FATAL HEMORRHAGE AND INCOMPLETE BLOCK TO EMBRYOGENESIS IN MICE LOCKING COAGULATION-FACTOR-V

COAGULATION factor V is a critical cofactor for the activation of prot hrombin to thrombin, the penultimate step in the generation of a fibri n blood clot(1,2). Genetic deficiency of factor V results in a congeni tal bleeding disorder (parahaemophilia)(3), whereas inheritance of a m utation rendering factor V resistant to inactivation is an important r isk factor for thrombosis(4,5). We report here that approximately half of homozygous embryos deficient in factor V (F upsilon(-/-)), which h ave been generated by gene targeting, die at embryonic day (E) 9-10, p ossibly as a result of an abnormality in the yolk-sac vasculature. The remaining F upsilon(-/-) mice progress normally to term, but die from massive haemorrhage within 2 hours or birth. Considered together with the milder phenotypes generally associated with deficiencies of other clotting factors(6,7), our findings demonstrate the primary role of t he common coagulation pathway and the absolute requirement for functio nal factor V for prothrombinase activity. They also provide direct evi dence for the existence of other critical haemostatic functions for th rombin in addition to fibrin clot formation, and identify a previously unrecognized role for the coagulation system in early mammalian devel opment.