Thrombin Generation Inhibition by Newer Anti Xa and Anti IIa Drugs in Prothrombin Complex Concentrates: Relevance to Endogenous Modulation of Thrombogenesis

Abstract 1196

Several anti-Xa agents (apixaban, otamixaban, rivaroxaban and edoxaban) and anti-IIa agents (dabigatran and melagatran) have been developed for clinical use. These agents are strong inhibitors of factor Xa and IIa and their potency is usually expressed in terms of the inhibitory parameters of these enzymes. These synthetic agents can also modulate thrombin and factor Xa generation in complex systems such as the platelet rich and platelet poor plasma and whole blood. The order of potency differs depending upon the type of matrix used due to cellular and protein binding and interaction with generated proteases and protein fragments. In order to compare these agents for their relative thrombin generation inhibitory profile, prothrombin complex based assay systems are developed utilizing 5 units/mL of non activated prothrombin complex such as Konyne® and Preconativ. Thrombin generation is triggered by tissue factor and monitored using a thrombin specific florometric substrate based assay (Technoclone, Vienna, Austria). All agents were tested in a concentration range of 0–1000 ng/mL. The relative inhibition of thrombin generation was calculated in terms of IC50. The factor Xa inhibitors were found to be relatively potent inhibitors of thrombin generation exhibiting an IC50 value of 25–96 ng/mL with the following order of potency- Rivaroxaban>Otamixaban>Apixaban. The anti IIa agents exhibited potency in the range of 125–225 ng/mL. Melagatran was more potent than dabigatran. In the plasma based anticoagulant assays such as PT, aPTT, heptest, the anti IIa agents were more potent than factor Xa drugs. Assay based differences were noted in all agents which did not follow the same patterns as thrombin generation inhibition in the prothrombin complex systems. These observations suggest that although considered to be single target, the newer anticoagulant drugs produce variable inhibitory effects on the protease network in complex systems such as plasma and prothrombin complexes. These effects may be related to the relative safety and efficacy profile of these agents and should be included in the preclinical profiling of these agents.