Pharmacodynamic models to evaluate antithrombotics in clinical pharmacology

The need to prevent thromboembolic events effectively and safely has stimulated an intense search for novel antithrombotics. Parameters derived from in vitro tests with patients' blood are essential for therapeutic monitoring of anticoagulants. Clinical pharmacologic evaluation of novel antithrombotic therapies based on such parameters can easily fail, however, by neglecting pivotal pathophysiologic determinants of thrombus formation. When vascular injury occurs, blood cells, plasma proteins, and the vessel wall intimately cooperate for an adequate local repair. Much remains to be learned about the local and transient interaction of these components. In most tests of platelet function and coagulation proteins, blood samples from treated individuals are stimulated in vitro to assess inhibitory effects. Limitations of such a test strategy for dose-finding studies with antithrombotics may be overcome by measuring activation markers specifically generated on the surface of blood cells or in plasma at the site of thrombosis in patients.