Highlights
- •Alterations in hypercoagulability and fibrinolysis are not associated with ACLF development in individuals with AD.
- •CRP, CLIF-C AD score, and Child-Pugh stage were independent predictors of ACLF.
- •We developed and validated the Padua predictive score, which accurately identified individuals with AD at risk of ACLF.
- •CRP and progression to ACLF, but not coagulopathy, were associated with development of bleeding unrelated to portal hypertension.
- •CRP and antifibrinolytic factor PAI-1 >50 ng/ml were associated with development of venous thrombosis.
Background & Aims
Hypercoagulability and hypofibrinolysis in acutely decompensated cirrhosis (AD) may
be implicated in disease progression and haemostatic complications. We conducted a
prospective study to: (1) characterise haemostatic alterations in AD; (2) evaluate
whether such alterations can predict acute-on-chronic liver failure (ACLF) and bleeding/thrombosis.
Methods
Hospitalised individuals with AD were prospectively recruited and underwent an extensive
haemostatic profiling including coagulation factors, thrombomodulin-modified thrombin
generation assay with evaluation of endogenous thrombin potential (ETP; marker for
plasmatic hypercoagulability), fibrinolytic factors, and plasmin–antiplasmin complex
(fibrinolysis activation marker). Inflammation severity was assessed by C-reactive
protein (CRP). In part 1 of the study, we compared haemostasis in AD vs. controls (stable decompensated and compensated cirrhosis). In part 2 of the study,
we prospectively followed individuals with AD for 1 year and investigated predictors
of ACLF and bleeding/thrombosis.
Results
A total of 169 individuals with AD were recruited (median model for end-stage liver
disease score 20; CLIF-C AD 54). Compared with controls, AD was associated with more
pronounced hypercoagulability (ETP: 871 vs. 750 vs. 605 nmol/L per min; p <0.0001), without differences in fibrinolysis activation. During follow-up, 55 individuals
developed ACLF. CLIF-C AD, CRP, and Child-Pugh were independently associated with
ACLF. A predictive model combining these variables (Padua model) accurately identified
individuals at higher risk of ACLF (AUROC 0.857; 95% CI 0.798–0.915; sensitivity 74.5%,
specificity 83.3%). Notably, CRP and progression to ACLF, but not baseline coagulopathy,
were associated with bleeding (n = 11); CRP and antifibrinolytic factor PAI-1 >50 ng/ml
were associated with thrombosis (n = 14). The prognostic value of the Padua model
was validated in an independent, bicentric European cohort (N = 301).
Conclusions
Inflammation severity, and not coagulopathy, is the most important predictor of ACLF
and bleeding in AD. The Padua model can be used to identify individuals with AD at
risk of ACLF.
Impact and implications
A better understanding of haemostasis in individuals with acutely decompensated cirrhosis
may help to identify those at higher risk of progression and complications. In this
prospective study, we found no significant association between alterations of haemostasis
and cirrhosis progression, indicating that the assessment of haemostatic alterations
is not useful to identify those at risk. However, we found that C-reactive protein
(a simple blood test that reflects severity of inflammation) and severity of chronic
liver disease itself (as assessed by specific scores) were associated with cirrhosis
progression and development of bleeding complications. Therefore, we developed a simple
predictive model – based on C-reactive protein and liver disease scores – that, if
validated by independent studies, could be used in clinical practice to assist physicians
in identifying individuals with decompensated cirrhosis at higher risk of disease
progression and death (i.e. in whom to consider an expedited evaluation for liver transplantation).
Graphical abstract
Graphical Abstract
Keywords
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References
- Acute-on-chronic liver failure in cirrhosis.Nat Rev Dis Primers. 2016; 216041
- Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.Gastroenterology. 2013; 144: 1426-1437
- Patterns of acute decompensation in hospitalized patients with cirrhosis and course of acute-on-chronic liver failure.United Eur Gastroenterol J. 2021; 9: 427-437
- The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.J Hepatol. 2020; 73: 842-854
- Derangements of coagulation and fibrinolysis in critically ill patients with sepsis and septic shock.Semin Thromb Hemost. 1998; 24: 33-44
- Systemic inflammation and disorders of hemostasis in the AD-ACLF syndrome.J Hepatol. 2021; 74: 1264-1265
- The search for disease-modifying agents in decompensated cirrhosis: from drug repurposing to drug discovery.J Hepatol. 2021; 75: S118-S134
- Reply to: “Systemic inflammation and disorders of hemostasis in the AD-ACLF syndrome”.J Hepatol. 2021; 74: 1265-1267
- EASL Clinical Practice Guidelines for the management of patients with decompensated cirrhosis.J Hepatol. 2018; 69: 406-460
- Subcommittee on control of anticoagulation of the scientific and standardization committee of the international society on thrombosis and haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients.J Thromb Haemost. 2005; 3: 692-694
- Baveno VII - renewing consensus in portal hypertension.J Hepatol. 2022; 76: 959-974
- Reversal of hypercoagulability in patients with HCV-related cirrhosis after treatment with direct-acting antivirals.Liver Int. 2018; 38: 2210-2218
- Acute kidney injury in decompensated cirrhosis is associated with both hypo-coagulable and hyper-coagulable features.Hepatology. 2020; 72: 1327-1340
- Diagnosis and management of acute kidney injury in patients with cirrhosis: revised consensus recommendations of the International Club of Ascites.Gut. 2015; 64: 531-537
- Recent advances in the management of acute variceal hemorrhage.J Clin Med. 2021; 10: 3818
- Identifying the four shades of acute decompensation of cirrhosis.United Eur Gastroenterol J. 2021; 9: 421-422
- The systemic inflammation hypothesis: towards a new paradigm of acute decompensation and multiorgan failure in cirrhosis.J Hepatol. 2021; 74: 670-685
- Systemic inflammation increases across distinct stages of advanced chronic liver disease and correlates with decompensation and mortality.J Hepatol. 2021; 74: 819-828
- Amelioration of systemic inflammation in advanced chronic liver disease upon beta-blocker therapy translates into improved clinical outcomes.Gut. 2021; 70: 1758-1767
- Factor VIII/protein C ratio independently predicts liver-related events but does not indicate a hypercoagulable state in ACLD.J Hepatol. 2022; 76: 1090-1099
- More pronounced hypercoagulable state and hypofibrinolysis in patients with cirrhosis with versus without HCC.Hepatol Commun. 2021; 5: 1987-2000
- Increased platelet aggregation in patients with decompensated cirrhosis indicates higher risk of further decompensation and death.J Hepatol. 2022; 77: 660-669
- Mixed fibrinolytic phenotypes in decompensated cirrhosis and acute-on-chronic liver failure with hypofibrinolysis in those with complications and poor survival.Hepatology. 2020; 71: 1381-1390
- Coagulopathy is not predictive of bleeding in patients with acute decompensation of cirrhosis and acute-on-chronic liver failure.Liver Int. 2021; 41: 2455-2466
- Balanced haemostasis with both hypo- and hyper-coagulable features in critically ill patients with acute-on-chronic-liver failure.J Crit Care. 2018; 43: 54-60
- Global hemostatic profiling in patients with decompensated cirrhosis and bacterial infections.JHEP Rep. 2022 Apr 20; 4: 100493
- Staging the pre-procedural prophylaxis in decompensated cirrhosis.Dig Liver Dis. 2022; 54: 1130-1132
- EASL Clinical Practice Guidelines on prevention and management of bleeding and thrombosis in patients with cirrhosis.J Hepatol. 2022; 76: 1151-1184
- Coagulation parameters and major bleeding in critically ill patients with cirrhosis.Hepatology. 2016; 64: 556-568
- Prevalence of bleeding and thrombosis in critically ill patients with chronic liver disease.Thromb Haemost. 2022; 122: 1006-1016
- Haemostatic alterations in patients with cirrhosis and hepatocellular carcinoma: laboratory evidence and clinical implications.Liver Int. 2022; 42: 1229-1240
- Global hemostatic status in patients with acute-on-chronic liver failure and septics without underlying liver disease.J Thromb Haemost. 2021; 19: 85-95
- Thrombin generation and cirrhosis: state of the art and perspectives.Semin Thromb Hemost. 2020; 46: 693-703
- Whole blood thrombin generation profiles of patients with cirrhosis explored with a near patient assay.J Thromb Haemost. 2020; 18: 834-843
Article info
Publication history
Published online: September 20, 2022
Accepted:
September 6,
2022
Received in revised form:
September 2,
2022
Received:
May 30,
2022
Footnotes
Author names in bold designate shared co-first authorship
Identification
Copyright
© 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
