Species specificity of the anticoagulant activity of human urinary soluble thrombomodulin.
The anticoagulant activities of human urinary soluble thrombomodulin (UTM) in blood taken from various species using several anticoagulant assay systems were compared; it was examined which coagulant assay system is appropriate for evaluation of the antithrombotic effects of UTM and how the species specificity of UTM is involved in the mechanisms of action of UTM. When anticoagulant activities were compared using activated partial thromboplastin time (APTT), thromboelastography (TEG), and thrombin generation test (TGT), the effect of UTM was found to be the strongest in humans among various species tested. Among the anticoagulant assays tested, TGT reflecting protein C (PC) activation by UTM, appeared to be more sensitive than APTT and TEG in detection of thrombomodulin activity. In the study of the mechanisms of action of UTM, UTM exhibited nearly the same antithrombin activity against human and rat thrombin; the rate of activation of human PC by thrombin/UTM complex was much higher than that of rat PC. Therefore, the species specificity of the anticoagulant activity of UTM may be attributable to thrombin/UTM-PC interaction, but not to UTM-thrombin interaction. From these results, we concluded that TGT reflecting PC activation by UTM will be a more useful assay than APTT and TEG for estimating the antithrombotic effects of UTM in humans. Furthermore, our findings suggest that UTM will exhibit more potent antithrombotic effects in humans than those in rats by strongly enhancing thrombin-catalyzed PC activation.