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
Rj. Stewart et al., 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, J BIOL CHEM, 275(47), 2000, pp. 36612-36620
A complex of D-dimer noncovalently associated with fragment E ((DD)E), a de
gradation product of crosslinked fibrin that binds tissue plasminogen activ
ator (t-PA) and plasminogen (Pg) with affinities similar to those of fibrin
, compromises the fibrin specificity of t-PA by stimulating systemic Pg act
ivation. In this study, we examined the effect of thrombin-activable fibrin
olysis 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 sti
mulate t-PA-mediated activation of Glu- or Lys-Pg by reducing k(cat) and in
creasing K-m for the reaction; (b) induces the release of 8 mol of lysine/m
ol of (DD)E, although most of the stimulatory activity is lost after releas
e 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. Becaus
e TAFIa- or CPB-exposed (DD)E produces little stimulation of Glu-Pg activat
ion 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 sugg
est a novel role for TAFIa. By attenuating systemic Pg activation by (DD)E,
TAFIa renders t-PA more fibrin-specific.