ACT is the standard monitor to evaluate anticoagulation by UFH in cardiac surgery requiring CPB. Although it is recommended to maintain ACT at more than 480 s during CPB [4], the threshold of 480 s has been developed only for UFH; the recommended ACT threshold for DTI or the combination of UFH and DTI has not been established. Indeed, intravenous DTI such as argatroban or bivalirudin is recommended as an alternative to UFH in a patient with heparin contraindications [4, 5], and the quality of anticoagulation with DTI may differ from that with UFH because several case reports indicated thrombus formation in the CPB circuit, although ACT showed a prolonged value of more than 480 s during CPB [1,2,3]. The difference between DTI and UFH in the risk of thrombus formation during CPB may be attributed to a characteristic of DTI inhibiting the initiation phase in coagulation but not the propagation and amplification phases [6, 7]. Furthermore, anticoagulation with dabigatran, an oral DTI, during CPB is still under exploration for future clinical use, and its safety in the clinical setting is not confirmed [8, 9]. Thus, we considered that anticoagulation in our case should be established by an adequate dose of UFH even though ACT was prolonged partially by dabigatran. However, we could not determine the dose of UFH according to ACT because ACT was prolonged due to both dabigatran and UFH. To evaluate the anticoagulation by dabigatran and UFH separately, we compared R between CK and CKH assays in TEG. As described in the case presentation, the prolongation of CKH-R indicates the effect of dabigatran because heparinase contained in the CKH reagent abrogates the effect of UFH. CKH-R showed a prolonged value of 18.3 min (normal range: 4.3–8.3), which corresponds to a plasma dabigatran concentration in the therapeutic range according to the results of an in vitro study investigating the effects of dabigatran on TEG [10].

We considered significant amount of dabigatran was contributing to prolonged ACT and administered idarucizumab to abrogate the effect of dabigatran so that we could evaluate the effect of UFH on ACT. Idarucizumab is the specific antidote for dabigatran and is approved for preemptive administration before an urgent surgery in which severe bleeding due to dabigatran is anticipated. Idarucizumab specifically binds to dabigatran with high affinity and instantly abrogates the anticoagulant activity of dabigatran without affecting the effect of UFH. It does not bind to thrombin substrates including factors V, VIII, and XIII or fibrinogen, nor exhibit thrombin-like activity, as demonstrated by a lack of activity in coagulation or platelet aggregation tests [11]. Thus, idarucizumab does not directly activate coagulation system, instead, it works by neutralizing dabigatran, which indirectly leads to the normalization of coagulation parameters such as R in TEG.

After administration of idarucizumab, ACT decreased from 419 to 327 s, indicating insufficient anticoagulation by UFH for the initiation of CPB. Although it was uncertain about the exact dose of UFH to increase ACT from 327 s to more than 480 s, we administered 200 U/kg of UFH based on our clinical experience and increased ACT more than 600 s. One of the advantages of performing TEG in a patient receiving both UFH and dabigatran is to facilitate the determination of the indication for idarucizumab. As described previously, anticoagulation by DTI during CPB should be avoided so far as possible due to the risk of thrombus formation. Indeed, it might seem routine administration of idarucizumab before heparinization for CPB could be reasonable in such a patient; however, the cost of idarucizumab, more than US $5000 for 5 g, does not always allow the routine dosing. Ecarin clotting time (ECT) is one of the specific assays for monitoring the effect of DTI such as dabigatran [12]; however, it is not a common laboratory test in clinical practice. CK-R in TEG which is a coagulation time activated by kaolin has been shown to correlate with plasma dabigatran concentration and could be a surrogate for ECT [13]. As the effect of UFH is abrogated by heparinase in CKH assay, prolongation of CKH-R could be a parameter to evaluate the effect of residual dabigatran. To avoid the unnecessary administration of idarucizumab, performing TEG in a patient receiving both UFH and dabigatran, especially evaluating CK-R and CHK-R, would be helpful to physicians.

There are two limitations in this case report. The first is the ability of heparin neutralization by heparinase used in CKH assay. As UFH activity could be accurately quantified by the ratio of CK-R to CKH-R in the range of 0.05 to 0.8 U/mL [14], the effect of dabigatran might be overestimated in case the heparin concentration is more than 0.8 U/mL. However, the concentration between 0.3 and 0.7 U/mL is recommended as a therapeutic range for the treatment of venous thromboembolism with UFH [15]. And it has been shown that the range for therapeutic vascular procedures including aortic endovascular surgery is between 0.5 and 1.0 U/mL [16]. Thus, we consider TEG could be applicable even if the patient received UFH in antithrombotic therapy or most vascular procedures requiring low-dose UFH. The second is the threshold of CKH-R prolongation to determine the administration of idarucizumab is not defined clearly. It has been shown that dabigatran could prolong ACT and CK-R in a dose-dependent manner [9]. And these parameters went up over the upper limit of the normal range at 50 ng/mL of dabigatran, which is slightly lower than the trough level of dabigatran (70–90 ng/mL) [17]. Thus, we speculate idarucizumab should be administered to minimize the effect of dabigatran on ACT when CKH-R exceeds the normal range.

In conclusion, global hemostasis test in TEG, especially comparing CK-R and CKH-R, could be useful to evaluate the residual effect of dabigatran in a patient receiving both UFH and dabigatran. It could help physicians to determine the need for idarucizumab and also an adequate dose of UFH to establish appropriate anticoagulation for CPB.