Altered thrombus formation in von Willebrand factor–deficient mice expressing von Willebrand factor variants with defective binding to collagen or GPIIbIIIa
Open Access
- 1 August 2008
- journal article
- Published by American Society of Hematology in Blood
- Vol. 112 (3), 603-609
- https://doi.org/10.1182/blood-2008-02-142943
Abstract
The role of von Willebrand factor (VWF) in thrombosis involves its binding to a number of ligands. To investigate the relative importance of these particular interactions in the thrombosis process, we have introduced mutations into murine VWF (mVWF) cDNA inhibiting VWF binding to glycoprotein (Gp) Ib, GPIIbIIIa, or to fibrillar collagen. These VWF mutants were expressed in VWF-deficient mice (VWF−/−) by using an hydrodynamic injection approach, and the mice were studied in the ferric chloride–induced injury model. Expression of the collagen and the GPIIbIIIa VWF-binding mutants in VWF−/− mice resulted in delayed thrombus growth and significantly increased vessel occlusion times compared with mice expressing wild-type (WT) mVWF (30 ± 3 minutes and 38 ± 4 minutes for the collagen and GPIIbIIIa mutants, respectively, vs 19 ± 3 minutes for WT mVWF). Interestingly, these mutants were able to correct bleeding time as efficiently as WT mVWF. In contrast, VWF−/− mice expressing the GPIb binding mutant failed to restore thrombus formation and were bleeding for as long as they were observed, confirming the critical importance of the VWF-GPIb interaction. Our observations suggest that targeting the VWF-collagen or VWF-GPIIbIIIa interactions could be an interesting alternative for new antithrombotic strategies.Keywords
This publication has 29 references indexed in Scilit:
- Correction of Bleeding Symptoms in von Willebrand Factor–Deficient Mice by Liver-Expressed von Willebrand Factor MutantsArteriosclerosis, Thrombosis, and Vascular Biology, 2008
- Update on the pathophysiology and classification of von Willebrand disease: a report of the Subcommittee on von Willebrand FactorJournal of Thrombosis and Haemostasis, 2006
- Mapping the Collagen-binding Site in the von Willebrand Factor-A3 DomainPublished by Elsevier BV ,2003
- Von Willebrand factorCurrent Opinion in Hematology, 2003
- Persistence of platelet thrombus formation in arterioles of mice lacking both von Willebrand factor and fibrinogenJCI Insight, 2000
- Localization of von Willebrand Factor-binding Sites for Platelet Glycoprotein Ib and Botrocetin by Charged-to-Alanine Scanning MutagenesisJournal of Biological Chemistry, 2000
- Hydrodynamics-based transfection in animals by systemic administration of plasmid DNAGene Therapy, 1999
- A mouse model of severe von Willebrand disease: Defects in hemostasis and thrombosisProceedings of the National Academy of Sciences of the United States of America, 1998
- BIOCHEMISTRY AND GENETICS OF VON WILLEBRAND FACTORAnnual Review of Biochemistry, 1998
- Role of the glycoprotein Ib-binding A1 repeat and the RGD sequence in platelet adhesion to human recombinant von Willebrand factorBlood, 1995