Fatal haemorrhage and incomplete block to embryogenesis in mice lacking coagulation factor V

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Abstract
COAGULATION factor V is a critical cofactor for the activation of prothrombin to thrombin, the penultimate step in the generation of a fibrin blood clot1,2. Genetic deficiency of factor V results in a congenital bleeding disorder (parahaemophilia) 3, whereas inheritance of a mutation rendering factor V resistant to inactivation is an important risk factor for thrombosis4,5. We report here that approximately half of homozygous embryos deficient in factor V (Fv−/−), which have been generated by gene targeting, die at embryonic day (E) 9–10, possibly as a result of an abnormality in the yolk-sac vasculature. The remaining Fv−/− mice progress normally to term, but die from massive haemorrhage within 2 hours of birth. Considered together with the milder phenotypes generally associated with deficiencies of other clotting factors6,7, our findings demonstrate the primary role of the common coagulation pathway and the absolute requirement for functional factor V for prothrombinase activity. They also provide direct evidence for the existence of other critical haemostatic functions for thrombin in addition to fibrin clot formation, and identify a previously unrecognized role for the coagulation system in early mammalian development.