Differential inhibition of tissue factor mediated activation of thrombin generation by Dabigatran, Apixaban, Rivaroxaban and Otamaxaban. Pharmacologic implications

Abstract

IntroductionNewer anticoagulant drugs Dabigatran (D), Rivaroxaban (R), Apixaban (A) and Otamaxaban (O) are monotherapeutic agents targeting thrombin and factor Xa. Beside inhibiting these enzymes these agents also inhibit the generation of thrombin. The purpose of this study was to investigate relative inhibitory effects of D, R, A and O on thrombin generation by using mass spec and functional methods.Materials and MethodsSeveral commercially available prothrombin complex concentrates (PCCs), and normal human plasma (NHP) were supplemented with each of the different inhibitors and proteomic profile was obtained in SELDI‐TOF analysis in the molecular weight (MW) range of 0–150,000. Functional thrombin generation studies were carried out using chromogenic and fleurogenic substrate methods.ResultsAll of the prothrombin complexes exhibited 2 major native peaks at 72 and 13.9 kDa and upon thromboplastin activation showed a 36 and 12.6 kDa peaks representing thrombin generation. D did not inhibit the generation of the 36 and 12.6 peaks whereas O,A and R inhibited the generation of these peaks in a conc dependent manner. Functional generation of thrombin was also inhibited by O, A and R but not by D.ConclusionsThe generation of 36 and 12.6 kDa peak signifies thrombin formation which is strongly inhibited by Xa inhibitors such as O, A and R. D is a relatively weaker inhibitor of this process.