The characterization of mice with a targeted combined deficiency of protein C and factor XI

Activated protein C functions directly as an anticoagulant and indirectly a s a profibrinolytic enzyme. To determine whether the fibrin deposition prev iously observed in PC-/- murine embryos and neonates was mediated through t he FXI pathway, PC+/-/FXI(-/-)mice were generated and crossbred to produce double-deficient progeny (PC-/-/FXI-/-). PC-/-/FXI-/mice survived the early lethality observed in the PC-/-/FXI+/+ neonates, with the oldest PC-/-/ FX I-/- animal living to 3 months of age. However, the majority of these anima ls was sedentary and significantly growth-retarded. On sacrifice or natural death, all of these PC-/-/FXI-/- mice demonstrated massive systemic fibrin deposition with concomitant hemorrhage and fibrosis, as confirmed through histological analyses. Several of these animals also presented with enlarge d lymph nodes and extensive lymphatic fluid in the thoracic cavity. Thus, a lthough a number of the PC-/-/FXI-/- mice survived the lethal perinatal coa gulopathy seen in the PC-/- neonates, they nonetheless succumbed to overwhe lming thrombotic disease in later life. This combined deficiency state prov ided the first clear indication that the course of a severe thrombotic diso rder could be manipulated by blocking the intrinsic pathway and provided th e first opportunity to study a total protein C deficiency in an adult anima l.