From the Department of Anesthesiology and Perioperative Medicine, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Cardiovascular Perfusion, Golisano Children's Hospital, University of Rochester Medical Center, Rochester, New York.
Anesth Analg. 2022 Jul 1;135(1):52-59. doi: 10.1213/ANE.0000000000006019. Epub 2022 Apr 7.
Heparin is the standard anticoagulant for cardiopulmonary bypass (CPB); however, there are problems with its use that make the development of suitable alternatives desirable. Currently, no ideal alternative exists. We have previously reported that the direct thrombin inhibitor dabigatran can prevent coagulation in simulated CPB at high concentrations. These high concentrations may cause difficulties in achieving the reversal of dabigatran with idarucizumab, given the markedly different pharmacokinetics of the 2 drugs. Herein, we test the hypothesis that the addition of the anti-Xa drug rivaroxaban would provide suitable anticoagulation at a lower concentration of dabigatran given likely synergy between the 2 classes of drugs. The primary goal of the study was to investigate whether the addition of rivaroxaban reduces the concentration of dabigatran necessary to allow 2 hours of simulated CPB.
The study was performed in sequential steps. Blood collected from consenting healthy donors was used throughout. First, we added graded concentrations of dabigatran and rivaroxaban alone and in combination and assessed inhibition of anticoagulation using thromboelastometry. Using results from this step, combinations of dabigatran and rivaroxaban were tested in both Chandler loop and simulated CPB circuits. Dabigatran and rivaroxaban were added before recalcification, and the circuits were run for 120 minutes. In both models of CPB, 120 minutes of circulation without visible thrombus was considered successful. In the Chandler loop system, idarucizumab was added to reverse anticoagulant effects. In the CPB circuits, the arterial line filters were examined using scanning electron microscope (SEM) to qualitatively assess for fibrin deposition.
In vitro analysis of blood samples treated with dabigatran and rivaroxaban showed that dabigatran and rivaroxaban individually prolonged clotting time (CT) in a dose-dependent manner. However, when combined, the drugs behaved synergistically. In the Chandler loop system, dabigatran 2400 and 4800 ng/mL plus rivaroxaban (150 ng/mL) effectively prevented clot formation and reduced the dynamics of clot propagation for 120 minutes. Idarucizumab (250-1000 µg/mL) effectively reversed anticoagulation. In the CPB circuits, dabigatran (2500 ng/mL) and rivaroxaban (200 ng/mL) were successful in allowing 120 minutes of simulated CPB and prevented fibrin deposition. Biomarkers of coagulation activation did not increase during simulated CPB. Heparin controls performed similarly to dabigatran and rivaroxaban.
The dual administration of oral anticoagulant drugs (dabigatran and Rivaroxaban) with different pharmacologic mechanisms of action produced synergistic inhibition of coagulation in vitro and successfully prevented clotting during simulated CPB.
肝素是体外循环（CPB）的标准抗凝剂；然而，其使用存在一些问题，这使得开发合适的替代品成为必要。目前，还没有理想的替代品。我们之前曾报道过，直接凝血酶抑制剂达比加群在高浓度下可防止模拟 CPB 中的凝血。鉴于这两种药物的药代动力学明显不同，这些高浓度可能会导致用依达鲁单抗逆转达比加群的难度。在这里，我们假设添加抗 Xa 药物利伐沙班可以在较低浓度的达比加群下提供适当的抗凝作用，因为这两种药物可能具有协同作用。该研究的主要目的是研究添加利伐沙班是否可以降低达比加群的浓度，从而允许进行 2 小时的模拟 CPB。
该研究分阶段进行。整个研究过程都使用了来自同意的健康供体的血液。首先，我们单独和联合添加不同浓度的达比加群和利伐沙班，并使用血栓弹性描记法评估抗凝抑制作用。根据这一步骤的结果，在 Chandler 环和模拟 CPB 回路中测试了达比加群和利伐沙班的组合。在重新钙化前添加达比加群和利伐沙班，并将回路运行 120 分钟。在这两种 CPB 模型中，120 分钟无可见血栓的循环被认为是成功的。在 Chandler 环系统中，添加依达鲁单抗逆转抗凝作用。在 CPB 回路中，使用扫描电子显微镜 (SEM) 检查动脉线过滤器，定性评估纤维蛋白沉积。
用达比加群和利伐沙班处理的血液样本的体外分析表明，达比加群和利伐沙班单独使用时，凝血时间（CT）呈剂量依赖性延长。然而，当联合使用时，这些药物表现出协同作用。在 Chandler 环系统中，达比加群 2400 和 4800 ng/mL 加利伐沙班（150 ng/mL）可有效防止血栓形成，并在 120 分钟内减少血栓传播的动力学。依达鲁单抗（250-1000 µg/mL）可有效逆转抗凝作用。在 CPB 回路中，达比加群（2500 ng/mL）和利伐沙班（200 ng/mL）可成功进行 120 分钟的模拟 CPB，并防止纤维蛋白沉积。凝血激活的生物标志物在模拟 CPB 期间没有增加。肝素对照与达比加群和利伐沙班的作用相似。
两种不同药理作用机制的口服抗凝药物（达比加群和利伐沙班）的联合应用，在体外产生协同的抗凝抑制作用，并成功防止模拟 CPB 中的血栓形成。
