Intravenous recombinant soluble human thrombomodulin prevents venous thrombosis in a rat model

Abstract

Thrombomodulin is an endothelial surface thrombin receptor. Thrombin bound to thrombomodulin loses all procoagulant activity and instead activates the protein C anticoagulant pathway. We developed a recombinant thrombomodulin analog and compared the effects of recombinant thrombomodulin (100 μg/ea), saline (controls), recombinant hirudin (1.0 mg/kg), and heparin (100 units/kg) on thrombus formation, activated partial thromboplastin time, and tail transection bleeding time in a rat model of stasis-induced venous thrombosis. Results showed that thrombus was detected in the vena cava in six of the six rats treated with saline solution, in zero of the six rats treated with recombinant thrombomodulin ( p < 0.05), in one of six rats treated with recombinant hirudin ( p < 0.05), and in zero of six rats treated with heparin ( p < 0.05). The activated partial thromboplastin time in rats receiving recombinant thrombomodulin was slightly longer than controls (22 ± 8 vs 37 ± 6, p < 0.05). The bleeding times in rats receiving recombinant thrombomodulin were approximately twice as long as controls (215 ± 68 vs 545 ± 173, p = 0.037). In all rats treated with recombinant hirudin or heparin, activated partial thromboplastin times were >120 seconds and bleeding times were >1200 seconds. We conclude that recombinant thrombomodulin inhibits venous thrombosis in a rat model with less prolongation of activated partial thromboplastin time and bleeding time than heparin or hirudin.