Influence of high-dose aprotinin on anticoagulation, heparin requirement, and celite-and kaolin-activated clotting time in heparin-pretreated patients undergoing open-heart surgery: A double-blind, placebo-controlled study

Abstract

Background: Aprotinin causes a prolongation of the celite-activated clotting time (CACT), but not of the kaolin-activated clotting time (KACT). Therefore, concern has been raised regarding the reliability of CACT to monitor anticoagulation in the presence of aprotinin. The current study was designed to test the efficacy of aprotinin to improve anticoagulation, and to investigate whether the prolongation of CACT reflects true anticoagulation or is an in vitro artifact. To elucidate this antithrombotic effect of aprotinin, this study was done in patients prone to reduced intraoperative heparin sensitivity. Methods: In a prospective, randomized, double-blind clinical trial, 30 male patients scheduled for elective primary coronary revascularization and treated with heparin for at least 10 days preoperatively, received either high-dose aprotinin (group A) or placebo (group c). The CACT and KACT were determined, but only CACT was used to control anticoagulation with heparin. Parameters of coagulation that are indicators of thrombin generation and activity (F1+2 prothrombin fragments, thrombin-antithrombin III complex, and fibrin monomers), parameters of fibrinolysis (D-dimers), aprotinin, and heparin plasma concentrations were measured. Postoperative blood loss and allogeneic blood transfused were recorded. Results: Total heparin administered was 36,200 units (95% confidence interval: 31,400-41,000; group C) compared with 27,700 (25,500-29,800) units (group A; P < 0.05). Hemostatic activation during cardiopulmonary bypass (CPB) was significantly reduced in group A compared with group C. After 60 min of CPB, all parameters were significantly different (P < 0.05) between the groups (group C vs. group A): F1+2 prothrombin fragments, 9.7 (8.9-11.7) ng/ml versus 7.5 (6.2-8.6) ng/ml; thrombin-anti-thrombin III complex (TAT), 53 (42-68) ng/ml versus 29 (23-38) ng/ml; and fibrin monomers, 23 (1243) ng/ml versus 8 (3-17) ng/ml. Fibrinolysis was also attenuated; D-dimers at the end of operation were 656 (396-1,089) and 2,710 (1,811-4,055) ng/ml for groups A and C, respectively (P < 0.05). The CACT 5 min after the onset of CPB was 552 (485-627) versus 869 (793-955) s for groups C and A, respectively (P < 0.05), whereas the KACT showed no differences between the groups (569 [481-675] vs. 614 [541-697] s for groups C and A, respectively; P = NS). The 24-h blood loss was 1,496 (1,125-1,995) versus 597 (448-794) ml for groups C and A, respectively (P < 0.05). Conclusions: Aprotinin treatment in combination with heparin leads to less thrombin generation during CPB. Aprotinin has anticoagulant properties. Celite-activated ACT is reliable for monitoring anticoagulation in the presence of aprotinin, because the prolonged CACT in the aprotinin group reflects improved anticoagulation. Kaolin-activated ACT does not reflect this effect of aprotinin.