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Blood, 1 December 2003, Vol. 102, No. 12, pp. 4006-4013.
Prepublished online as a Blood First Edition Paper on July 31, 2003; DOI 10.1182/blood-2003-05-1519.
 Previous Article | Table of Contents | Next Article 
HEMOSTASIS, THROMBOSIS, AND VASCULAR BIOLOGY
Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment
Helen V. Yarovoi,
Dubravka Kufrin,
Don E. Eslin,
Michael A. Thornton,
Sandra L. Haberichter,
Qizhen Shi,
Hua Zhu,
Rodney Camire,
Steve S. Fakharzadeh,
M. Anna Kowalska,
David A. Wilcox,
Bruce S. Sachais,
Robert R. Montgomery, and
Mortimer Poncz
From the Children's Hospital of Philadelphia, Philadelphia, PA; Medical College of Wisconsin, Milwaukee; and The University of Pennsylvania School of Medicine, Philadelphia.
Activated platelets release their granule content in a concentrated fashion at sites of injury. We examined whether ectopically expressed factor VIII in developing megakaryocytes would be stored in  -granules and whether its release from circulating platelets would effectively ameliorate bleeding in a factor VIIInull mice model. Using the proximal glycoprotein 1b promoter to drive expression of a human factor VIII cDNA construct, transgenic lines were established. One line had detectable human factor VIII that colocalizes with von Willebrand factor in platelets. These animals had platelet factor VIII levels equivalent to 3% to 9% plasma levels, although there was no concurrent plasma human factor VIII detectable. When crossed onto a factor VIIInull background, whole blood clotting time was partially corrected, equivalent to a 3% correction level. In a cuticular bleeding time study, these animals also had only a partial correction, but in an FeCl3 carotid artery, thrombosis assay correction was equivalent to a 50% to 100% level. These studies show that factor VIII can be expressed and stored in platelet -granules. Our studies also suggest that platelet-released factor VIII is at least as potent as an equivalent plasma level and perhaps even more potent in an arterial thrombosis model. (Blood. 2003;102:4006-4013)
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