Abstract 15816: Differentiation of Newer Oral Anti-Xa and Anti-IIa Agents with a Reference to the Regulatory Functions of Thrombin
Introduction: The newer anticoagualnts represent a group of synthetic antithrombin (Dabigatran: Boehringer Ingelheim) and anti-Xa agents (Abixaban;Bistol Meyer Squib/Pfizer; Rivaroxaban: Bayer/Jenssen; Edoxaban; Diachi Sankyo; Bietrixaban: Portola). All agents are low molecular weiht synthetic organomimetic drugs (MW < 500 Da) with targeted antithrombin and anti-Xa activities. Their biochemical and pharmacologic properties differ. Although effective in their specific dosage for given indications these agents differ in their safety profiles, bleeding, risk of myocardial infarction and gastrointestinal disturbances have been reported. The purpose of this study is to differentiate these agents in various biochemical and pharmacologic systems to explain the observed differences in their safety and efficacy profiles.
Methods: Dabigatran and rivaroxaban were obtained from commercial sources and apixaban was of a synthetic origin. Each of these agents were profiled in clot based whole blood and plasma assays. Thrombin generation studies were performed using a flourogenic and chromogenic substrate assay. In addition the effect of these agents on clot stability was also measured. The effect of these agents on platelet aggregation was measured using the aggregometry and flow cyotmetry assays.
Results: All agents produced a concentration dependent anticoagulant effect in the global clotting assays in both the whole blood and plasma samples. Assay based variations were observed. The rank order was Dabigatran>Rivaroxaban>Apixaban. In comparison to the anti-Xa inhibitors, dabigatran was found to be relatively weaker inhibition of thrombin and Xa generation in various systems. Dabigatran also produced a strong inhibition of thrombin-thrombomodulin mediated activation of protein C, thrombin activatible fibrinolysis inhibitor (TAFI) and factor XIII.
Conclusions: While each of the newer oral anticoagulants are potent inhibitors of thrombin and Xa, the anti-Xa agents are relatively potent inhibitors of thrombin generation, however, do not compromise its regulatory function. In contrast, Dabigatran and related antithrombin agents may compromise thrombin’s regulatory functions such as activation of protein C, TAFI and Factor XIII.
- © 2012 by American Heart Association, Inc.