Intravenous dabigatran provides adequate anticoagulation for cardiopulmonary bypass using a rabbit model

by Selleckchem | Mar 17 2023

Background–: Heparin anticoagulation has been used successfully for cardiopulmonary bypass (CPB). However, an alternative anticoagulant approach is desirable due to the cases of heparin-induce thrombocytopenia. Dabigatran provides anticoagulation for an in-vitro model of simulated CPB. The current analysis tests the hypothesis that dabigatran provides sufficient anticoagulation for CPB in intact rabbits.

Methods –: Nonlinear mixed effects models were used to estimate dabigatran parameters for a 2-compartment pharmacokinetic model in 10 New Zealand White rabbits. A dabigatran infusion designed to maintain a plasma concentration of 90 µg/mL was run throughout CPB based on the pharmacokinetics. Animals were subjected to sternotomy, and anticoagulated with intravenous dabigatran (6 animals) or heparin (4 animals). Rabbits were cannulated centrally using the right atrium and ascending aorta and CPB was maintained for 120 minutes. Measurement of activated clotting time, thromboelastometric reaction time (R), and blood gases were performed during CPB. Then, the animals were sacrificed and the brain and one kidney were removed for histology. Sections of the arterial filters were inspected using electron microscopy.

Results –: The observed dabigatran concentrations during CPB were above the target concentration, ranging from 137 ± 40 μg/mL at 5 min of CPB to 428 ± 150 μg/mL at 60 min, and 295 ± 35 μg/mL at 120 min. All rabbits completed 2 hours of CPB without visible thrombosis. In the two groups reaction time (R) values were elevated, reaching 10262 ± 4198 sec (dabigatran group) and 354 ± 141 sec (heparin group) at 120 min of CPB. Brains and kidneys showed no evidence of thrombosis or ultrastructural damage. Sections of the arterial line filter showed minimal or no fibrin. There was no significant difference in outcomes between dabigatran and heparin treated animals.

Conclusions –: In this first-use, proof of concept study, we have shown that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis using a rabbit CPB model.

Comments：

The study aimed to investigate whether dabigatran, an alternative anticoagulant to heparin, can provide sufficient anticoagulation during cardiopulmonary bypass (CPB) in intact rabbits. A pharmacokinetic model was used to estimate dabigatran parameters for a 2-compartment model in 10 New Zealand White rabbits. The rabbits were anticoagulated with either intravenous dabigatran (6 animals) or heparin (4 animals) and subjected to sternotomy. CPB was maintained for 120 minutes, during which activated clotting time, thromboelastometric reaction time (R), and blood gases were measured. After sacrifice, brain and one kidney were removed for histology and sections of the arterial filter were inspected using electron microscopy.

The results showed that the observed dabigatran concentrations during CPB were above the target concentration and ranged from 137 ± 40 μg/mL to 428 ± 150 μg/mL. All rabbits completed 2 hours of CPB without visible thrombosis. The R values were elevated in both groups, reaching 10262 ± 4198 sec in the dabigatran group and 354 ± 141 sec in the heparin group at 120 min of CPB. There was no significant difference in outcomes between the dabigatran and heparin-treated animals. The brains and kidneys showed no evidence of thrombosis or ultrastructural damage, and sections of the arterial line filter showed minimal or no fibrin.

In conclusion, the study demonstrated that dabigatran provides acceptable anticoagulation similar to heparin to prevent thrombosis in a rabbit CPB model. This proof of concept study provides a potential alternative anticoagulant approach to heparin, which may be desirable due to the cases of heparin-induced thrombocytopenia. Further studies are required to validate the results and to evaluate the safety and efficacy of dabigatran in human CPB.