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J Thorac Cardiovasc Surg 2003;125:165-171
© 2003 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology (CSP)

Nuclear factor {kappa}B mediates a procoagulant response in monocytes during extracorporeal circulation

Elizabeth N. Morgan, MD, Timothy H. Pohlman, MD, Craig Vocelka, BS, Angela Farr, BA, Gina Lindley, BS, Wayne Chandler, MD, Jeanette M. Griscavage-Ennis, PhD, Edward D. Verrier, MD

From the Department of Surgery, Division of Cardiothoracic Surgery, University of Washington School of Medicine, Seattle, Wash.

Received for publication Sept 24, 2001. Revisions requested Oct 26, 2001; revisions received Jan 29, 2002. Accepted for publication Feb 12, 2002. Address for reprints: Timothy H. Pohlman, MD, Harborview Medical Center, 325 9th Ave, Box 359796, Seattle, WA 98104 (E-mail: tpohlman{at}u.washington.edu).

Objective: The objective of this study was to examine the mechanism of procoagulant activity and inhibition in whole blood during extracorporeal circulation.
Methods: In this study we examine the development of procoagulant activity and monocyte activation in heparinized whole blood passing through a closed circuit consisting of a pump and silicone envelope membrane oxygenator for 6 hours.
Results: Anaphylatoxins, C3a and C5a, determined by means of enzyme-linked immunosorbant assay, appeared in the blood within 30 minutes of circulation. Circulated blood developed a marked potential for coagulation demonstrated in a 1-step clotting assay that reached maximal activity by 4 hours of circulation. This procoagulant activity was neutralized by anti-tissue factor antibody, suggesting a prominent role for the extrinsic pathway in pump-induced intravascular coagulation. Isolation of monocytes from circulated blood revealed that tissue factor expression is upregulated on the cell surface. Furthermore, we observed nuclear factor {kappa}B nuclear translocation in monocytes from blood passing through the circuit, suggesting that tissue factor expression was due to monocyte stimulation and transcriptional activation of the tissue factor gene. Tissue factor expression resulted in an approximately 30-fold increase in thrombin generation. Monocyte nuclear factor {kappa}B activation, monocyte tissue factor expression, thrombin generation, and the procoagulant activity of blood in extracorporeal circulation were all blocked by the proteasome inhibitor MG132.
Conclusions: We conclude that intravascular tissue factor expression during extracorporeal circulation of blood is due to nuclear factor {kappa}B-mediated activation of monocytes (possibly by complement), which can be controlled pharmacologically.






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