INCOMPLETE EMBRYONIC LETHALITY AND FATAL NEONATAL HEMORRHAGE CAUSED BY PROTHROMBIN DEFICIENCY IN MICE

Deficiency of blood coagulation factor V or tissue factor causes the d eath of mouse embryos by 10.5 days of gestation, suggesting that part of the blood coagulation system is necessary for development. This Fun ction is proposed to require either generation of the serine protease thrombin and cell signaling through protease-activated receptors or an activity of tissue factor that is distinct from blood clotting. We fi nd that murine deficiency of prothrombin clotting factor 2 (Cf2) was a ssociated with the death of approximately 50% of CM-/- embryos by embr yonic day 10.5 (E10.5), and surviving embryos had characteristic defec ts in yolk sac vasculature. Most of the remaining Cf2(-/-) embryos die d by E15.5, but those surviving to E18.5 appeared normal. The rare CM- /- neonates died of hemorrhage on the first postnatal day. These studi es suggest that a part of the blood coagulation system is adapted to p erform a developmental function. Other mouse models show that the abse nce of platelets or of fibrinogen does not cause fetal wastage. Theref ore, the role of thrombin in development may be independent of its eff ects on blood coagulation and instead may involve signal transduction on cells other than platelets.