Altered thrombus formation in von Willebrand factor-deficient mice expressing von Willebrand factor variants with defective binding to collagen or GPIIbIIIa
| Autor: | Isabelle Marx, Olivier D. Christophe, Alain Rupin, Cécile V. Denis, Tony Verbeuren, Peter J. Lenting, Marie-Odile Vallez |
|---|---|
| Rok vydání: | 2008 |
| Předmět: |
congenital
hereditary and neonatal diseases and abnormalities medicine.medical_specialty Ratón Immunology Mutant Mutagenesis (molecular biology technique) Hemorrhage Platelet Glycoprotein GPIIb-IIIa Complex Biology Biochemistry Mice Von Willebrand factor Bleeding time hemic and lymphatic diseases Internal medicine von Willebrand Factor medicine Animals Thrombus chemistry.chemical_classification Mice Knockout Hematology medicine.diagnostic_test Genetic Variation Thrombosis Cell Biology medicine.disease Molecular biology chemistry Platelet Glycoprotein GPIb-IX Complex cardiovascular system biology.protein Mutagenesis Site-Directed Mutant Proteins Collagen Glycoprotein circulatory and respiratory physiology Protein Binding |
| Zdroj: | Blood. 112(3) |
| ISSN: | 1528-0020 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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