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DL Wolf, PH Lin, S Hollenbach, A Wong, DR Phillips and U Sinha
COR Therapeutics Inc, South San Francisco, CA 94080, USA.
The plasma clotting factors used to treat hemophiliacs who have developed
inhibitory antibodies have a shared history of limited clinical safety and
utility. To improve on existing bypass factors, we have developed a
reversibly acylated form of human plasma factor Xa capable of providing a
time-dependent release of procoagulant activity. Factor Xa was treated with
p-amidinophenyl p'-anisate to generate anisoyl Xa. The chemical
modification of the protein involves acylation of the active site serine
residue of factor Xa. Anisoyl Xa deacylated in a time, pH, and
temperature-dependent manner. Active factor Xa generated on deacylation of
anisoyl Xa exhibited amidolytic and prothrombinase complex activities in in
vitro assays, the level being comparable to those of untreated factor Xa.
When Anisoyl Xa was infused into rabbits, active factor Xa was generated on
deacylation of the acylated enzyme, which shortened the activated partial
thromboplastin time (APTT) in a dose-dependent manner. The duration of
effect on rabbit APTT could be directly correlated to the level of human
plasma factor Xa. Because anisoyl Xa bypasses the "tenase" complex that is
compromised in hemophilia A and B and is unaffected by inhibitory
antibodies, it has the potential to be used as an effective bypass therapy.
This article has been cited by other articles:
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| Copyright © 1995 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
