Tissue factor inhibitors Christian T Ruff, David A Morrow, and Robert P Giugliano
Introduction Anticoagulation is the cornerstone of therapy in the treatment of venous and arterial thromboembolism. Traditional anticoagulants – unfractionated heparin (UFH), lowmolecular-weight heparin (LMWH), and warfarin – have many significant limitations. Both UFH and warfarin have narrow therapeutic windows of adequate anticoagulation without bleeding and a highly variable dose-response relation among individuals that requires frequent monitoring by laboratory testing. 1-3 UFH, and to a lesser extent LMWH, is associated with the occurrence of thrombocytopenia, a potentially fatal complication that may be associated with thrombosis. 4,5 Importantly, current antithrombotic strategies do not suppress generation of thrombin, the critical enzyme that generates fibrin and activates platelets. 6-9 An important aspect of this system is that at each branch in the pathway, one molecule of enzyme is able to activate many molecules of its substrate protein, thereby amplifying each step in the cascade. Given this cascade of interactions, an approach that intervenes at the earliest trigger to activation of the system has a potential for more effective inhibition of thrombin generation than strategies that rely upon inhibition of later steps.