A Novel Antidote-Controlled Anticoagulant Reduces Thrombin Generation and Inflammation and Improves Cardiac Function in Cardiopulmonary Bypass Surgery

doi:doi:10.1016/j.ymthe.2006.04.006

Molecular Therapy (2006) 14, 408–415; doi: 10.1016/j.ymthe.2006.04.006

A Novel Antidote-Controlled Anticoagulant Reduces Thrombin Generation and Inflammation and Improves Cardiac Function in Cardiopulmonary Bypass Surgery

Shahid M. Nimjee^1,2, J. R. Keys², G. A. Pitoc², G. Quick², C. P. Rusconi^2,3 and Bruce A. Sullenger^1,2

¹University Program in Genetics and Genomics, Durham, NC 27710, USA
²Division of Experimental Surgery, Department of Surgery, Duke University Medical Center, Durham, NC 27710, USA
³Regado Biosciences, Inc., Research Triangle Park, NC 27701, USA

Correspondence: Bruce A. Sullenger, E-mail: b.sullenger@cgct.duke.edu

Received 18 January 2006; Revised 24 March 2006; Accepted 16 April 2006.

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Abstract

Heparin and protamine are the standard anticoagulant–antidote regimen used in almost every cardiopulmonary bypass (CPB) procedure even though both are associated with an array of complications and toxicities. Here we demonstrate that an anticoagulant aptamer–antidote pair targeting factor IXa can replace heparin and protamine in a porcine CPB model and also limit the adverse effects on thrombin generation, inflammation, and cardiac physiology associated with heparin and protamine use. These results demonstrate that targeting clotting factors upstream of thrombin in the coagulation cascade can potentially reduce the perioperative pathologies associated with CPB and suggest that the aptamer–antidote pair to FIXa may improve the outcome of patients undergoing CPB. In particular, this novel anticoagulant–antidote pair may prove to be useful in patients diagnosed with heparin-induced thrombocytopenia or those who have been sensitized to protamine, particularly patients who have insulin-dependent diabetes.