Biosynthesis and clearance of prothrombin in warfarin-treated rats

Abstract

The steady-state concentration of abnormal plasma prothrombin in warfarin-treated rats (10 mg/kg) was found to be approx. 6% of the plasma prothrombin level in normal rats. The clearance of abnormal plasma prothrombin in warfarin-treated rats was studied using either cycloheximide, to inhibit the synthesis, or vitamin K, to block the appearance of abnormal prothrombin in plasma. The clearance of abnormal plasma prothrombin corresponded to a half-life of approx. 6 h, which is similar to the half-life of normal plasma prothrombin. The de novo synthesis of prothrombin in warfarin-treated and normal rats was compared by measuring the incorporation of [3H]leucine into plasma prothrombin 90 min after an intravenous injection of the isotope. In warfarin-treated rats, accumulated prothrombin precursor was carboxylated and transported into circulation by injecting vitamin K 30 min after isotope administration. On comparing the incorporation of [3H]leucine into plasma prothrombin in warfarin-treated and normal rats, no significant difference in the de novo synthesis was detected. Our results suggest that the secretion of prothrombin in warfarin-treated rats is decreased to 6% of the normal rate. As the de novo synthesis is not affected by warfarin treatment, more than 90% of the newly synthesized prothrombin appears to be degraded intracellularly.