Defective γ-Glutamyl Carboxylase Activity and Bleeding in Rambouillet Sheep

Abstract

A flock of Rambouillet sheep was examined because of increased lamb mortality caused by ineffective hemostasis at parturition. Neonatal-affected lambs presented with inadequate hemostasis at the umbilicus, pale mucus membranes, and markedly prolonged activated clotting time. Affected lambs had consistently prolonged 1-stage prothrombin times and activated partial thromboplastin times that supported a defect in the common pathway or defects in both the intrinsic and extrinsic pathway of the coagulation cascade. Decreased activity of vitamin K-dependent procoagulant factors II, VII, IX, and X in male and female lambs suggested either a defect of the hepatic enzyme γ-glutamyl carboxylase, or vitamin K1 2,3 epoxide reductase. Affected lamb hepatic γ-glutamyl carboxylase activity was markedly decreased compared with that of age- and sex-matched control lambs, while vitamin K1 2,3 epoxide reductase and glucose-6-phosphatase activities were similar between an affected and normal lamb. Subcutaneous vitamin K1 supplementation did not increase vitamin K-dependent procoagulant factor activities in 3 lambs administered vitamin K1 daily. These data confirm defective γ-glutamyl carboxylase activity as the cause of impaired coagulation of sheep in this flock. This flock represents the only viable animal model of hereditarily defective γ-glutamyl carboxylase activity.