Effective reversal of edoxaban-associated bleeding with four-factor prothrombin complex concentrate in a rabbit model of acute hemorrhage.

New-generation oral anticoagulants, specifically targeted at thrombin or factor Xa, have been shown to be effective for prevention and treatment of arterial and venous thromboembolism. The safety of these agents, in particular related to the associated risk of major haemorrhage, is at least as good as the safety of conventional gents such as vitamin K antagonist. However, a substantial proportion of patients will present with a major bleeding complication while using these drugs. Despite the relatively short half-lives of new anticoagulants, physicians are eager to have reversing agents available that can be used in case of very serious or life-threatening bleeding.

One of the most promising and widely available agents that may be used to reverse the anticoagulant effect of factor Xa inhibitors (and possibly also thrombin inhibitors) is prothrombin complex concentrate (PCC). Studies in non-bleeding healthy volunteers demonstrated that PCCs can reverse the prolongation of prothrombin time and inhibition of thrombin generation induced by the novel anticoagulants. However, studies in bleeding patients are not available so far.

In the present study, the effect of 4-factor PCC on the anticoagulant effect of edoxaban, a factor Xa inhibitor, was studied in a rabbit bleeding model. Rabbits receiving edoxaban had about 10-fold more blood loss and an 8-fold increased time to hemostasis after a standardised kidney incision compared to controls. Administration of PCC (50 IU/kg) significantly reduced blood loos from 30 to 9 mL and ttime to hemostasis from 23 to 8 min. Biomarkers, such as prothrombin time and thrombin generation parameters, were normalised to a significant extent by the administration of PCC.

This study is another piece of evidence that PCC may be an effective reversal agent for novel oral anti-Xa agents. Systematic studies documenting clinically relevant outcomes in patients who present with major bleeding complications are needed before a final recommendation regarding the use of these agents for this situation can be made. However, in the mean time PCCs remain the best candidate for novel oral anticoagulant reversal in case of severe haemorrhage.

– Marcel Levi

Discuss this article on the Nataonline forum