Antithrombotic Therapy on Antithrombin Resistance in a Mouse Model

Area of Science:

• Hematology
• Thrombosis Research
• Pharmacology

Background:

• Antithrombin resistance (ATR) is a genetic condition leading to thrombotic predisposition.
• It stems from abnormal prothrombin (FII) with reduced binding affinity to antithrombin (AT).
• Limited data exist on anticoagulant efficacy in ATR patients.

Purpose of the Study:

• To develop and validate mouse models for studying ATR.
• To investigate the efficacy of various anticoagulants in ATR models.
• To understand the antithrombotic effects of anticoagulants targeting thrombin (FIIa).

Main Methods:

• Generated knock-in mice expressing human FII R596L equivalent (FII R593L).
• Confirmed ATR characteristics via blood coagulation analysis.
• Assessed thrombotic tendency using an inferior vena cava stenosis model.
• Evaluated anticoagulants: unfractionated heparin, LMWH, pentasaccharide, and DOACs.

Main Results:

• ATR model mice (R593L Homo/Hetero) showed reduced FII levels but confirmed ATR properties.
• Significantly increased thrombus formation was observed in ATR mice compared to wild-type.
• Anticoagulants with anti-FIIa activity demonstrated higher efficacy in R593L mice.

Conclusions:

• FII R593L knock-in mice accurately model ATR and exhibit a strong thrombotic tendency.
• Anticoagulants targeting FIIa are highly effective in managing ATR-related thrombosis.