Prothrombin deficiency results in embryonic and neonatal lethality in mice
Prothrombin deficiency results in embryonic and neonatal lethality in mice
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DOI：
10.1073/pnas.95.13.7597
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发表时间：
1998-06-23
影响因子：
11.1
通讯作者：
Degen, SJF
中科院分区：
文献类型：
--
作者：
Sun, WY;Witte, DP;Degen, SJF
凝血酶原（PII）转化为丝氨酸蛋白酶凝血酶（FIIa）是凝血级联反应中的关键步骤，因为FIIa触发血小板活化，将纤维蛋白原转化为纤维蛋白，并激活促进并最终抑制凝血的调节途径。然而，几个观察结果表明，与简单地阻止失血相比，FIB可以起到更广泛的生理作用，包括鉴定多种G蛋白偶联的凝血酶激活受体，以及FIIa在体外试验系统中充分记录的促有丝分裂活性。为了更详细地探索FIB在体内的生理作用，产生了FIB缺陷（FIB-/-）小鼠。PII基因的失活导致部分胚胎死亡，超过一半的PII-/-胚胎在胚胎第9.5天至第11.5天之间死亡。在此妊娠时间范围内，在许多FIS-/-胚胎中观察到卵黄囊腔出血和不同程度的组织坏死。然而，至少有四分之一的FIB-/-小鼠存活到足月，但最终它们也发生了致命的出血事件，并在出生后几天内死亡。这项研究直接表明，在发育期间以及出生后的生活中，FIB在维持血管完整性方面很重要。
The conversion of prothrombin (FII) to the serine protease, thrombin (FIIa), is a key step in the coagulation cascade because FIIa triggers platelet activation, converts fibrinogen to fibrin, and activates regulatory pathways that both promote and ultimately suppress coagulation. However, several observations suggest that FII may serve a broader physiological role than simply stemming blood loss, including the identification of multiple G protein coupled, thrombin-activated receptors, and the well-documented mitogenic activity of FIIa in in vitro test systems, To explore in greater detail the physiological roles of FII in vivo, FII deficient (FII-/-) mice were generated. Inactivation of the FII gene leads to partial embryonic lethality with more than one-half of the FII-/- embryos dying between embryonic days 9.5 and 11.5. Bleeding into the yolk sac cavity and varying degrees of tissue necrosis were observed in many FII-/- embryos within this gestational time frame. However, at least one-quarter of the FII-/- mice survived to term, but ultimately they, too, developed fatal hemorrhagic events and died within a few days of birth, This study directly demonstrates that FII is important in maintaining vascular integrity during development as well as postnatal life.