High-Dose Dabigatran Is an Effective Anticoagulant for Simulated Cardiopulmonary Bypass Using Human Blood

Abstract

BACKGROUND: Currently no ideal alternative exists for heparin for cardiopulmonary bypass (CPB). Dabigatran is a direct thrombin inhibitor for which a reversal agent exists. The primary end point of the study was to explore whether Dabigatran was an effective anticoagulant for 120 minutes of simulated CPB. METHODS: The study was designed in 2 sequential steps. Throughout, human blood from healthy donors was used for each experimental step. Initially, increasing concentrations of Dabigatran were added to aliquots of fresh whole blood, and the anticoagulant effect measured using kaolin/tissue factor–activated thromboelastography (rapidTEG). The dynamics of all thromboelastography (TEG) measurements were studied with repeated measures analysis of variance (ANOVA). Based on these data, aliquots of blood were treated with high-concentration Dabigatran and placed in a Chandler loop as a simple ex vivo bypass model to assess whether Dabigatran had sufficient anticoagulant effects to maintain blood fluidity for 2 hours of continuous contact with the artificial surface of the PVC tubing. Idarucizumab, humanized monoclonal antibody fragment, was used to verify the reversibility of Dabigatran effects. Finally, 3 doses of Dabigatran were tested in a simulated CPB setup using a heart–lung machine and a commercially available bypass circuit with an arteriovenous (A-V) loop. The primary outcome was the successful completion of 120 minutes of simulated CPB with dabigatran anticoagulation, defined as lack of visible thrombus. Thromboelastographic reaction (R) time was measured repeatedly in each bypass simulation, and the circuits were continuously observed for clot. Scanning Electron Microscopy (SEM) was used to visualize fibrin formation in the filters meshes during CPB. RESULTS: In in vitro blood samples, Dabigatran prolonged R time and reduced the dynamics of clot propagation (as measured by speed of clot formation [Angle], maximum rate of thrombus generation [MRTG], and time to maximum rate of thrombus generation [TMRTG]) in a dose-dependent manner. In the Chandler Loop, high doses of Dabigatran prevented clot formation for 120 minutes, but only at doses higher than expected. Idarucizumab decreased R time and reversed anticoagulation in both in vitro and Chandler Loops settings. In the A-V loop bypass simulation, Dabigatran prevented gross thrombus generation for 120 minutes of simulated CPB. CONCLUSIONS: Using sequential experimental approaches, we showed that direct thrombin inhibitor Dabigatran in high doses maintained anticoagulation of blood for simulated CPB. Idarucizumab reduced time for clot formation reversing the anticoagulation action of Dabigatran.

Rivaroxaban Reduces the Dabigatran Dose Required for Anticoagulation During Simulated Cardiopulmonary Bypass

“…All CPB experiments were performed as previously described. 5 Briefly, a mixture of 115 mL of citrated human blood, 15 mL of 25% Human Albumin (Baxalta US Inc), and 20 mL of PlasmaLyte-A (Baxter Healthcare Corp) was circulated in a commercially available circuit consisting of 3/16" (arterial) and 1/4" (venous) PVC tubing, a Capiox FX 05 Baby-Fx oxygenator with biopassive coating (Xcoating, Terumo Cardiovascular systems) with integrated arterial filter, and a Hard shell reservoir. The circuit was set up in a CPB pump (COBE Cardiovascular, Inc).…”

“…We have previously shown that Dab can be formulated in a solution suitable for parenteral use and, at high concentrations (≥7500 ng/ml), is an effective and reversible anticoagulant in simulated CPB with human blood. 5 However, at such high concentrations, the reversal of Dab may be problematic in vivo, given the markedly different volumes of distribution of the 2 drugs. 6 It has been previously shown that direct thrombin inhibitors and anti-Xa agents are synergistic, 7 likely due to inhibition of sequential steps in the coagulation cascade.…”

Alternatives to heparin anticoagulation for cardiopulmonary bypass and extracorporeal membrane oxygenation

“…64 Because of concerns for toxicity with the increased dosage necessary for CPB, it has not yet been used in humans for this purpose. 77 Dabigatran is also a substrate of pglycoprotein, and can potentially be subject to interactions with p-glycoprotein inhibitors or inducers. 59 Recently, Nadtochiy et al performed a simulation of CPB using human blood and dabigatran and monitored anticoagulation response via TEG.…”

“…59 Recently, Nadtochiy et al performed a simulation of CPB using human blood and dabigatran and monitored anticoagulation response via TEG. 77 Bypass was maintained for 120 minutes followed by successful reversal with idarucizumab. Additional trials will be needed prior to clinical use.…”

Searching for an Alternate Anticoagulant for Cardiopulmonary Bypass: Does Two Plus Two Equal Two?

“…Idarucizamab successfully reversed the parenteral dabigatran effects, at least in vitro. 3 Unfortunately, the plasma levels of dabigatran utilized on simulated CPB (5000–10,000 ng/mL) were more than an order of magnitude higher than those reversed by idarucizimab in its initial clinical trial (3–640 ng/mL). 5 Such high levels of dabigatran may not be reliably reversed in vivo and have been associated with hepatic toxicity.…”