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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2005;25:2463.)
© 2005 American Heart Association, Inc.

Brief Reviews

Positive Feedbacks of Coagulation

Their Role in Threshold Regulation

Jolyon Jesty; Edward Beltrami

From the Division of Hematology, Health Sciences Center (J.J.), and the Department of Applied Mathematics and Statistics (E.B.), Stony Brook University, Stony Brook, NY.

Correspondence to Jolyon Jesty, Division of Hematology, Health Sciences Center, Stony Brook University, Stony Brook, NY 11794-8151 E-mail jolyon.jesty{at}sunysb.edu

Series Editor: Yale Nemerson

Tissue factor (TF), the initiator of coagulation, continuously circulates in the plasma, and the clotting system "idles," generating very low levels of active clotting enzymes, clotting products, and by-products. Given the enormous amplification potential of the clotting cascade, rigorous control is required to ensure that such low-level stimulation does not cause massive system amplification and response. We propose that among the various mechanisms of regulation, activation thresholds may play a major role. These arise when positive-feedback reactions, of which there are several in the clotting system, are regulated by inhibitors. Such thresholds act like switches, so that small stimuli and/or nonproductive local conditions will generate no response, whereas larger stimuli or the existence of local prothrombotic conditions will produce a full, explosive response. We review here the evidence for system idling, the structures of the various feedback mechanisms of clotting, the mechanisms by which they can produce threshold behavior, and the possible role of thresholds in system regulation.

The clotting cascade has enormous amplification potential and requires critical regulation. When the positive-feedback reactions of clotting are regulated by inhibitors, thresholds result. These act like switches, with small stimuli and/or nonproductive local conditions generating no response, and larger stimuli or prothrombotic conditions producing a full, explosive response.

Key Words: blood coagulation • positive feedback • threshold • protease • inhibitor

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