Effect of Combined Anticoagulation Using Heparin and Bivalirudin on the Hemostatic and Inflammatory Responses to Cardiopulmonary Bypass in the Rat

Abstract

Despite high-dose heparin anticoagulation, cardiopulmonary bypass (CPB) is still associated with marked hemostatic activation. The purpose of this study was to determine whether a reduced dose of bivalirudin, added as an adjunct to heparin, would reduce thrombin generation and circulating markers of inflammatory system activation during CPB as effectively as full-dose bivalirudin, without adversely affecting postoperative hemostasis. Using a model of normothermic CPB in rats, the authors prospectively compared markers of thrombin generation (thrombin-antithrombin complexes) and inflammatory markers (tumor necrosis factor alpha, interleukin 1beta, interleukin 6, and interleukin 10) in three groups: conventional high-dose heparin (H), full-dose bivalirudin (B), and a combined group (standard high-dose heparin with the addition of reduced dose bivalirudin or H&B), at baseline, after 60 min of CPB, and 60 min after CPB. Postoperative hemostasis was also assessed. Groups H&B and B showed reduced thrombin-antithrombin complex formation during CPB compared with group H (P = 0.0003), and this persisted after CPB for group B (P = 0.009). Perioperative increases in interleukin 6 and interleukin 10 showed a trend toward being reduced in animals receiving bivalirudin (P = 0.06). Evidence of residual anticoagulation was found in group H&B as measured by activated clotting time (P = 0.04) and activated partial thromboplastin time (P = 0.02), but no intergroup difference in primary hemostasis was found. Bivalirudin attenuates hemostatic activation during experimental CPB with potential effects on markers of the inflammatory response. However, with this dosing regimen, the combination of heparin and bivalirudin does not seem to confer any measurable advantages over full-dose bivalirudin anticoagulation.