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In vivo bypass of hemophilia A coagulation defect by Factor XIIa implant

Nature Biotechnology volume 18, pages 289–295 (2000)Cite this article

Abstract

Hemophilia 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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Figure 1: Diagram of dual-compartment chamber and the experimental design for generating Factor VIIa.
Figure 2: Generation of bypass activity from purified Factor VII.
Figure 3: Generation of bypass activity in Factor VIII-deficient plasma.
Figure 4: Time-dependent bypass activity of Factor XIIa implant, in vivo.

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Author information

Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Uniformed Services University School of Medicine, USUHS, Bethesda, 10814, MD

    Tung T. Ton-That & Harvey B. Pollard

  2. Laboratory of Cell Biology and Genetics, National Institute of Diabetes, Digestive and Kidney Diseases, National Institutes of Health , Bethesda, 20892, MD

    Tung T. Ton-That, David Doron & Harvey B. Pollard

  3. Office of the Director, National Institutes of Health , Bethesda, 20892, MD

    Bette S. Pollard

  4. Veterinary Resources Program, National Center for Research Resources, National Institutes of Health, Bethesda, 20892, MD

    John Bacher

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  1. Tung T. Ton-That
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  2. David Doron
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  5. Harvey B. Pollard
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Correspondence to Harvey B. Pollard.

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Ton-That, T., Doron, D., Pollard, B. et al. In vivo bypass of hemophilia A coagulation defect by Factor XIIa implant . Nat Biotechnol 18, 289–295 (2000). https://doi.org/10.1038/73727

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