Con: Heparin is not the best anticoagulant for cardiopulmonary bypass

Abstract

T O SAY THAT heparin is the best anticoagulant for cardiopulmonary bypass (CPB) is to say that no further alternatives to heparin should be sought. However, this is clearly not the case. Heparm is not the 1deal anticoagulant, and the quest for better heparin alternatives should be continued. Extracorporeal circulation induces a total body inflammatory response, resulting in the activation of various inflammatory cascades, only one of which is the coagulation cascade. Thrombin is the major player in the coagulation cascade. Thrombin contributes not only to fibrin generation but also to platelet activation and to activation of the fibrinolytic system. Antithrombin (AT) is the major plasma inhibitor of thrombin. Neutralization of thrombm by AT proceeds slowly in the absence of heparin but is dramatically accelerated in the presence of heparln. I Thus, heparin serves to facilitate the reaction between thrombin and antithrombin. Once the thrombin/antithrombin (TAT) complex is generated, heparin dissociates from the TAT complex and is able to bind another molecule of AT, thus allowing one molecule of heparm to provide multiple rounds of thrombln inhibition. However, during CPB, inactivation of thrombin is incomplete. Despite seemingly adequate heparlnizatlon, there ~s evidence for continued thrombin and fibrin formation in the microcirculation during CPB, as evidenced by the continued generation of prothrombin fragment 1.2 (F1.2), TAT complex, and fibrinopeptide A (FPA). 2,3 This coagulation in the microcirculation places the microvasculature at risk for occlusion. Although heparin is very effective at catalyzing the inhibition of free, circulating, or fluid-phase thrombin by AT, it is a less effective catalyst if the thrombin is bound to fibrin or to a surface. 4 Heparin thus incompletely inhibits clot-bound, fibrin-bound, or solid-phase thrombin because thrombin is protected from inactivation by the heparm/AT complex. Consequently, the bound thrombin remains enzymatically active and is able to facihtate further thrombin generation. When a cardmc patient's blood comes in contact with the large artificial surface of the CPB circuit (approximately 6 m2), contact activation and the extrinsic coagulation cascade are also stimulated. 2 Any thrombin that is accreted onto the CPB circuit may escape inhibition by heparin/AT, thus allowing continued thrombm generation. The continued generation of F1.2, TAT, and FPA despite adequate heparinization for CPB suggests that significant amounts of thrombin escape inhibition and are therefore able to facdltate additional thrombin generation