Overexpression of factor VII ameliorates bleeding diathesis of factor VIII-deficient mice with inhibitors.

Abstract

INTRODUCTION:

Factor VIII (FVIII) treatment for hemophilia A has difficulties in correcting bleeding diathesis in the presence of inhibitors.

MATERIALS AND METHODS:

An adeno-associated virus type 8 (AAV8) vector containing the factor VII (FVII) gene or the activated factor VII (FVIIa) gene was used to investigate the therapeutic effect of FVII or FVIIa overexpression in FVIII-deficient mice with inhibitors.

RESULTS:

Following repeated human FVIII injection, FVIII-deficient mice developed anti-human FVIII antibodies that cross-reacted with mouse FVIII. High transgene expression of murine FVII or murine FVIIa was achieved using the AAV8 vector and resulted in increased blood FVII activity greater than 800% of normal murine FVII levels in vector-injected FVIII-deficient mice. Thromboelastography analysis showed significant improvements in clotting time, clot formation time, α angle, and mean clot firmness in AAV8 vector-injected FVIII-deficient mice with inhibitors. Overexpression of FVIIa ameliorated the bleeding phenotype of FVIII-deficient mice with inhibitors and significantly increased the survival rate after tail clipping. In addition, overexpression of FVII increased the survival rate of FVIII-deficient mice with inhibitors after tail clipping though it was not as efficient as FVIIa overexpression.

CONCLUSIONS:

These data suggest that FVII overexpression is an alternative strategy for the treatment of hemophilia A with inhibitors.

• Authors: Atsushi Yasumoto, Seiji Madoiwa, Yuji Kashiwakura, Akira Ishiwata, Tsukasa Ohmori, Hiroaki Mizukami, Keiya Ozawa, Yoichi Sakata, Jun Mimuro
• Journal: Thrombosis research (Thromb Res) Vol. 131 Issue 5 Pg. 444-9 (May 2013) ISSN: 1879-2472 [Electronic] United States
• PMID: 23566532 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2013 Elsevier Ltd. All rights reserved.

Chemical References

• Factor VII
• Factor VIIa

Topics

• Animals
• Dependovirus (genetics)
• Factor VII (biosynthesis, genetics)
• Factor VIIa (biosynthesis, genetics)
• Genetic Therapy
• Hemophilia A (drug therapy, genetics, immunology, therapy)
• Hemorrhage (drug therapy, genetics, therapy)
• Humans
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Survival Rate
• Transfection