Dabigatran in Rabbit Cardiopulmonary Bypass: Comment

Nadtochiy et al.  report using intravenous dabigatran, a direct thrombin inhibitor (DTI), for anticoagulation in an animal model of simulated cardiopulmonary bypass (CPB).  Activated clotting time, thromboelastometric reaction time, and fibrin deposition in sections of the arterial line filters were analyzed to compare anticoagulation with dabigatran or heparin. In their CPB model, the authors suggest that dabigatran provides adequate anticoagulation similar to heparin for preventing thrombosis.

The need for a safe and effective heparin alternative for cardiac surgery in patients with heparin-induced thrombocytopenia is important because the main limitation for all heparin alternatives, including danaparoid, lepirudin, bivalirudin, and argatroban, is the lack of a specific reversal agent.  The fact that the monoclonal antibody fragment idarucizumab can effectively reverse dabigatran suggests it may represent a potential heparin alternative for anticoagulation in cardiac surgery with CPB. Unfortunately, unlike the oral form of dabigatran (dabigatran etexilate mesylate, Pradaxa, Boehringer Ingelheim, Germany), intravenous dabigatran is not clinically available.

However, the CPB model studied by Nadtochiy et al. (Chandler Loop, Neuffen, Germany) resembles an extracorporeal membrane oxygenation (ECMO) model more than a conventional CPB circuit. While ECMO is a completely closed system, CPB is open, because blood is drained directly or via cardiotomy suction into a hard shell venous reservoir allowing blood-air contact. Blood stasis must be avoided when using the short-acting DTI bivalirudin to prevent thrombus formation in the CPB circuit. During our previous experience with lepirudin, the first DTI studied in cardiac surgery with CPB, we frequently noted clot formation in the surgical field and the cardiotomy reservoir after the conclusion of CPB despite adequate drug levels. However, clot formation is rare when heparin is used. Most likely, the differential effect of heparin and DTIs on hemostatic activation and thrombin generation provides an explanation.  In addition to contact activation on the nonendothelial surfaces of the CPB system, cardiotomy suction plays an important role in hemostatic activation, as highly activated tissue factor–enriched blood from the operating field is drained into the venous reservoir.  Heparin inhibits the final step of fibrin formation by inhibiting plasma, but not clot-bound thrombin, and inhibits the activation of factor X after initiation of coagulation via the extrinsic tissue factor–dependent factor VII activation. In addition to these direct effects on coagulation, heparin also increases plasma concentrations of tissue factor inhibitor, thereby attenuating extrinsic hemostatic activation.  In contrast, DTIs effectively inhibit plasma and clot-bound thrombin, but the effects on other coagulation cascades are limited to negative feedback loops targeting the propagation phase via inhibition of coagulation factors V and VIII.  (fig. 1). The effect of heparin on both the propagation phase and the final fibrin formation phase may explain the inhibition of thrombin generation in cardiac surgery compared with DTIs.

We acknowledge the authors’ novel evaluation of intravenous dabigatran in cardiac surgery. However, the data they reported only support a potential application in a closed-circuit system like ECMO. Furthermore, a model attempting to simulate anticoagulation during CPB requires the implementation of cardiotomy suction and a venous cardiotomy reservoir. In this regard, we fully agree with Nadtochiy et al. that additional work is needed before intravenous dabigatran can be declared a potential anticoagulant for cardiac surgery with CPB.