BACKGROUND: 

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.

METHODS: 

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.

RESULTS: 

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.

CONCLUSIONS: 

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.

中文翻译：

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利伐沙班减少模拟体外循环期间抗凝所需的达比加群剂量

背景： 

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，因此需要开发合适的替代品。目前，不存在理想的替代方案。我们之前报道过直接凝血酶抑制剂达比加群在高浓度下可以防止模拟体外循环中的凝血。鉴于这两种药物的药代动力学显着不同，这些高浓度可能会导致难以实现达比加群与伊达赛珠单抗的逆转。在此，我们测试了这样的假设：考虑到两类药物之间可能存在协同作用，添加抗 Xa 药物利伐沙班将在较低浓度的达比加群下提供适当的抗凝作用。该研究的主要目标是调查添加利伐沙班是否会降低模拟 CPB 2 小时所需的达比加群浓度。

方法： 

该研究按顺序步骤进行。整个过程中使用的是从同意的健康捐献者那里采集的血液。首先，我们添加了单独和组合的达比加群和利伐沙班的分级浓度，并使用血栓弹力测定法评估了抗凝抑制作用。利用该步骤的结果，在钱德勒环路和模拟 CPB 环路中测试了达比加群和利伐沙班的组合。在重新钙化之前添加达比加群和利伐沙班，并且电路运行 120 分钟。在这两种 CPB 模型中，120 分钟的循环且没有可见血栓就被认为是成功的。在钱德勒环系统中，添加了 idarucizumab 以逆转抗凝作用。在 CPB 回路中，使用扫描电子显微镜 (SEM) 检查动脉管路过滤器，以定性评估纤维蛋白沉积。

结果： 

对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分别以剂量依赖性方式延长凝血时间（CT）。然而，当结合使用时，这些药物会产生协同作用。在钱德勒环系统中，达比加群 2400 和 4800 ng/mL 加利伐沙班 (150 ng/mL) 有效防止血栓形成并降低血栓传播的动态，持续 120 分钟。Idarucizumab (250–1000 µg/mL) 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) 成功允许模拟 CPB 120 分钟并防止纤维蛋白沉积。在模拟体外循环期间，凝血激活的生物标志物没有增加。肝素对照的表现与达比加群和利伐沙班相似。

结论： 

具有不同药理作用机制的口服抗凝药物（达比加群和利伐沙班）的双重给药在体外产生协同抑制凝血作用，并成功防止模拟体外循环期间的凝血。