Background: Cirrhosis-related coagulation derangements result in altered hemostasis, and hypercoagulability markers such as von Willebrand factor (VWF) antigen and the factor VIII-to-protein C ratio (FVIII/PC) have prognostic significance. We sought to use plasma proteomic profiling to characterize plasma protein signatures in alcoholic versus non-alcoholic cirrhosis, and to identify protein biomarkers of prognostic significance associated with hypercoagulability of alcohol-associated cirrhosis.

Aims: To characterize and differentiate plasma protein signatures in alcohol versus non-alcoholic cirrhosis, with a focus on VWF and FVIII/PC in alcohol-associated cirrhosis.

Methods: Thirteen patients with alcohol-associated cirrhosis (4 Child-Pugh Class A, 9 Class C), 7 with non-alcoholic steatohepatitis (NASH) cirrhosis (4 Class A, 3 Class C), and 5 controls without cirrhosis were recruited between April and June 2021 with informed consent and Institutional Review Board approval. Blood was drawn and plasma sent for proteomic profiling (Eve Technologies). Proteomic profiles were compared using pairwise t-test and Wilcoxon rank sum test, identifying proteins that best clustered groups with linear discriminant analysis using Wilk’s Lambda criteria. Boruta feature selection was performed to identify candidate proteins associated with VWF antigen or FVIII/PC in alcohol-associated cirrhosis. Statistical analysis was performed using R (v4, R Core Team); P-values < 0.05 were considered statistically significant.

Results: Of study patients, 9 were female; 17 had cardiovascular risk factors and 3 chronic kidney disease. Eleven proteins involved in inflammation, complement activation, or endothelial activation uniquely segregated alcohol-associated cirrhosis, NASH cirrhosis, and controls (Figure 1). Several plasma proteins were significantly associated with VWF antigen or FVIII/PC in alcohol-associated cirrhosis (Figure 2).

Conclusion(s): Plasma proteomic profiling identifies unique complement, inflammation, and endothelial activation signatures in alcohol-associated versus NASH cirrhosis. Endotheliopathy may contribute to the prognostic value of VWF antigen and FVIII/PC in alcohol-associated cirrhosis. Further investigations may highlight the interconnection of complement and inflammation with the endothelium in the pathogenesis and coagulopathy of cirrhosis.

Figure 1. Clustering based on selected proteomic features.

Linear discriminant -LD- based on Wilk’s Lambda criteria and linear regression analysis with proteins that best clustered groups of patients based on etiology of cirrhosis. Each point represents a patient and the unique profiling for the following proteins: soluble vascular cell adhesion molecule -1 -sVCAM1-, interleukin 17A -IL-17A-, Follistatin, plasminogen activator inhibitor-1 -PAI-1-, Brain-derived neurotrophic factor -BDNF-, tumor necrosis factor a -TNFa-, complement 3 and 3b -c 3, c3b-, serum amyloid A -SAA-, complement component 4 -C4-, and Bone Morphogenetic Protein -BMP9-.

Figure 2. Boruta-selected proteins of importance for distinguishing A- FVIII/Protein C Ratio and B- vWF Ag.

Complement component 5 -C5-, macrophage inflammatory protein-1d -MIP-d-, complement component 3 -C3-, plasminogen activator inhibitor-1 -PAI-1-, soluble vascular cell adhesion molecule -1 -sVCAM1-, macrophage-derived chemokine -MDC-, interleukin 7 -IL-7- .

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ISTH Congress Abstracts - https://abstracts.isth.org/abstract/unique-protein-profiles-with-inflammatory-complement-and-endothelial-activation-signature-identified-patients-with-alcohol-associated-and-non-alcoholic-steatohepatitis-associated-cirrhosis/