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J Thorac Cardiovasc Surg 1998;115:1179-1188
© 1998 Mosby, Inc.

CARDIOPULMONARY SUPPORT AND PHYSIOLOGY

Heparinless cardiopulmonary bypass with active-site blocked factorIXa: A preliminary study on the dog

From the Departments of Surgery,^a Physiology,^band Medicine,^c Columbia University College of Physicians andSurgeons, New York, N.Y., the Department of Pathology,^d Universityof New Mexico, Albuquerque, N.M., and the Division of Hematology/Oncology,^eCornell University Medical College, New York, N.Y.

Received for publication July 30, 1997. Revisions requested Sept. 11, 1997. Revisions received Dec. 18, 1997. Accepted for publication Dec. 19, 1997. Address for reprints: Talia Spanier, MD/Ann Marie Schmidt, MD,Columbia University College of Physicians and Surgeons, 630 West 168 St., P&S17-501, New York, NY 10032.

Objective: Cardiopulmonary bypass is apotent stimulus for activation of procoagulant pathways. Heparin, thetraditional antithrombotic agent, however, is often associated with increasedperioperative blood loss because of its multiple sites of action in thecoagulation cascade and its antiplatelet and profibrinolytic effects.Furthermore, heparin-mediated immunologic reactions (that is, heparin-inducedthrombocytopenia) may contraindicate its use. Cardiopulmonary bypass with aselective factor IXa inhibitor was tested to see whether it could effectivelylimit bypass circuit/intravascular space thrombosis while decreasingextravascular bleeding, thereby providing an alternative anticoagulant strategywhen heparin may not be safely administered.
Methods:Active site-blocked factor IXa, a competitive inhibitor of the assembly offactor IXa into the factor X activation complex, was prepared by modification ofthe enzyme's active site by the use of dansyl glutamicacid-glycine-arginine-chlormethylketone. Twenty mongrel dogs (five were givenstandard heparin/protamine; 15 were given activated site-blocked factor IXadoses ranging from 300 to 600 µg/kg) underwent 1 hour of hypothermiccardiopulmonary bypass, and blood loss was monitored for 3 hours after theprocedure.
Results: Use of activatedsite-blocked factor IXa as an anticoagulant in cardiopulmonary bypass limitedfibrin deposition within the extracorporeal circuit as assessed by scanningelectron microscopy, comparable with the antithrombotic effect seen withheparin. In contrast to heparin, effective antithrombotic doses of activatedsite-blocked factor IXa significantly diminished blood loss in the thoraciccavity and in an abdominal incisional bleeding model.
Conclusion:These initial studies on the dog suggest that administration of activatedsite-blocked factor IXa may be an effective alternative anticoagulant strategyin cardiopulmonary bypass when heparin is contraindicated, affording inhibitionof intravascular/extracorporeal circuit thrombosis with enhanced hemostasis inthe surgical wound.

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