al. High levels of factor VIII and risk of extra-hepatic portal vein obstruction. J Hepatol 2009; 50 (05) 916-922
    CrossrefPubMedGoogle Scholar
  • 13 Rietveld IM, Lijfering WM, le Cessie S. et al. High levels of coagulation factors and venous thrombosis risk: strongest association for factor VIII and von Willebrand factor. J Thromb Haemost 2019; 17 (01) 99-109
    CrossrefPubMedGoogle Scholar
  • 14 Yerdel MA, Gunson B, Mirza D. et al. Portal vein thrombosis in adults undergoing liver transplantation: risk factors, screening, management, and outcome. Transplantation 2000; 69 (09) 1873-1881
    CrossrefPubMedGoogle Scholar
  • 15 Ma J, Yan Z, Luo J, Liu Q, Wang J, Qiu S. Rational classification of portal vein thrombosis and its clinical significance. PLoS One 2014; 9 (11) e112501
    CrossrefPubMedGoogle Scholar
  • 16 Bauer J, Johnson S, Durham J. et al. The role of TIPS for portal vein patency in liver transplant patients with portal vein thrombosis. Liver Transpl 2006; 12 (10) 1544-1551
    CrossrefPubMedGoogle Scholar
  • 17 de Franchis R, Bosch J, Garcia-Tsao G. et al. Baveno VII – renewing consensus in portal hypertension. J Hepatol 2022; 76 (04) 959-974
    CrossrefPubMedGoogle Scholar
  • 18 Weinberg EM, Palecki J, Reddy KR. Direct-acting oral anticoagulants (DOACs) in cirrhosis and cirrhosis-associated portal vein thrombosis. Semin Liver Dis 2019; 39 (02) 195-208
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Villa E, Cammà C, Marietta M. et al. Enoxaparin prevents portal vein thrombosis and liver decompensation in patients with advanced cirrhosis. Gastroenterology 2012; 143 (05) 1253-1260 .e4
    CrossrefPubMedGoogle Scholar
  • 20 Sarin SK, Philips CA, Kamath PS. et al. Toward a comprehensive new classification of portal vein thrombosis in patients with cirrhosis. Gastroenterology 2016; 151 (04) 574.e3-577.e3
    CrossrefPubMedGoogle Scholar
  • 21 Rugivarodom M, Charatcharoenwitthaya P. Nontumoral portal vein thrombosis: a challenging consequence of liver cirrhosis. J Clin Transl Hepatol 2020; 8 (04) 432-444
    PubMedGoogle Scholar
  • 22 Turon F, Driever EG, Baiges A. et al. Predicting portal thrombosis in cirrhosis: a prospective study of clinical, ultrasonographic and hemostatic factors. J Hepatol 2021; 75 (06) 1367-1376
    CrossrefPubMedGoogle Scholar
  • 23 Anton A, Campreciós G, Pérez-Campuzano V, Orts L, García-Pagán JC, Hernández-Gea V. The pathophysiology of portal vein thrombosis in cirrhosis: getting deeper into Virchow's triad. J Clin Med 2022; 11 (03) 800
    CrossrefPubMedGoogle Scholar
  • 24 Scheiner B, Balcar L, Nussbaumer RJ. et al. Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD. J Hepatol 2022; 76 (05) 1090-1099
    CrossrefPubMedGoogle Scholar
  • 25 Driever EG, Magaz M, Adelmeijer J. et al. 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 (09) 2075-2082
    CrossrefPubMedGoogle Scholar
  • 26 La Mura V, Tripodi A, Tosetti G. et al. Resistance to thrombomodulin is associated with de novo portal vein thrombosis and low survival in patients with cirrhosis. Liver Int 2016; 36 (09) 1322-1330
    CrossrefPubMedGoogle Scholar
  • 27 Gîrleanu I, Trifan A, Stanciu C, Sfarti C. Portal vein thrombosis in cirrhotic patients - it is always the small pieces that make the big picture. World J Gastroenterol 2018; 24 (39) 4419-4427
    CrossrefPubMedGoogle Scholar
  • 28 Ferlitsch M, Reiberger T, Hoke M. et al. von Willebrand factor as new noninvasive predictor of portal hypertension, decompensation and mortality in patients with liver cirrhosis. Hepatology 2012; 56 (04) 1439-1447
    CrossrefPubMedGoogle Scholar
  • 29 Raffa S, Reverter JC, Seijo S. et al. Hypercoagulability in patients with chronic noncirrhotic portal vein thrombosis. Clin Gastroenterol Hepatol 2012; 10 (01) 72-78
    CrossrefPubMedGoogle Scholar
  • 30 Tripodi A, Primignani M, Lemma L. et al. Detection of the imbalance of procoagulant versus anticoagulant factors in cirrhosis by a simple laboratory method. Hepatology 2010; 52 (01) 249-255
    CrossrefPubMedGoogle Scholar
  • 31 Carnevale R, Raparelli V, Nocella C. et al. Gut-derived endotoxin stimulates factor VIII secretion from endothelial cells. implications for hypercoagulability in cirrhosis. J Hepatol 2017; 67 (05) 950-956
    CrossrefPubMedGoogle Scholar