Nature Biotechnology
18, 289 - 295 (2000)
doi:10.1038/73727
In vivo bypass of hemophilia A coagulation defect by Factor XIIa implant
Tung T. Ton-That1, 2, David Doron2, Bette S. Pollard3, John Bacher4
& Harvey B. Pollard1, 21
Department of Anatomy and Cell Biology, Uniformed Services
University School of Medicine, USUHS, Bethesda, MD
10814. 2
Laboratory of Cell Biology and Genetics, National Institute
of Diabetes, Digestive and Kidney Diseases, National Institutes of Health
, Bethesda, MD 20892. 3
Office of the Director, National Institutes of Health
, Bethesda, MD 20892. 4
Veterinary Resources Program, National Center for Research
Resources, National Institutes of Health, Bethesda,
MD 20892.
Correspondence should be addressed to Harvey B. Pollard hpollard@usuhs.milhemophilia Ahemophilia BcoagulationcalciumFactor VIIFactor VIIaFactor VIIIFactor IXFactor XaFactor XIIaphospholipidsbypass activityHemophilia A and B coagulation defects, which are caused by deficiencies
of Factor VIII and Factor IX, respectively, can be bypassed by administration
of recombinant Factor VIIa. However, the short half-life of recombinant Factor
VIIa in vivo negates its routine clinical use. We report here an in vivo method
for the continuous generation of Factor VIIa. The method depends on the implantation
of a porous chamber that contains Factor Xa or XIIa, and continuously generates
Factor VIIa bypass activity from the subject's own Factor VII, which enters
the chamber by diffusion. Once inside, the Factor VII is cleaved to Factor
VIIa by the immobilized Factor Xa or XIIa. The newly created Factor VIIa diffuses
out of the chamber and back into the circulation, where it can bypass the
deficient Factors VIII or IX, and enable coagulation to occur. In vitro, this
method generates sufficient Factor VIIa to substantially correct Factor VIII-deficient
plasma when assessed by the classical aPTT coagulation assay. In vivo, a Factor
XIIa peritoneal implant generates bypass activity for up to one month when
tested in rhesus monkeys. Implantation of such a chamber in a patient with
hemophilia A or B could eventually provide a viable alternative to replacement
therapies using exogenous coagulation factors.
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