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J Thorac Cardiovasc Surg 2005;130:107-113
© 2005 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Recombinant human antithrombin III restores heparin responsiveness and decreases activation of coagulation in heparin-resistant patients during cardiopulmonary bypass

^a Departments of Anesthesiology and Cardiothoracic Surgery, St Louis, Mo
^k Departments of Anesthesiology, Surgery, Pathology, and Immunology, Washington University School of Medicine, St Louis, Mo
^b Department of Anesthesiology, Emory University School of Medicine, and the Division of Cardiothoracic Anesthesiology and Critical Care, Emory Healthcare, Atlanta, Ga
^c Department of Anesthesiology, Westfalische Wilhelms-Universiteit, Münster, Klinik für Anasthesiologie, Münster, Germany
^d Department of Anaesthesia, St Thomas’ Hospital, London, United Kingdom
^e Department of Anaesthesia, Papworth Hospital, Cambridge, United Kingdom
^f Department of Anesthesiology, Universitäts-Klinikum Großhadern, Institut für Anästhesiologie, Munich, Germany
^g Department of Anesthesiology, Ruprecht-Karls-Universiteit, Heidelberg, Germany
^h Department of Anesthesiology, Klinikum der Universiteit Regensburg, Regensburg, Germany
ⁱ Clinical Research, GTC Biotherapeutics, Inc, Framingham, Mass
^j Eli Lilly & Co, Lilly Corporate Center, Indianapolis, Ind.

Received for publication August 2, 2004; revisions received September 26, 2004; accepted for publication October 6, 2004.

^_* Address for reprints: M. S. Avidan, MBBCh, Department of Anesthesiology, Box 8054, Washington University School of Medicine, 660 South Euclid, St Louis, MO 63110 (Email: avidanm{at}msnotes.wustl.edu).

OBJECTIVES: We sought to evaluate the efficacy of recombinant human antithrombin III for restoration of heparin responsiveness in heparin-resistant patients scheduled for cardiac surgery.

METHODS: This was a multicenter, randomized, double-blind, placebo-controlled study in heparin-resistant patients undergoing elective cardiac surgery. Patients were considered heparin resistant if the activated clotting time was less than 480 seconds after 400 U/kg heparin. Fifty-two heparin-resistant patients were randomized into 2 cohorts. One cohort received a single bolus (75 U/kg) of recombinant human antithrombin III (n = 28), and the other, the placebo group (n = 24), received a normal saline bolus. If the activated clotting time remained less than 480 seconds, this was defined as treatment failure, and 2 units of fresh frozen plasma were transfused. Patients were monitored for adverse events during hospitalization.

RESULTS: Six (21%) of the patients in the recombinant human antithrombin III group received fresh frozen plasma transfusions compared with 22 (92%) of the placebo-treated patients (P < .001). Two units of fresh frozen plasma did not restore heparin responsiveness. There was no increased incidence of adverse events associated with recombinant human antithrombin III administration. Postoperative 24-hour chest tube bleeding was not different in the 2 groups. Surrogate measures of hemostatic activation suggested that there was less activation of the hemostatic system during cardiopulmonary bypass in the recombinant human antithrombin III group.

CONCLUSION: Treatment with recombinant human antithrombin III in a dose of 75 U/kg is effective in restoring heparin responsiveness and promoting therapeutic anticoagulation for cardiopulmonary bypass in the majority of heparin-resistant patients. Two units of fresh frozen plasma were insufficient to restore heparin responsiveness. There was no apparent increase in bleeding associated with recombinant human antithrombin III.

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