HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Spanier, T. Articles by Schmidt, A. Search for Related Content PubMed PubMed Citation Articles by Spanier, T. Articles by Schmidt, A.

The Journal of Thoracic and Cardiovascular Surgery, Vol 116, 860-869, Copyright © 1998 by The American Association for Thoracic Surgery and The Western Thoracic Surgical Association

ARTICLES

Selective anticoagulation with active site-blocked factor IXA suggests separate roles for intrinsic and extrinsic coagulation pathways in cardiopulmonary bypass

TB Spanier, JM Chen, MC Oz, NM Edwards, W Kisiel, DM Stern, EA Rose and AM Schmidt
Department of Surgery, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.

BACKGROUND: Multiple stimuli converge in cardiopulmonary bypass to create a tremendous prothrombotic stimulus. The ideal anticoagulant for cardiopulmonary bypass should selectively target only the intravascular stimuli, thereby eliminating pathologic clotting in the bypass circuit while preserving hemostasis in the thoracic cavity. We propose the inhibition of factor IX as such a targeted anticoagulant strategy. METHODS: 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 IX in this setting and to assess more subtle markers of thrombin generation, macrophage procoagulant activity, and cellular tissue factor expression. Seven baboons that received activated factor IX (460 microg/kg) and 7 that received heparin (300 IU/kg) and protamine underwent cardiopulmonary bypass for 90 minutes and were followed after the operation for 3 hours. RESULTS: Analysis of plasma factor IX activity demonstrated adequate inhibition (<20%) of factor IX throughout cardiopulmonary bypass. Activated factor IX-treated baboons demonstrated similar circuit patency to heparin-treated baboons but had significantly diminished intraoperative blood loss. Preservation of extravascular hemostasis was further demonstrated in activated factor IX-treated animals by (1) significantly increased levels of thrombin-antithrombin III complex and prothrombin activation peptide (F1+2) without intravascular thrombosis, (2) significantly greater macrophage procoagulant activity in pericardial-derived monocytes, and (3) immunohistochemical evidence of tissue factor expression in pericardial mesothelial cells and macrophages. CONCLUSIONS: Anticoagulation with activated factor IX allows for intravascular anticoagulation with maintenance of extravascular hemostasis. These findings suggest activated factor IX as an agent that not only exemplifies a targeted approach to selective anticoagulation in cardiac surgery but also further characterizes the procoagulant milieu during cardiopulmonary bypass.

This article has been cited by other articles:

				E. L. Howard, K. C.D. Becker, C. P. Rusconi, and R. C. Becker Factor IXa Inhibitors as Novel Anticoagulants Arterioscler. Thromb. Vasc. Biol., April 1, 2007; 27(4): 722 - 727. [Abstract] [Full Text] [PDF]

				J. P. Sheehan and E. N. Walke Depolymerized holothurian glycosaminoglycan and heparin inhibit the intrinsic tenase complex by a common antithrombin-independent mechanism Blood, May 15, 2006; 107(10): 3876 - 3882. [Abstract] [Full Text] [PDF]

				J. R. Toomey, R. E. Valocik, P. F. Koster, M. A. Gabriel, M. McVey, T. K. Hart, E. H. Ohlstein, A. A. Parsons, and F. C. Barone Inhibition of Factor IX(a) Is Protective in a Rat Model of Thromboembolic Stroke Stroke, February 1, 2002; 33(2): 578 - 585. [Abstract] [Full Text] [PDF]

				F. Follis and C. A. Schmidt Cardiopulmonary bypass in patients with heparin-induced thrombocytopenia and thrombosis Ann. Thorac. Surg., December 1, 2000; 70(6): 2173 - 2181. [Abstract] [Full Text] [PDF]

				A. M. Schmidt, E. A. Rose, and D. M. Stern Commentary J. Thorac. Cardiovasc. Surg., September 1, 1999; 118(3): 429 - 431. [Full Text] [PDF]

				T. F. Choudhri, B. L. Hoh, C. J. Prestigiacomo, J. Huang, L. J. Kim, A. M. Schmidt, W. Kisiel, E. S. Connolly , Jr., and D. J. Pinsky Targeted Inhibition of Intrinsic Coagulation Limits Cerebral Injury in Stroke without Increasing Intracerebral Hemorrhage J. Exp. Med., July 5, 1999; 190(1): 91 - 100. [Abstract] [Full Text] [PDF]