Gene targeting in hemostasis. Factor XI

Factor XI (FXI) is the zymogen of a plasma serine protease (FXIa) that cont ributes to hemostasis by activating factor IX (FIX). This reaction appears to be important for sustaining thrombin production after initial fibrin for mation, to consolidate and protect fibrin clots from degradation by fibrino lysis. Humans with congenital FXI deficiency have a variable propensity to bleed after trauma or surgery, but do not experience the "spontaneous" hemo rrhage in joints and soft tissue characteristic of hemophilia (FVIII or FIX deficiency). Mice homozygous for a disruption of the FXI gene (FXI-/-) hav e prolonged activated partial thromboplastin times and no detectable plasma FXI activity. Like their human counterparts, FXI-/- animals are generally healthy, reproduce normally, and do not develop spontaneous hemorrhage. In tail bleeding time assays, FXI-/- animals may have slightly prolonged bleed ing compared to FXI+/+ and FXI+/- animals, however, a consistent hemostatic deficit has not been identified. More impressive results are obtained when FXI-/- mice are crossed with protein C deficient mice. Severe FXI deficien cy partially ameliorates the devastating hypercoagulable state associated w ith severe protein C deficiency, indicating that FXI plays a role in certai n thrombotic conditions.