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Thrombin inhibitors suppress the thrombin-thrombomodulin-mediated generation of activated protein C
R Linder1, M Blombäck, N Egberg
1Department of Cardiology, Karolinska Hospital, Stockholm, Sweden. Rikard.Linder@medks.ki.se
Insights
Direct thrombin inhibitors and heparin reduce activated protein C generation. Heparin showed a greater inhibitory effect than direct thrombin inhibitors, potentially explaining cardiovascular events during treatment.
Area of Science:
- Biochemistry
- Pharmacology
- Cardiovascular Medicine
Background:
- Direct thrombin inhibitors offer theoretical advantages over heparin for unstable coronary artery disease but show limited clinical benefit.
- A potential reason for limited efficacy is the greater inhibition of activated protein C (APC) generation and activity by direct thrombin inhibitors compared to heparin.
Purpose of the Study:
- To test the hypothesis that direct thrombin inhibitors inhibit APC generation more than heparin.
- To evaluate the in vitro inhibitory effects of direct thrombin inhibitors (inogatran, hirudin) and heparin (unfractionated heparin, dalteparin) with antithrombin on APC generation.
Main Methods:
- An in vitro purified system using human protein C activated by the thrombin-thrombomodulin complex.
- Addition of direct thrombin inhibitors, unfractionated heparin+antithrombin, or dalteparin+antithrombin before activation.
- Dose-dependent evaluation of APC generation inhibition.
Main Results:
- All tested inhibitors dose-dependently inhibited thrombin-thrombomodulin-mediated APC generation at concentrations below clinical plasma levels.
- Contrary to the hypothesis, unfractionated heparin+antithrombin and dalteparin+antithrombin inhibited APC generation more significantly than direct thrombin inhibitors (hirudin, inogatran).
Conclusions:
- The in vitro inhibition of APC generation by both direct thrombin inhibitors and heparin may contribute to cardiovascular events during treatment for unstable coronary artery disease.
- This APC generation inhibition could also explain rebound cardiovascular events after discontinuing antithrombotic therapy.
Abstract:
In the treatment of unstable coronary artery disease, direct thrombin inhibitors have shown no or only limited benefit as compared with heparin, despite theoretical advantages. One explanation may be that the direct thrombin inhibitors to a greater extent than heparin have an inhibiting effect on the generation and activity of activated protein C. In the present study, this hypothesis was tested in an in vitro, "purified" system, where human protein C underwent activation to activated protein C by the thrombin-thrombomodulin complex. Direct thrombin inhibitors, inogatran and hirudin, unfractionated heparin+antithrombin, or dalteparin+antithrombin, were added to the system before activation to evaluate their inhibitory effect on the generation of activated protein C. At inhibitor concentrations well below the achieved plasma levels in major clinical trials, the thrombin-thrombomodulin-mediated activation of protein C was inhibited by all the studied inhibitors in a dose-dependent manner, but, contrary to our hypothesis, to a greater extent by unfractionated heparin+antithrombin and dalteparin+antithrombin than by the direct thrombin inhibitors, hirudin and inogatran. Despite difficulties to draw conclusions for the in vivo situation, the in vitro inhibition, by all studied inhibitors, of the generation of activated protein C, found in this study may be a possible explanation for ongoing cardiovascular events despite adequate treatment with thrombin inhibitors, in patients with unstable coronary artery disease. This inhibition of the generation of activated protein C may also contribute to the rebound in cardiovascular events after withdrawal of effective antithrombotic treatment.