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J. Biol. Chem., Vol. 283, Issue 15, 9776-9786, April 11, 2008

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The Nature of the Stable Blood Clot Procoagulant Activities^*

From the Department of Biochemistry, University of Vermont, Colchester, Vermont 05446

The function of tissue factor (Tf)-initiated coagulation is hemorrhage control through the formation and maintenance of an impermeable platelet-fibrin barrier. The catalytic processes involved in the clot maintenance function are not well defined, although the rebleeding problems characteristic of individuals with hemophilias A and B suggest a link between specific defects in the Tf-initiated process and defects in the maintenance function. We have previously demonstrated, using a methodology of "flow replacement" (or resupply) of ongoing Tf-initiated reactions with fresh reactants, that procoagulant complexes are produced during Tf-initiated coagulation, which are capable of reinitiating coagulation without input from extrinsic factor Xase activity (Orfeo, T., Butenas, S., Brummel-Ziedins, K. E., and Mann, K. G. (2005) J. Biol. Chem. 280, 42887–42896). Here we used Tf-initiated reactions in normal and hemophilia blood or in their corresponding proteome mixtures as sources of procoagulant end products and then varied the resupplying material to determine the identity of the catalysts that drive the new cycle of thrombin formation. The central findings are as follows: 1) the prothrombinase complex (fVa-fXa-Ca²⁺-membrane) accumulated during the episode of Tf-initiated coagulation is the primary catalyst responsible for the observed pattern of prothrombin activation after resupply; 2) impairments in intrinsic factor Xase function, i.e. hemophilias A and B, result in an impaired capacity to mount a resupply response; and 3) in normal hemostasis the intrinsic factor Xase function contributes to the durability of the resupply response.

Received for publication, September 5, 2007 , and in revised form, January 14, 2008.

^* This work was supported by National Institutes of Health Grant PPG HL46703 (Project 1) (to K. G. M.). 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: 208 South Park Dr., Rm. T227, Colchester, VT 05446. Fax: 802-656-2256; E-mail: kenneth.mann{at}uvm.edu.

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