title: Reducing thrombin formation during cardiopulmonary bypass: is there a benefit of the additional anticoagulant action of aprotinin?
abstract: During cardiopulmonary bypass (CPB), contact-phase activation of factor XII, prekallikrein, and high molecular weight kininogen initiates the intrinsic pathway of coagulation. To prevent gross clot formation during CPB, heparin is commonly used as an anticoagulant. There is a wide variability in the sensitivity of individual patients to the actions of heparin. We did not find a significant correlation between plasma heparin levels and concentrations of D-dimers, thrombin-antithrombin III complexes (TAT), and prothrombin fragments F1+2 as markers of fibrinolysis and coagulation activation. In addition, heparin cannot completely inhibit thrombin formation and action and may play a central role in the coagulation disorders associated with CPB. F1+2 and TAT rise throughout the course of CPB and fibrin monomers are generated. Attempts to improve anti-coagulation using heparin-coated bypass circuits and specific inhibitors of thrombin have not thus far proven successful. The serine protease inhibitor aprotinin can inhibit contact-phase activation, as evidenced by generation of significantly fewer prothrombin fragments F1+2, thrombin-antithrombin III complexes, fibrinopeptide A, and fibrin monomers in aprotinin-treated patients undergoing cardiac surgery. Studies performed with a simulated CPB system have shown attenuation of plasma kallikrein C1 inhibitor complex (PKC1 I) with aprotinin and the recombinant Arg 15 aprotinin. This action of aprotinin to inhibit contact-phase activation may influence the degree of anticoagulation with heparin. Patients treated with aprotinin require approximately 20% less heparin to achieve an activated clotting time (ACT) of 400 s than control patients. Despite lower plasma concentrations of heparin, aprotinin-treated patients had significantly lower concentrations of the markers of coagulation activation (thrombin-antithrombin III complex, fibrin monomers, and antiplasmin-plasmin complex). We have also investigated the role of aprotinin in contact-phase [correction of contact phase] activation of fibrinolysis. Patients treated with aprotinin showed higher concentrations of single-chain urinary type plasminogen activator (scuPA) at the end of CPB compared with control patients, indicating reduced contact- phase [correction of contact phase] activation.
authors.affiliation: German Heart Center, Institute of Anesthesiology, Munich, Germany.
authors.forename: W
authors.initials: W
authors.lastname: Dietrich
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use*; D007611:Aprotinin / Q000627:therapeutic use*; D001777:Blood Coagulation / Q000187:drug effects / Q000502:physiology; D002315:Cardiopulmonary Bypass / Q000009:adverse effects*; D003167:Complement Activation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D013917:Thrombin / Q000096:biosynthesis*
chemical_list: D000925:Anticoagulants; D007611:Aprotinin; D013917:Thrombin