(Circulation. 1995;92:1883-1890.)
© 1995 American Heart Association, Inc.
Articles |
Superficial Accumulation of Plasminogen During Plasma Clot Lysis
From Gaubius Laboratory, TNO-PG, Leiden, Netherlands.
Correspondence to Dr D.C. Rijken, Gaubius Laboratory, TNO-PG, PO Box 2215, 2301 CE Leiden, Netherlands. E-mail dc.rijken@pg.tno.nl.
Background Binding of plasminogen to partially degraded fibrin is an important step in fibrinolysis, influencing its rate and fibrin specificity. Little is known about the spatial distribution of plasminogen and of plasminogen-binding sites inside thrombi during lysis. In the present study, we investigated this problem, which is important for a better understanding of the local regulation of fibrinolysis and the rate-limiting factors of therapeutic thrombolysis.
Methods and Results An experimental system was used that allowed
continuous visualization and quantification by fluorescence
microscopy of the spatial distribution of
fluorescein-labeled plasminogen inside and
outside model thrombi. Strong superficial accumulation of
plasminogen was observed during lysis of a plasma clot
induced by tissue-type or urokinase-type plasminogen
activators in the surrounding plasma. A distinctly visible
plasminogen-accumulating shell moved continuously with the
reducing surface of the clot. The accumulation decreased in conditions
of exhaustive activation of plasminogen in the outer
plasma. It was found in a purified system that a thin superficial layer
(
50 µm wide) of a plasmin-treated fibrin clot exposes about 2.5
plasminogen-binding sites per fibrin monomer with a
Kd of 2.2 µmol/L. At a
physiological concentration of
plasminogen (1.5 µmol/L) in the outer medium,
plasminogen was concentrated about 10-fold in this layer.
The binding was dose-dependently inhibited by 
-aminocaproic
acid.
Conclusions We conclude that the generation of potent surface-associated plasminogen-binding sites during thrombolysis results in a strikingly high plasminogen concentration at the dynamically changing surface of a lysing clot. The necessity of a continuous plasminogen supply from the plasma supports the use of fibrin-specific and plasminogen-sparing agents for thrombolytic therapy.
Key Words: binding sites • plasminogen • plasminogen activators • fibrinolysis • thrombolysis
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