PROTHROMBIN DEFICIENCY RESULTS IN EMBRYONIC AND NEONATAL LETHALITY INMICE

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 regu latory pathways that both promote and ultimately suppress coagulation. However, several observations suggest that FII may serve a broader ph ysiological role than simply stemming blood loss, including the identi fication of multiple G protein coupled, thrombin-activated receptors, and the well-documented mitogenic activity of FIIa in in vitro test sy stems, 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. Bleed ing into the yolk sac cavity and varying degrees of tissue necrosis we re observed in many FII-/- embryos within this gestational time frame. However, at least one-quarter of the FII-/- mice survived to term, bu t ultimately they, too, developed fatal hemorrhagic events and died wi thin a few days of birth, This study directly demonstrates that FII is important in maintaining vascular integrity during development as wel l as postnatal life.