Plasminogen activator inhibitor is significantly elevated in liver transplant recipients with decompensated NASH cirrhosis

Abstract

BackgroundNon-alcoholic fatty liver disease is a prohaemostatic state with abnormal primary, secondary and tertiary haemostasis. Plasminogen activator inhibitor (PAI)-1 is the best-established marker for prohaemostasis in non-alcoholic fatty liver disease. While epidemiological studies demonstrate decompensated non-alcoholic steatohepatitis (NASH) cirrhosis patients have increased rates of venous thromboembolism, including portal vein thrombosis, mechanistic studies have focused exclusively on patients without or with compensated cirrhosis. We aimed to characterizecharacterise PAI-1 levels in decompensated NASH cirrhosis.MethodsPAI-1 level was measured in consecutive adult liver transplant recipients immediately prior to liver transplantation. Multivariable models were constructed using linear regression to assess factors related to PAI-1 level.ResultsForty-six subjects with mean age 57 (IQR 53–62) years and Model for Endstage Liver Disease (MELD) score of 34 (IQR 30–40) were enrolled. Baseline characteristics were similar between NASH (n=10) and non-NASH (n=36) subjects except for rates of diabetes and hyperlipidaemia. Mean PAI-1 level was greater in NASH (53.9, 95% CI 33.3 to 74.5 mg/mL) when compared with non-NASH (36.1, 95% CI 28.7 to 43.5), p=0.040. NASH remained independently predictive of PAI-1 level prior to transplant on adjusted multivariable modelling (β 40.13, 95% CI 14.41 to 65.86, p=0.003). Conclusions: PAI-1 level is significantly elevated in decompensated NASH cirrhosis independent of other pro-haemostatic factors. This may explain the greater rates of venous thromboembolism in decompensated NASH cirrhosis. Future study focusing on prevention of venous thromboembolism in this population is paramount to improve patient-oriented outcomes given the high morbidity and mortality of venous thromboembolism and the significant impact it has on transplant candidacy.

Serum proteomic profiling of patients with compensated advanced chronic liver disease with and without clinically significant portal hypertension

“…Thus, abundance of these proteins might be considered protective against worsening PH [ 50 , 52 ]. PAI-1 that was identified in the serum of CSPH group of patients in our study goes in hand with the role of reactive endothelium, culminating in hemodynamic and haemostatic changes in individuals with elevated portal pressure ( Fig 6 ) [ 26 , 34 ]. PAI-1 promotes thrombotic risk and can aggravate liver disease and PH by local ischemia and microthrombus formation [ 26 ].…”

“…PAI-1 that was identified in the serum of CSPH group of patients in our study goes in hand with the role of reactive endothelium, culminating in hemodynamic and haemostatic changes in individuals with elevated portal pressure ( Fig 6 ) [ 26 , 34 ]. PAI-1 promotes thrombotic risk and can aggravate liver disease and PH by local ischemia and microthrombus formation [ 26 ]. NETs might also contribute to intrahepatic circulatory disturbance by promoting platelet aggregation, resulting in microthrombosis, congestion and subsequent parenchymal extinction [ 55 , 56 ].…”

Cellular Factors Involved in the Hepatitis D Virus Life Cycle

“…For instance, TGF-β induces the expression of plasmogen-activator inhibitor type-1 (PAI-1), which in term inhibits fibronylisis. Thus, the overexpression of PAI-1 is associated with hepatic fibrosis and cirrhosis [ 263 , 264 , 265 ]. According to Choi et al, the protein expression of PAI-1 in TGF-β-stimulated Huh7 cells was markedly increased upon expression of L-HDAg, revealing yet another mechanism for HDV pathogenicity.…”

Extracellular vesicles from periodontal pathogens regulate hepatic steatosis via Toll‐like receptor 2 and plasminogen activator inhibitor‐1

“…Plasminogen activator inhibitor‐1 (PAI‐1) is a well‐known regulator of the fibrinolysis system (Targher et al., 2008 ) and is produced by various cell types, including hepatocytes, vascular endothelial cells, and adipocytes (Alessi et al., 1997 ; Busso et al., 1994 ; Erickson et al., 1985 ). PAI‐1 has received attention for its roles in metabolic syndrome (Alessi et al., 2003 ; Alessi & Juhan‐Vague, 2006 ) and has been shown to be an independent risk factor for NAFLD progression (Alsharoh et al., 2022 ; Levine et al., 2021 ; Rivas et al., 2021 ). Patients with NAFLD showed elevated PAI‐1 serum levels compared to healthy people.…”