Coagulation factor V is a critical cofactor for the activation of prothrombin to thrombin, the penultimate step in the generation of a fibrin blood clot. Genetic deficiency of factor V results in a congenital bleeding disorder (parahaemophilia), whereas inheritance of a mutation rendering factor V resistant to inactivation is an important risk factor for thrombosis. 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 factors, 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.
Hemonectin, a component of bone marrow extracellular matrix, is a lineage- and organ-specific attachment molecule for cells of the granulocytic lineage. We hypothesized that hemonectin is an important marker of fetal granulopoiesis that is developmentally regulated during the ontogeny of the hematopoietic system. Murine hematopoiesis originates in the yolk sac and subsequently appears in the liver, spleen, and bone marrow. Using an affinity-purified polyclonal antibody to purified hemonectin as a probe of developing hematopoietic organs, we observe that hemonectin is coordinately expressed at developmental stages of the mouse in those tissues that are supporting hematopoiesis. Multiparameter flow cytometric analysis reveals that approximately 7% of fetal liver cells express hemonectin by day 13 of gestation, and that 32% of the cells are positive by day 19. Additionally, restricted hemonectin expression is noted in other tissues (cartilage, skin, developing bone, and capillary endothelial cells), suggesting that this molecule subserves other developmental functions and/or belongs to a previously unrecognized family of molecules.
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