HIT II is a serious side effect of heparin that may cause thrombocytopenia and thromboembolism when platelet factor 4/heparin complex and HIT antibody form an immune complex to activate blood platelets [
1]. Re-administration of heparin has been contraindicated for HIT II patients, but HIT antibody is transient and becomes negative in about 50 to 85 days [
5]. Thus, an increasing number of reports suggest that reuse of heparin may not necessarily cause redevelopment of HIT II after HIT antibody becomes negative [
6,
7]. However, since redevelopment of HIT II has been reported [
1], we did not use heparin in our case. In the treatment of HIT II, when APTT is used as an index, it is often adjusted to 1.5 to 3.0 times the pre-dose value, but there is no clear standard for APTT and ACT in heart surgery using cardiopulmonary bypass [
8]. In this case, argatroban was titrated to achieve a target APTT of 60 to 100 s, and ACT was maintained for 400 s or more during cardiopulmonary bypass as in the normal heart surgery.
Argatroban, a direct thrombin inhibitor that binds avidly and reversibly to the catalytic site of thrombin and that does not require other cofactors to exert its antithrombotic action, is often used in open-heart surgery for patients with HIT II [
9,
10]. After initial bolus administration at 0.1–0.3 mg/kg and continuous dosing at 5–10 μg/kg/min during cardiopulmonary bypass, additional bolus doses and an increase in the continuous dose are often required to achieve the target ACT [
11,
12]. Similarly, in our case, additional administration was required to achieve the target ACT after continuous dosing at about 11.3 μg/kg/min after bolus administration of about 0.3 mg/kg. In all previously reported cases of open-heart surgery in pediatric patients with HIT II, ACT far exceeded the target level after additional administration of argatroban based on ACT [
13]. In addition, many reports suggest that 7–26 h are required for ACT to return to the preadministration level, and intra- and postoperative recovery of blood coagulation ability is prolonged, causing increased bleeding and blood transfusion volumes [
9,
11,
14]. This may be because argatroban has an onset time of as long as 30 min, and a similarly long half-life of about 30 min. Unlike heparin, there are no antagonists for argatroban, and thus its effects cannot be antagonized upon excessive administration. For these reasons, we decided to use argatroban concomitantly with nafamostat mesilate, which has a shorter half-life (23 min) than that of argatroban. Nafamostat mesilate is inactivated due to hydrolysis by carboxylesterase which is present in blood and liver and the short duration of action is quite favorable for use with an extracorporeal circulation system [
2,
3]. On the other hand, nafamostat mesilate is insufficient to inhibit extrinsic coagulation, and when used alone for extracorporeal circulation, a large amount of thrombus may be formed in the reservoir [
15]. Therefore, we also used Celite ACT, which reflects the effect of both argatroban and nafamostat mesilate, and kaolin ACT, which does not reflect the effect of nafamostat mesilate due to its adsorption [
4], as markers of the anticoagulant effects of only argatroban, and as a basis for discontinuation of continuous administration of argatroban. Using this approach, ACT recovered to ≤ 200 s comparatively early, at 5 h after discontinuation of argatroban. Concomitant argatroban and nafamostat mesilate have been used only in one case for open-heart surgery for HIT II patients [
16], but in no pediatric cases. After 3 h from the start of anesthesia, kaolin ACT exceeded 500 s and the effect of argatroban seemed to be sufficient, and as a result, nafamostat administration may not be necessary. Further clinical studies are needed to determine whether the combination of nafamostat mesilate and argatroban contributes to a decrease dose of argatroban and reduced perioperative bleeding. Celite and kaolin ACTs can be used as markers to obtain close control of the required dose of argatroban in combination with nafamostat mesilate during the surgical procedure of HIT II patients.