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A soluble tissue factor mutant is a selective anticoagulant and antithrombotic agent
R F Kelley1, C J Refino, M P O'Connell
1Department of Protein Engineering, Genentech, Inc., South San Francisco, CA 94080, USA.
Blood
|May 1, 1997
Summary
Researchers developed mutant tissue factor (TF) inhibitors to target blood coagulation. These TF mutants showed antithrombotic effects in rabbits with reduced bleeding risk compared to heparin, indicating TF x FVIIa is a promising drug target.
Area of Science:
- Biochemistry
- Pharmacology
- Hematology
Background:
- Thrombotic diseases require safer anticoagulants.
- Inhibiting specific coagulation cascade steps is a key strategy.
- Tissue Factor (TF) and Factor VIIa (FVIIa) initiate extrinsic pathway coagulation.
Purpose of the Study:
- To develop and test a mutant human tissue factor (hTFAA) as a specific antagonist of the extrinsic coagulation pathway.
- To evaluate the antithrombotic efficacy and bleeding risk of hTFAA and its rabbit homologue (rTFAA) in a rabbit arterial thrombosis model.
Main Methods:
- Engineered soluble TF (sTF) with K165A:K166A mutations to create hTFAA.
- Assessed FX activation, prothrombin time (PT), and activated partial thromboplastin time (aPTT) in human and rabbit plasma.
- Tested antithrombotic effects and bleeding time in a rabbit arterial thrombosis model.
Main Results:
- hTFAA exhibited reduced catalytic efficiency for FX activation compared to wild-type sTF x FVIIa.
- hTFAA and rTFAA demonstrated antithrombotic effects in rabbits.
- rTFAA was more potent than hTFAA in rabbit plasma and achieved efficacy at a lower dose.
- Both mutants caused less bleeding than heparin at equivalent antithrombotic doses.
Conclusions:
- Mutant TF antagonists effectively inhibit the TF x FVIIa complex.
- TF x FVIIa is a viable target for developing novel anticoagulant therapies.
- These TF mutants offer a potentially safer alternative to existing anticoagulants like heparin.