Coagulation Mechanisms in Hepatic Fibrosis

Hepatic fibrosis arises from chronic liver injury and is characterised by excessive deposition of extracellular matrix driven by activated hepatic stellate cells. Beyond its role in arresting bleeding, the coagulation cascade contributes directly to fibrogenesis. Key coagulation proteases such as thrombin and factor Xa engage protease-activated receptors on stellate cells and sinusoidal endothelial cells, promoting cell contraction, proliferation and secretion of collagen. Microvascular thrombosis within the sinusoidal network exacerbates parenchymal hypoxia and inflammatory signalling, further amplifying fibrotic activation. Components of the fibrinolytic system, including thrombin-activatable fibrinolysis inhibitor and plasma kallikrein, modulate the balance between matrix deposition and clearance, shaping the microenvironment. Crosstalk between coagulation factors and cytokine-mediated pathways—for example, transforming growth factor-β/Smad signalling—underpins the transition from acute repair to chronic scarring. Understanding these interconnected mechanisms has prompted evaluation of antiplatelet and anticoagulant strategies, as well as targeted inhibitors of protease-activated receptors, in preclinical and clinical settings.

Research from Nature Portfolio

Recent work has demonstrated that antagonism of protease-activated receptor-2 markedly attenuates experimental liver fibrosis. Administration of a selective PAR-2 inhibitor in a toxin-induced model led to significant reductions in alanine aminotransferase and aspartate aminotransferase activities, collagen deposition and α-smooth muscle actin expression. Mechanistic studies revealed downregulation of TGF-β1/Smad2/3 phosphorylation in hepatic stellate cells, indicating that blockade of PAR-2 interrupts a central profibrotic signalling axis and offers a promising antifibrotic strategy for translation.

Coagulation Mechanisms in Hepatic Fibrosis publication trend

The graph below shows the total number of articles in coagulation mechanisms in hepatic fibrosis across all publications each year (not limited to Nature Index journals).

Technical terms

Hepatic stellate cells (HSCs): Perisinusoidal cells that, when activated by injury signals, transform into myofibroblast-like cells and secrete extracellular matrix.

Protease-activated receptors (PARs): G-protein-coupled receptors cleaved and activated by coagulation proteases such as thrombin and factor Xa, triggering intracellular profibrotic pathways.

Microvascular thrombosis: Formation of small clots within the liver’s sinusoidal network, contributing to hypoxia, inflammation and stellate cell activation.

Extracellular matrix (ECM): A complex network of collagen, fibronectin and other proteins deposited by activated stellate cells during fibrosis.

Fibrinolysis: The enzymatic breakdown of fibrin clots, modulated by factors such as thrombin-activatable fibrinolysis inhibitor and plasmin.

References

1. Coagulation, Microenvironment and Liver Fibrosis. Cells (2018).
2. Thrombin and factor Xa link the coagulation system with liver fibrosis. BMC Gastroenterology (2018).
3. Microvascular Thrombosis and Liver Fibrosis Progression: Mechanisms and Clinical Applications. Cells (2023).
4. ENMD-1068 inhibits liver fibrosis through attenuation of TGF-β1/Smad2/3 signaling in mice. Scientific Reports (2017).
5. Plasma Kallikrein as a Modulator of Liver Injury/Remodeling. Frontiers in Pharmacology (2021).