Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice
Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice
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DOI：
10.1172/jci3011
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发表时间：
1998-10-15
影响因子：
15.9
通讯作者：
Castellino, FJ
中科院分区：
文献类型：
--
作者：
Jalbert, LR;Rosen, ED;Castellino, FJ
通过靶向PC基因失活产生的蛋白C（PC）缺陷等位基因杂合子小鼠的交配产生了预期的PC基因型孟德尔分布。在胚胎第17.5天和出生时获得的PC完全缺乏（PC-/-）的幼崽在宏观上似乎发育正常，但具有明显的出血和血栓形成体征，并且在分娩后24小时内不能存活。E17.5 PC-/-小鼠的组织和血管的显微镜检查显示其正常发育，但观察到脑中分散的微血管血栓形成，并伴有肝脏中的局灶性坏死。此外，在纤维蛋白沉积部位附近的脑中观察到出血。PC-/-新生儿中这些病理的严重程度被夸大。在PC-/-新生小鼠的凝血试验中未检测到血浆凝血酶原时间纤维蛋白原，提示纤维蛋白原耗竭和继发性消耗性凝血病。因此，虽然总PC缺乏症不影响胚胎的解剖发育，但PC-/-小鼠的大脑和肝脏中发生了严重的围产期消耗性凝血病，这表明总PC缺乏症与短期生存不一致。
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.