HEPATOLOGY, VOL. 73, NO. 1, 2021 Vascular Liver Disorders, Portal Vein Thrombosis, and Procedural Bleeding in Patients With Liver Disease: 2020 Practice Guidance by the American Association for the Study of Liver Diseases 1 2-4 5,6 1 7 Patrick G. Northup , Juan Carlos Garcia-Pagan , Guadalupe Garcia-Tsao, Nicolas M. Intagliata, Riccardo A. Superina, 8 9 10,11 Lara N. Roberts, Ton Lisman , and Dominique C. Valla hepatic venous systems in both patients with and New Features and Changes without cirrhosis along with thrombophilia testing recommendations. From the Previous American • A review of the strengths and weaknesses of the various classification systems for portal vein throm- Association for the Study of bosis and a proposal for standard nomenclature re- Liver Diseases Guidelines garding characterization of portal vein thrombosis location, time course, and progression. • An overview of the current understanding of bleed- • A comprehensive review of procedural and medical ing and thrombosis in cirrhosis. therapies for treatment of portal vein thrombosis in- • An evidence-based justification for bleeding risk as- cluding the use of direct oral anticoagulants. sessment in patients with cirrhosis before invasive • A step-by-step treatment and surveillance algorithm procedures, including current concepts in preproce- for portal vein thrombosis in patients with cirrhosis. dural testing and laboratory analysis and their role • Updated diagnostic, treatment, and management in predicting bleeding complications. recommendations for sinusoidal obstruction syn- • An outline of established and recently identified drome, hereditary hemorrhagic telangiectasia, and risk factors for venous thrombosis in the portal and hepatic vein thrombosis. Abbreviations: AASLD, American Association for the Study of Liver Diseases; ACLF, acute-on-chronic liver failure; AKI, acute kidney injury; aPTT, activated partial thromboplastin time; BCS, Budd-Chiari syndrome; CTP, Child-Turcotte-Pugh; DDAVP, 1-deamino-8-D-arginine vasopressin; DIPS, direct intrahepatic portosystemic shunt; DOAC, direct oral anticoagulant; EACA, epsilon-aminocaproic acid; EHPVO, extrahepatic portal vein obstruction; EVL, endoscopic variceal ligation; FDA, U.S. Food and Drug Administration; FFP, fresh frozen plasma; HA, hepatic artery; HAA, hepatic artery aneurysm; HHT, hereditary hemorrhagic telangiectasia; HV, hepatic vein; HVT, hepatic vein thrombosis; INCPH, idiopathic noncirrhotic portal hypertension; INR, international normalized ratio; IVC, inferior vena cava; LMWH, low-molecular-weight heparin; LT, liver transplantation; LVM, liver vascular malformation; PSVD, portosinusoidal vascular disease; PT, prothrombin time; PV, portal vein; PVR, portal vein recanalization; PVT, portal vein thrombosis; ROTEM, rotational thromboelastometry; SAA, splenic artery aneurysm; SOS, sinusoidal obstruction syndrome; TEG, thromboelastography; TIPS, transjugular intrahepatic portosystemic shunt; TIPS-PVR, transjugular intrahepatic portosystemic shunt-portal vein recanalization; tPA, tissue plasminogen activator; UFH, unfractionated heparin; VKA, vitamin K antagonist; VTE, venous thromboembolism; VWF, von Willebrand factor. Received November 16, 2020; accepted November 16, 2020. Funding for the development of this Practice Guidance was provided by the American Association for the Study of Liver Diseases. © 2020 by the American Association for the Study of Liver Diseases. 366 HEPATOLOGY, Vol. 73, No. 1, 2021 NORTHUP ET AL. • Classification and management recommendations as well as thrombosis, especially in the splanchnic for idiopathic noncirrhotic portal hypertension and vasculature. the portosinusoidal vascular disorders. This American Association for the Study of Liver • Surveillance and evaluation recommendations for Diseases (AASLD) Guidance provides a data-supported hepatic and splenic artery aneurysms. approach to the management of vascular liver disorders, • A review of the management issues in vascular liver portal (PVT) and hepatic vein thrombosis (HVT), disorders specific to children and guidance on early and procedural bleeding in patients with liver disease. intervention in extrahepatic portal vein obstruction It differs from AASLD Guidelines, which are sup- in children. ported by systematic reviews of the literature, formal rating of the quality of evidence and strength of the recommendations, and, if appropriate, meta-analysis of results using the Grading of Recommendations Preamble Assessment Development and Evaluation system. In Previous guidelines reviewing vascular disor- contrast, this document was developed by consen- (1-3) ders of the liver focused on thrombosis of large sus of an expert panel and provides guidance state- vessels, such as the portal vein (PV) and hepatic ments based on formal review and analysis of the vein (HV). However, increased understanding and literature on the topics with oversight provided by the research in hemostasis and bleeding in patients with AASLD Practice Guidelines Committee at all stages cirrhosis has led to more diagnostic and therapeutic of Guidance development. The AASLD Practice opportunities targeting prevention of bleeding, espe- Guidelines Committee chose to commission a guid- cially procedural bleeding. Therefore, this Guidance ance on this topic because a sufficient number of ran- covers bleeding related to disturbances in the hemo- domized controlled trials were not available to support static system predisposed by chronic liver disease the development of a meaningful guideline. View this article online at wileyonlinelibrary.com. DOI 10.1002/hep.31646 Potential conflict of interest: Dr. Valla consults for Galmed and Intercept. Dr. Garcia-Pagan consults for Cook Medical, Gore, Shionogi, and Vifor. He received grants from Conatus, Theravance, Exalenz, and Mallinckrodt. Dr. Intagliata received grants from Dova. Dr. Roberts received grants from Sanofi. ARTICLE INFORMATION: 1 From the Division of Gastroenterology and Hepatology, Center for the Study of Hemostasis in Liver Disease, University of 2 Virginia, Charlottesville, VA; Barcelona Hepatic Hemodynamic Laboratory, Liver Unit, Hospital Clinic, Institut d’Investigacions 3 Biomèdiques August Pi I i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain; Centro de Investigación Biomédica en 4 Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Barcelona, Spain; Health Care Provider of the European Reference 5 Network on Rare Liver Disorders (ERN RARE-Liver), Barcelona, Spain; Department of Internal Medicine, Section of Digestive 6 7 Diseases, Yale University, New Haven, CT; Veterans Administration Healthcare System, West Haven, CT; Department of Transplant 8 Surgery, Ann and Robert H. Lurie Children’s Hospital of Chicago, Chicago, IL; Department of Haematological Medicine, King’s 9 Thrombosis Centre, King’s College Hospital National Health Service (NHS) Foundation Trust, London, United Kingdom; Section of Hepatobiliary Surgery and Liver Transplantation, Surgical Research Laboratory, Department of Surgery, University Medical Centre 10 11 Groningen, University of Groningen, Groningen, the Netherlands; Hepatology Service, Hospital Beaujon, Clichy, France; Health Care Provider of the European Reference Network on Rare Liver Disorders (ERN RARE-Liver), Barcelona, Spain. ADDRESS CORRESPONDENCE AND REPRINT REQUESTS TO: Patrick G. Northup, M.D., M.H.S., F.A.A.S.L.D. 1215 Lee Street Division of Gastroenterology and Hepatology Charlottesville, VA 22908-0708 Center for the Study of Hemostasis in Liver Disease E-mail: [email protected] University of Virginia Tel.: +1-434-243-6246 367 NORTHUP ET AL. HEPATOLOGY, January 2021 pathways are disturbed in complex ways, such that Current Understanding of it is difficult to determine in an individual patient exactly where the balance is using currently available Coagulation and Hemostasis clinical tests. in Cirrhosis Traditional laboratory measures of coagulation, such as prothrombin time (PT), international normalized Patients with cirrhosis have multiple alterations (4) ratio (INR), and activated partial thromboplastin time in their hemostatic system. First, defective hepatic (aPTT), have proven inadequate and often misleading synthetic capacity results in decreased plasma lev- in the evaluation of hemostasis in cirrhosis because these els of coagulation factors, inhibitors of coagulation, measures only partially evaluate the hemostasis system and fibrinolytic factors. Second, circulating platelet and neglect the counterbalanced factors mentioned numbers are decreased because of a combination of above (Table 1). Global tests of hemostasis, including decreased thrombopoietin (TPO) synthesis, spleno- plasma-based thrombin generation tests, plasma-based megaly with sequestration, accelerated platelet turn- (5) fibrinolysis assays, and whole-blood viscoelastic tests of over, and decreased megakaryocyte production. clot formation, have been instrumental in developing the Third, plasma levels of hemostatic proteins that are current concept of rebalanced hemostasis. For example, primarily synthesized by endothelial cells are sub- (6) although traditional laboratory measures of coagulation stantially elevated. Fourth, low-grade intrahepatic may suggest a bleeding tendency, more advanced hemo- and/or systemic activation of the hemostatic system (7) stasis tests, including plasma-based thrombin generation results in consumption of hemostatic proteins. tests and whole-blood viscoelastic tests such as throm- Fifth, acquired disorders in platelet function