Caspase Inhibition Reduces Hepatic Tissue Factor-Driven Coagulation In Vitro and In Vivo.

Area of Science:

• Hepatology
• Hematology
• Biochemistry

Background:

• Tissue factor (TF) is a key initiator of blood coagulation.
• Hepatocytes express TF, but it typically lacks procoagulant activity.
• Hepatocyte apoptosis, common in liver diseases, can enhance TF procoagulant activity.

Purpose of the Study:

• To investigate the effect of a pan-caspase inhibitor (IDN-7314) on hepatocyte TF activity.
• To assess the impact of IDN-7314 on TF-mediated coagulation in vivo during apoptotic liver injury.

Main Methods:

• Primary mouse hepatocytes were treated with Fas ligand (Jo2) with or without IDN-7314.
• TF procoagulant activity and TF-positive microvesicle release were measured.
• Wild-type mice received Jo2 and IDN-7314 to evaluate coagulation and liver injury markers.

Main Results:

• Jo2 induced hepatocyte TF activity and microvesicle release, which was reduced by IDN-7314.
• In mice, Jo2 increased coagulation markers and fibrin deposition; IDN-7314 pretreatment mitigated these effects.
• IDN-7314 reduced caspase activation, hepatocellular injury, and procoagulant changes in Jo2-treated mice.

Conclusions:

• Caspase activity plays a critical role in TF-mediated coagulation following apoptotic liver injury.
• Liver-selective caspase inhibition could be a therapeutic strategy for prothrombotic conditions in chronic liver disease.