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J. Biol. Chem., Vol. 280, Issue 52, 42887-42896, December 30, 2005

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The Tissue Factor Requirement in Blood Coagulation^*

From the Department of Biochemistry, University of Vermont, Burlington, Vermont 05405

Formation of thrombin is triggered when membrane-localized tissue factor (TF) is exposed to blood. In closed models of this process, thrombin formation displays an initiation phase (low rates of thrombin production cause platelet activation and fibrinogen clotting), a propagation phase (>95% of thrombin production occurs), and a termination phase (prothrombin activation ceases and free thrombin is inactivated). A current controversy centers on whether the TF stimulus requires supplementation from a circulating pool of blood TF to sustain an adequate procoagulant response. We have evaluated the requirement for TF during the progress of the blood coagulation reaction and have extended these analyses to assess the requirement for TF during resupply ("flow replacement"). Elimination of TF activity at various times during the initiation phase indicated: a period of absolute dependence (<10 s); a transitional period in which the dependence on TF is partial and decreases as the reaction proceeds (10–240 s); and a period in which the progress of the reaction is TF independent (>240 s). Resupply of reactions late during the termination phase with fresh reactants, but no TF, yielded immediate bursts of thrombin formation similar in magnitude to the original propagation phases. Our data show that independence from the initial TF stimulus is achieved by the onset of the propagation phase and that the ensemble of coagulation products and intermediates that yield this TF independence maintain their prothrombin activating potential for considerable time. These observations support the hypothesis that the transient, localized expression of TF is sufficient to sustain a TF-independent procoagulant response as long as flow persists.

Received for publication, May 19, 2005 , and in revised form, October 6, 2005.

^* This work was supported by National Institutes of Health Grant PPG HL46703 (to K. G. M.) (Project 1 from the National Institutes of Health). Portions of this work were presented at the 46th annual meeting of the American Society of Hematology, December 4–7, 2004, in San Diego, CA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Given Bldg., 89 Beaumont Ave., Burlington, VT 05405-0068. Tel.: 802-656-0335; Fax: 802-862-8229; E-mail: Kenneth.Mann{at}uvm.edu.

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