Denis C, Methia N, Frenette P S, Rayburn H, Ullman-Culleré M, Hynes R O, Wagner D D
The Center for Blood Research, Harvard Medical School, Boston, MA 02115, USA.
Proc Natl Acad Sci U S A. 1998 Aug 4;95(16):9524-9. doi: 10.1073/pnas.95.16.9524.
von Willebrand factor (vWf) deficiency causes severe von Willebrand disease in humans. We generated a mouse model for this disease by using gene targeting. vWf-deficient mice appeared normal at birth; they were viable and fertile. Neither vWf nor vWf propolypeptide (von Willebrand antigen II) were detectable in plasma, platelets, or endothelial cells of the homozygous mutant mice. The mutant mice exhibited defects in hemostasis with a highly prolonged bleeding time and spontaneous bleeding events in approximately 10% of neonates. As in the human disease, the factor VIII level in these mice was reduced strongly as a result of the lack of protection provided by vWf. Defective thrombosis in mutant mice was also evident in an in vivo model of vascular injury. In this model, the exteriorized mesentery was superfused with ferric chloride and the accumulation of fluorescently labeled platelets was observed by intravital microscopy. We conclude that these mice very closely mimic severe human von Willebrand disease and will be very useful for investigating the role of vWf in normal physiology and in disease models.
血管性血友病因子（vWf）缺乏会导致人类严重的血管性血友病。我们通过基因靶向技术构建了该疾病的小鼠模型。vWf基因缺陷小鼠出生时外观正常，能够存活且具有生育能力。在纯合突变小鼠的血浆、血小板或内皮细胞中，既检测不到vWf，也检测不到vWf前体多肽（血管性血友病抗原II）。突变小鼠出现止血缺陷，出血时间显著延长，约10%的新生小鼠出现自发性出血事件。与人类疾病一样，由于缺乏vWf提供的保护，这些小鼠的凝血因子VIII水平大幅降低。在血管损伤的体内模型中，突变小鼠的血栓形成缺陷也很明显。在此模型中，将外翻的肠系膜用氯化铁灌注，并通过活体显微镜观察荧光标记血小板的聚集情况。我们得出结论，这些小鼠非常接近地模拟了人类严重的血管性血友病，对于研究vWf在正常生理和疾病模型中的作用将非常有用。
