Thrombin inhibitors suppress the thrombin-thrombomodulin-mediated generation of activated protein C

In the treatment of unstable coronary artery disease, direct thrombin inhib itors have shown no or only limited benefit as compared with heparin, despi te theoretical advantages. One explanation may be that the direct thrombin inhibitors to a greater extent than heparin have an inhibiting effect on th e generation and activity of activated protein C. In the present study, thi s hypothesis was tested in an in vitro, "purified" system, where human prot ein C underwent activation to activated protein C by the thrombin-thrombomo dulin complex. Direct thrombin inhibitors, inogatran and hirudin, unfractio nated heparin+antithrombin, or dalteparin+antithrombin, were added to the s ystem before activation to evaluate their inhibitory effect on the generati on of activated protein C. At inhibitor concentrations well below the achie ved plasma levels in major clinical trials, the thrombin-thrombomodulin-med iated activation of protein C was inhibited by all the studied inhibitors i n a dose-dependent manner, but, contrary to our hypothesis, to a greater ex tent by unfractionated heparin+antithrombin and dalteparin+antithrombin tha n by the direct thrombin inhibitors, hirudin and inogatran. Despite difficu lties to draw conclusions for the in vivo situation, the in vitro inhibitio n, by all studied inhibitors, of the generation of activated protein C, fou nd in this study may be a possible explanation for ongoing cardiovascular e vents despite adequate treatment with thrombin inhibitors, in patients with unstable coronary artery disease. This inhibition of the generation of act ivated protein C may also contribute to the rebound in cardiovascular event s after withdrawal of effective antithrombotic treatment. (C) 1999 Elsevier Science Ltd. All rights reserved.