Prothrombin deficiency results in embryonic and neonatal lethality in mice

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.

凝血酶原（prothrombin，FII）转化为丝氨酸蛋白酶（serine protease）凝血酶（thrombin，FIIa）是凝血级联反应中的关键步骤，因为FIIa可触发血小板活化、将纤维蛋白原转化为纤维蛋白，并激活既能促进凝血又最终抑制凝血的调控通路。然而多项观察结果表明，FII的生理功能可能远超单纯阻止失血的范畴，其中包括已鉴定出多种G蛋白偶联凝血酶激活受体（G protein-coupled, thrombin-activated receptors），以及FIIa在体外实验系统中被充分证实的促有丝分裂活性。为更深入地探究FII在体内的生理功能，研究人员构建了凝血酶原缺陷型（FII(−/−)）小鼠模型。FII基因的失活会导致部分胚胎致死，超过半数的FII(−/−)胚胎会在胚胎第9.5天至11.5天之间死亡。在该妊娠时段内的多数FII(−/−)胚胎中，均可观察到卵黄囊腔出血及不同程度的组织坏死。不过，仍有至少四分之一的FII(−/−)小鼠能够存活至足月，但最终它们仍会出现致命性出血事件，并在出生后数日内死亡。本研究直接证实，FII在胚胎发育及出生后生命阶段中，对维持血管完整性均具有重要作用。