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Experimental studies on a recombinant hirudin, CGP 39393
1National Institute for Biological Standards and Control, South Mimms, Potters Bar, Hertfordshire, UK.
Thrombosis and Haemostasis
|April 8, 1991
Summary
Recombinant desulphatohirudin (r-hirudin) effectively inhibits thrombus formation in rabbits. Careful dosing is crucial to balance antithrombotic effects and avoid prolonged bleeding times.
Area of Science:
- Biochemistry
- Pharmacology
- Hematology
Background:
- Recombinant desulphatohirudin (r-hirudin) is a potent anticoagulant.
- Understanding its in vitro and in vivo efficacy is crucial for therapeutic development.
Purpose of the Study:
- To evaluate the in vitro anticoagulant activities of r-hirudin.
- To assess the antithrombotic and bleeding effects of r-hirudin in vivo.
Main Methods:
- In vitro studies using activated partial thromboplastin time (APTT) and thrombin generation tests.
- In vivo assessment using a rabbit venous stasis model for antithrombotic effect.
- In vivo bleeding time assessment using a rabbit ear template model.
Main Results:
- R-hirudin demonstrated dose-dependent anticoagulation in APTT assays, with plasma becoming unclottable above 5 µg/ml.
- Full inhibition of thrombin generation required at least 10 µg/ml of r-hirudin.
- A dose of 150 µg/kg r-hirudin completely prevented thrombus formation in rabbits without prolonging bleeding time.
- Higher doses of r-hirudin led to increased bleeding time ratios compared to heparin.
Conclusions:
- R-hirudin exhibits significant in vitro anticoagulant and in vivo antithrombotic properties.
- Therapeutic dosing of r-hirudin requires careful titration to optimize efficacy and minimize bleeding risk.
- The risk of excessive bleeding increases with higher doses of r-hirudin.