PB0033 - Validated in vivo model to assess direct oral anticoagulant reversal agents

Background: Acute cardiovascular events such as myocardial infarction and ischaemic stroke are the most common causes of mortality and morbidity in cardiovascular disease. Often these events are associated with thromboembolism, therefore a large population of patients with risk factors for cardiovascular complications has indications for long-term anticoagulant therapy. Such treatment approaches improve prognosis for the patients; however, they increase the risk of life-threatening bleeding. Development of agents that rapidly reverse anticoagulation is required to reduce the risk of major bleeding and improve survival of such patients in emergency situations or to prepare them for surgery interventions. Recently developed non-vitamin K antagonist oral anticoagulants are intended for long-term use and majority do not have antidotes available, therefore a general antidote would be very beneficial.

Aims: Following the unmet clinical need, the aim of this study was to validate an in-vivo model that allows assess efficacy of novel anticoagulant reversal agents.

Methods: Thrombus formation was induced by applying a piece of filter paper saturated with 30% FeCl3 to the right carotid artery, blood flow was recorded until complete occlusion of the vessel and the time to occlusion (TTO) was measured. To mimic patients receiving anticoagulant treatment, we used FXa inhibitor rivaroxaban in Sprague Dawley rats. Rivaroxaban was administered at a concentration just enough to attenuate coagulation. As a reversal treatment, procoagulant concentrate (PC) was injected intravenously after rivaroxaban, but prior to FeCl3 injury. Blood samples were collected to perform in vitro coagulation assays.

Results: Rivaroxaban administration significantly extended TTO. Coagulation tests revealed an increase in aPTT and PT in treated animals. Injections of PC demonstrated reversal of rivaroxaban anticoagulant effect as shown by reduced TTO and restored aPTT and PT.

Conclusion(s): Here we report a fast and reproducible in-vivo model that can be used for preclinical efficacy testing of direct anticoagulant antidotes for life-threatening bleeding.