Activated protein C functions directly as an anticoagulant and indirectly as a profibrinolytic enzyme. To determine whether the fibrin deposition previously observed in PC-/- routine embryos and neonates was mediated through the 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-/-/FXI-/- animal living to 3 months of age. However, the majority of these animals 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 enlarged lymph nodes and extensive lymphatic fluid in the thoracic cavity. Thus, although a number of the PC-/-/FXI-/- mice survived the lethal perinatal coagulopathy seen in the PC-/- neonates, they nonetheless succumbed to overwhelming thrombotic disease in later life. This combined deficiency state provided the first clear indication that the course of a severe thrombotic disorder could be manipulated by blocking the intrinsic pathway and provided the first opportunity to study a total protein C deficiency in an adult animal.