Journal of Biological Chemistry
Volume 275, Issue 47, 24 November 2000, Pages 36612-36620
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ENZYME CATALYSIS AND REGULATION
Thrombin-activable Fibrinolysis Inhibitor Attenuates (DD)E-mediated Stimulation of Plasminogen Activation by Reducing the Affinity of (DD)E for Tissue Plasminogen Activator: A POTENTIAL MECHANISM FOR ENHANCING THE FIBRIN SPECIFICITY OF TISSUE PLASMINOGEN ACTIVATOR*

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A complex of d-dimer noncovalently associated with fragment E ((DD)E), a degradation product of cross-linked fibrin that binds tissue plasminogen activator (t-PA) and plasminogen (Pg) with affinities similar to those of fibrin, compromises the fibrin specificity of t-PA by stimulating systemic Pg activation. In this study, we examined the effect of thrombin-activable fibrinolysis inhibitor (TAFI), a latent carboxypeptidase B (CPB)-like enzyme, on the stimulatory activity of (DD)E. Incubation of (DD)E with activated TAFI (TAFIa) or CPB (a) produces a 96% reduction in the capacity of (DD)E to stimulate t-PA-mediated activation of Glu- or Lys-Pg by reducing k cat and increasingK m for the reaction; (b) induces the release of 8 mol of lysine/mol of (DD)E, although most of the stimulatory activity is lost after release of only 4 mol of lysine/mol (DD)E; and (c) reduces the affinity of (DD)E for Glu-Pg, Lys-Pg, and t-PA by 2-, 4-, and 160-fold, respectively. Because TAFIa- or CPB-exposed (DD)E produces little stimulation of Glu-Pg activation by t-PA, (DD)E is not degraded into fragment E and d-dimer, the latter of which has been reported to impair fibrin polymerization. These data suggest a novel role for TAFIa. By attenuating systemic Pg activation by (DD)E, TAFIa renders t-PA more fibrin-specific.

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Published, JBC Papers in Press, September 1, 2000, DOI 10.1074/jbc.M005483200

*

This work was supported by Heart and Stroke Foundation of Ontario Grants T-3768 and T-2881 and Medical Research Council of Canada Grant MT-3992.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Recipient of a Traineeship award from the Heart and Stroke Foundation of Canada.

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Research Scholar of the Heart and Stroke Foundation of Canada.