Modifying murine von Willebrand factor A1 domain for in vivo assessment of human platelet therapies

作者：Chen Jianchun; Tan Kui; Zhou Hairu; Lo Hsuan Fu; Roux Diana Tronik Le; Liddington Robert C; Diacovo Thomas G^*

来源：Nature Biotechnology, 2008, 26(1): 114-119.

DOI：10.1038/nbt1373

The A1 domain of von Willebrand factor (VWF-A1) plays a crucial role in hemostasis and thrombosis by initiating platelet adhesion at sites of arterial injury through interactions with the platelet receptor glycoprotein Ib alpha (GPIb alpha)(1-5). Here we report that murine VWF-A1 supports limited binding of human platelets. However, atomic models of GPIb alpha-VWF-A1 complexes identified an electrostatic 'hot-spot' that, when mutated in murine VWF-A1, switches its binding specificity from mouse to human GPIba. Furthermore, mice expressing this mutant VWF-A1 display a bleeding phenotype that can be corrected by infusion of human platelets. Mechanistically, human platelets correct the phenotype by forming occlusive thrombi, an event that can be abrogated by blockade of GPIba or by the preadministration of inhibitors of platelet activation or adhesion (clopidogrel (Plavix) and abciximab (ReoPro), respectively). Thus, by modifying a protein interface, we have generated a potential biological platform for preclinical screening of antithrombotics that specifically target human platelets.

• 出版日期2008-1
• 单位中国地震局; 河北医科大学