Argatroban as a Potential Anticoagulant in Cardiopulmonary Bypass-Studies in a Dog Model

Abstract

Argatroban is a selective thrombin inhibitor synthesized in Japan. Argatroban, which has a high affinity for thrombin, and markedly inhibits thrombin-induced reactions, has been used in patients with artherosclerosis obliterans. The efficiency of argatroban, instead of heparin, as an anticoagulant in dog models of cardiopulmonary bypass was explored. In the first study, argatroban was administered as a bolus plus infusion for 1 h during cardiopulmonary bypass at doses of 1.0 mg + 10 μg/kg per min, 2.0 mg + 10 μg/kg per min and 3.0 mg + 10 μg/kg per min ( n = 2 per group). Activated clotting time and arterial gas analyses were performed beforehand and 10 min thereafter. In the second study, there were four groups. In the first group ( n = 5) no coated extracorporeal circuit was used and heparin (2 mg/kg) was used as an anticoagulant. In the second group ( n = 5). a coated extracorporeal circuit was used and heparin was used (2 mg/kg) as an anticoagulant. In the third group ( n = 3), no coated extracorporeal circuit was used and argatroban (2.0 mg + 10μg/kg per min) was used as an anticoagulant. In the fourth group ( n = 5), a coated extracorporeal circuit was used and argatroban was used (2.0 mg + 10 μg/kg per min) as an anticoagulant. All animals were perfused for 120 min at 40 ml/kg per minute. Platelet count, activated clotting time, thrombin—antithrombin III complex, antithrombin III. fibrinogen, fibrinogen degradation products and C3a were measured to evaluate platelet, coagulofibrinolytic and the complement system. Activated clotting time values and the effect of argatroban during cardiopulmonary bypass indicated a dose-dependent response. The next highest dosing group (2.0 mg + 10 μg/kg per minute) had activated clotting time values of 250–300 seconds during cardiopulmonary bypass and fell after reaching near-normal levels within 60 minutes. No clots were noted in the extracorporeal circuit. The argatroban group showed lower levels in their coagulofibrinolytic system compared with the heparin group. The platelet count remained at a high level in the argatroban group. It is concluded that the combination of heparinized cardiopulmonary bypass circuits, and the use of argatroban as an anticoagulant, is safe and reduces the activation of coagulation and fibrinolytic systems and preserves platelet count.