Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice.
Combined factor VII/protein C deficiency results in intrauterine coagulopathy in mice.
复制标题
因子 VII/蛋白 C 联合缺乏会导致小鼠宫内凝血病。
DOI：
10.1172/jci9095
复制
发表时间：
2000
期刊：
影响因子：
--
通讯作者：
Castellino,FJ
中科院分区：
文献类型：
--
作者：
Chan,JC;Cornelissen,I;Collen,D;Ploplis,VA;Castellino,FJ
为了确定凝血因子VII(FVII)基因的额外缺失是否影响在蛋白C基因缺陷(PC-/-)胚胎和新生儿中观察到的凝血障碍，我们将凝血因子VII(FVII+/-)和蛋白C(PC+/-)基因双重杂合的小鼠杂交产生具有9种预测基因组合的后代。FVII-/-/PC-/-胚胎，尽管存在预期的孟德尔频率，但显示出在FVII或PC单一缺陷胚胎中未观察到的表型。在E12.5天后(DPC)，FVII-/-/PC-/-胚胎表现出血管内和血管外的凝血障碍，并在E17.5dpc时伴随大量出血和周围水肿，导致出生后立即死亡。FVII+/-/PC-/-胚胎表现出不那么严重的表型，提示有基因剂量效应。另外一个杂合子或纯合子FVII缺陷导致的PC-/-胚胎和新生儿得不到挽救以及凝血障碍加重，可能是由于FVIIa依赖的组织因子途径抑制物功能丧失以及因子Va和VIIa水平缺乏控制而导致的凝血因子Xa和凝血酶生成增加。在没有胎儿FVII的情况下，胚胎中存在纤维蛋白，这表明在胚胎因子VII依赖的途径之外存在显著的凝血生成潜力。
To determine whether an additional loss of the coagulation factor VII (FVII) gene influenced the coagulopathy observed in protein C gene–deficient(PC–/–)embryos and neonates, we crossed mice doubly heterozygous for the factor VII(FVII+/–)and protein C (PC+/–) genes to produce offspring possessing the 9 predicted genotypic combinations.FVII–/–/PC–/–embryos, although present at their expected Mendelian frequency, displayed a phenotype that had not been observed in either theFVIIorPCsingly deficient embryos. At E12.5 days postcoitum (dpc),FVII–/–/PC–/–embryos demonstrated an intra- and extravascular coagulopathy that progressed with substantial concomitant hemorrhage and peripheral edema by E17.5dpc, resulting in mortality immediately after birth.FVII+/–/PC–/–embryos showed a less severe phenotype, suggesting a gene dosage effect. The lack of rescue ofPC–/–embryos and neonates and augmented coagulopathy resulting from an additional heterozygous or homozygousFVIIdeficiency are probably due to increased factor Xa and thrombin generation, resulting from loss of FVIIa-dependent tissue factor pathway inhibitor function and the absence of control at the levels of factors Va and VIIIa. The presence of fibrin in embryos in the absence of fetal FVII suggests that significant clot-generating potential exists outside of the embryonic factor VII–dependent pathway.