Faculty Collaboration Database

Factor VIII ectopically expressed in platelets: efficacy in hemophilia A treatment. Blood 2003 Dec 01;102(12):4006-13

Date

07/26/2003

Pubmed ID

12881300

DOI

10.1182/blood-2003-05-1519

Scopus ID

2-s2.0-10744231807 (requires institutional sign-in at Scopus site)   132 Citations

Abstract

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 alpha-granules and whether its release from circulating platelets would effectively ameliorate bleeding in a factor VIIInull mice model. Using the proximal glycoprotein 1b alpha 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 alpha-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.

Author List

Yarovoi HV, Kufrin D, Eslin DE, Thornton MA, Haberichter SL, Shi Q, Zhu H, Camire R, Fakharzadeh SS, Kowalska MA, Wilcox DA, Sachais BS, Montgomery RR, Poncz M

Authors

Robert R. Montgomery MD Adjunct Professor in the Pediatrics department at Medical College of Wisconsin
Qizhen Shi MD, PhD Professor in the Pediatrics department at Medical College of Wisconsin
David A. Wilcox PhD Professor in the Pediatrics department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Blood Coagulation Tests
Blood Platelets
Carotid Arteries
Cytoplasmic Granules
Disease Models, Animal
Factor VIII
Genetic Therapy
Hemophilia A
Hemorrhage
Humans
Mice
Mice, Transgenic
Microscopy, Confocal
Sequence Deletion
Thrombosis