Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice

被引:139
作者
Jalbert, LR
Rosen, ED
Moons, L
Chan, JCY
Carmeliet, P
Collen, D
Castellino, FJ
机构
[1] Flanders Interuniv Inst Biotechnol, Ctr Transgene Technol & Gene Therapy, B-3000 Louvain, Belgium
[2] Univ Notre Dame, WM Keck Ctr Transgene Res, Notre Dame, IN 46556 USA
[3] Univ Notre Dame, Dept Chem & Biochem, Notre Dame, IN 46556 USA
关键词
protein C deficiency; coagulation; gene deletion; inflammation; embryonic development;
D O I
10.1172/JCI3011
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Matings of mice heterozygous for a protein C (PC) deficient allele, produced by targeted PC gene inactivation, yielded the expected Mendelian distribution of PC genotypes. Pups with a total deficiency of PC (PC-/-), obtained at embryonic day (E) 17.5 and at birth, appeared to develop normally macroscopically, but possessed obvious signs of bleeding and thrombosis and did not survive beyond 24 h after delivery. Microscopic examination of tissues and blood vessels of E17.5 PC-/- mice revealed their normal development, but scattered microvascular thrombosis in the brain combined with focal necrosis in the liver was observed. In addition, bleeding was noted in the brain near sites of fibrin deposition. The severity of these pathologies was exaggerated in PC-/- neonates. Plasma clottable fibrinogen was not detectable in coagulation assays in PC-/- neonatal mice, suggestive of fibrinogen depletion and secondary consumptive coagulopathy. Thus, while total PC deficiency did not affect the anatomic development of the embryo, severe perinatal consumptive coagulopathy occurred in the brain and liver of PC-/- mice, suggesting that a total PC deficiency is inconsistent with short-term survival.
引用
收藏
页码:1481 / 1488
页数:8
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