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Binding of Tissue-Plasminogen Activator to Fibrin: Effect of
Ultrasound
Farhan Siddiqi,
Tatjana M. Odrljin,
Philip J. Fay,
Christopher Cox, and
Charles W. Francis
From the Vascular Medicine Unit, Department of Medicine and
Biostatistics Department, University of Rochester School of Medicine & Dentistry, Rochester, NY.
Ultrasound reversibly alters the structure of polymerized fibrin, an
effect that could influence tissue-plasminogen activator (t-PA)
binding. We have, therefore, characterized the effects of ultrasound on
binding of t-PA to fibrin using a novel system in which radiolabeled,
active-site blocked, single chain tissue-plasminogen activator flowed
through a fibrin gel at constant rate, and specific binding was
determined by monitoring incorporation of radiolabel. Results using
polymerized fibrin were compared with those using a surface of fibrin
immobilized on Sepharose beads in a similar system. Interaction of t-PA
with surface-immobilized fibrin involved two classes of binding sites
(Kd = 31 nmol/L and 244 nmol/L) and a maximum binding ratio of 3.8 mol t-PA/mol fibrin. Ultrasound increased Kd for the high affinity site
to 46 nmol/L (P < .0001), but it had no significant effects
on the Kd 244 nmol/L site nor on Bmax. Tissue-plasminogen
activator binding to noncrosslinked fibrin involved two sites with Kds
of 267 nmol/L and 952 nmol/L, while a single Kd 405 nmol/L site was
identified for crosslinked fibrin. Ultrasound had no significant effect
on the binding affinity for noncrosslinked fibrin, but Bmax
was increased in the presence of ultrasound, from 31 µmol/L to 43 µmol/L (P < .0001). Ultrasound decreased the Kd for
crosslinked fibrin to 343 nmol/L (P = .026) and also
increased Bmax from 22 µmol/L to 25 µmol/L
(P = .015). Ultrasound also affected the kinetics of t-PA
binding to fibrin, significantly accelerating the rate of dissociation
by 77% ± 5% for noncrosslinked fibrin and by 69% ± 3% for
crosslinked fibrin (P < .001 for each). These results
indicate that ultrasound exposure accelerates t-PA binding, alters
binding affinity, and increases maximum binding to polymerized fibrin,
effects that may result from ultrasound-induced changes in fibrin
structure.
Blood, Vol. 91 No. 6 (March 15), 1998:
pp. 2019-2025
© 1998 by The American Society of Hematology.
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