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Procoagulant activity of reversibly acylated human factor Xa
D L Wolf1, P H Lin, S Hollenbach
1COR Therapeutics Inc, South San Francisco, CA 94080, USA.
Blood
|December 1, 1995
Summary
Researchers developed a modified plasma factor Xa, anisoyl Xa, for hemophilia treatment. This bypass factor releases active factor Xa over time, offering a potentially safer and more effective therapy for patients with inhibitory antibodies.
Area of Science:
- Biochemistry
- Hematology
- Pharmacology
Background:
- Plasma clotting factors for hemophilia with inhibitors have safety and utility limitations.
- Existing bypass therapies require improvement for enhanced clinical efficacy.
Purpose of the Study:
- To develop an improved bypass factor for hemophilia treatment.
- To create a modified human plasma factor Xa with time-dependent procoagulant activity release.
Main Methods:
- Human plasma factor Xa was acylated with p-amidinophenyl p'-anisate to create anisoyl Xa.
- Anisoyl Xa's deacylation kinetics (time, pH, temperature) were studied.
- In vitro amidolytic and prothrombinase activities of generated factor Xa were assessed.
- Anisoyl Xa was infused into rabbits to evaluate its effect on activated partial thromboplastin time (APTT).
Main Results:
- Anisoyl Xa deacylation yielded active factor Xa with comparable in vitro amidolytic and prothrombinase activities to native factor Xa.
- In vivo, anisoyl Xa infusion in rabbits led to dose-dependent APTT shortening.
- The duration of APTT normalization correlated with plasma factor Xa levels.
Conclusions:
- Anisoyl Xa provides a time-dependent release of active factor Xa.
- This modified factor bypasses the compromised tenase complex in hemophilia A and B.
- Anisoyl Xa shows potential as an effective bypass therapy for hemophiliacs with inhibitory antibodies.