SELECTIVE ANTICOAGULATION WITH ACTIVE SITE-BLOCKED FACTOR IXA SUGGESTS SEPARATE ROLES FOR INTRINSIC AND EXTRINSIC COAGULATION PATHWAYS IN CARDIOPULMONARY BYPASS

Background: Multiple stimuli converge in cardiopulmonary bypass to cre ate a tremendous prothrombotic stimulus. The ideal anticoagulant for c ardiopulmonary bypass should selectively target only the intravascular stimuli, thereby eliminating pathologic clotting in the bypass circui t while preserving hemostasis in the thoracic cavity:We propose the in hibition of factor IX as such a targeted anticoagulant strategy Method s: We prepared an inhibitor of activated factor IX and applied it to a primate model of cardiopulmonary bypass to confirm the anticoagulant efficacy of activated factor Iii in this setting and to assess more su btle markers of thrombin generation, macrophage procoagulant activity, and cellular tissue factor expression, Seven baboons that received ac tivated factor IS (460 mu g/kg) and 7 that received heparin (300 IU/kg ) and protamine underwent cardiopulmonary bypass for 90 minutes and we re followed after the operation for 3 hours. Results: Analysis of plas ma factor IX activity demonstrated adequate inhibition (<20%) of facto r Iii throughout cardiopulmonary bypass. Activated factor Iii-treated baboons demonstrated similar circuit patency to heparin-treated baboon s but had significantly diminished intraoperative blood loss. Preserva tion of extravascular hemostasis was further demonstrated in activated factor IS-treated animals by (1) significantly increased levels of th rombin-antithrombin III complex and prothrombin activation peptide (F1 +2) without intravascular thrombosis, (2) significantly greater macrop hage procoagulant activity in pericardial-derived monocytes, and (3) i mmunohistochemical evidence of tissue factor expression in pericardial mesothelial cells and macrophages. Conclusions: Anticoagulation with activated factor Iii allows for intravascular anticoagulation with mai ntenance of extravascular hemostasis, These findings suggest activated factor Iii as an agent that not only exemplifies a targeted approach to selective anticoagulation in cardiac surgery but also further chara cterizes the procoagulant milieu during cardiopulmonary bypass.