Thrombotic safety of prothrombin complex concentrate (Beriplex P/N) for dabigatran reversal in a rabbit model

Abstract

IntroductionIn vivo animal data have shown prothrombin complex concentrate (PCC) to be effective in preventing bleeding induced by excessive plasma levels of the direct thrombin inhibitor dabigatran. This animal model study was designed to determine the risk of thrombosis associated with administration of a PCC (Beriplex P/N) to reverse dabigatran-induced bleeding. Materials and methodsAnesthetized rabbits were treated with initial 0, 75, 200 or 450μgkg-1 dabigatran boluses followed by continuous infusions to maintain elevated plasma dabigatran levels. At 15min after the start of dabigatran administration, PCC doses of 0, 50 or 300IUkg-1 were administered. Thereafter, coagulation in an arteriovenous (AV) shunt was evaluated and histopathologic examination for thrombotic changes performed. Venous thrombosis was also assessed in a modified Wessler model. ResultsAt the suprapharmacologic dose of 300IUkg-1, PCC increased thrombus weight during AV shunting, but this effect could be prevented by dabigatran at all tested doses. AV shunt occlusion after PCC administration was delayed by 75μgkg-1 dabigatran and abolished by progressively higher dabigatran doses. High-dose treatment with 300IUkg-1 PCC resulted in histologically evident low-grade pulmonary thrombi; however, that effect could be blocked by dabigatran in a dose-dependent manner (p=0.034). In rabbits treated with high-dose PCC, dabigatran inhibited thrombus formation during venous stasis. PCC effectively reversed dabigatran-induced bleeding. ConclusionsIn this animal study, thrombosis after PCC administration could be prevented in the presence of dabigatran. PCC reversed dabigatran-induced excessive bleeding while retaining protective anticoagulatory activity of dabigatran.