High antithrombin III levels attenuate hemostatic activation and leukocyte activation during cardiopulmonary bypass

Abstract

Despite heparinization, cardiac surgery involving cardiopulmonary bypass (CPB) induces a powerful activation of the coagulation and inflammation system. This is caused by the contact of the blood with the large non-endothelial surfaces of CPB, the release and reinfusion of tissue factor-enriched blood from the operation field, the surgical trauma, and the reperfusion of ischemic tissue. As a result, the plasma coagulation factors and platelets are progressively consumed, the complement system and leukocytes are activated, and the proteases and cytokines are released. Clinical consequences of this sequel are hemorrhage, transfusions, and organ damage. Particularly in the myocardium, this systemic activation of the inflammatory system may further trigger regional reperfusion injury and thereby contribute to myocardial stunning, impaired contractility, and low cardiac output. Thrombin plays a pivotal role in the modulation of leukocyte activation: It increases neutrophil recruitment, neutrophil rolling by the expression of endothelial P- and E-selectin, neutrophil adhesion by the expression of intracellular adhesion molecule 1, and the production of endothelial platelet-activating factor. 1 The current investigation assesses the impact of enhanced antithrombin (AT) activity, induced by a high dose of ATIII before the initiation of CPB, on key biochemical markers of hemostatic and leukocyte activation. Methods Patients and anticoagulation protocol. After approval by the local ethics committee and informed consent were obtained, 80 patients undergoing elective coronary artery bypass grafting were enrolled in this prospective, randomized, controlled investigation. No patient received warfarin (Coumadin, Bristol-Myers Squibb, New York, NY) or antiplatelet therapy within 10 days before surgery. Two groups with 40 patients each were formed. In group one (H), in accordance with the departmental standard, anticoagulation was performed according to the results of the Hepcon HMS Plus (Medtronic, Minneapolis, Minn). In group two (HATIII), an additional bolus of 50 IU/kg ATIII (Grifols, Langen, Germany) was given with the initial bolus of heparin before CPB. Blood samples were collected 10 minutes after the administration of the heparin bolus before CPB and after termination of CPB before protamine infusion. Anesthesia was performed using a total intravenous technique with propofol, sufentanil, midazolam, and pancuronium bromide. Normothermic CPB was accomplished with nonheparin-coated systems, membrane oxygenators, and roller pumps. None of the patients received antifibrinolytic agents or the kallikrein inhibitor aprotinin. Laboratory analysis. Heparin anti-Xa activity was determined using the STA-Rotachrom Heparin (Roche, Mannheim, Germany). ATIII was determined using the Coamatic LR Antithrombin Chromogenix assay (Hemochron Diagnostica, Essen, Germany). Prothrombin 1 and 2 fragments (PTF12) were assessed using the Enzygnost F1-2 micro assay (Dade Behring, Marburg, Germany). Soluble fibrin was measured using the COATEST Soluble Fibrin assay (Chromogenix, Milano, Italy). Interleukin (IL)-6 was measured using the IL-6 enzyme-linked immunosorbent assay (DPC Biermann, Nauheim, Germany). Polymorphonuclear leukocyte (PMNL) elastase was determined with the use of a luminescence immunoassay (Auto-CliniLumat LB 952, Bertold, Wildbad, Germany).