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Uncoupling fibrin from integrin receptors hastens fibrinolysis at the
platelet-fibrin interface
JV Braaten, WG Jerome and RR Hantgan
Department of Biochemistry, Bowman Gray School of Medicine, Wake Forest
University, Winston-Salem, NC 27157-1016.
A well-characterized in vitro model system composed of thrombin- stimulated
gel-filtered human platelets, fibrin-(ogen), plasminogen, and recombinant
tissue plasminogen activator (rt-PA) was used to examine the relationship
between platelet-fibrin adhesive interactions and the lytic resistance of a
platelet-rich thrombus. Laser light scattering kinetic experiments
demonstrated that the ligand-mimetic peptide D-RGDW and an anti-alpha IIb
beta 3 monoclonal antibody both inhibited clot retraction, but neither
integrin-targeted reagent affected the overall delay in lysis of "bulk"
fibrin caused by thrombin- stimulated platelets. However, lysis of the
model platelet-rich thrombus did proceed some 30% more quickly when treated
with a plasminogen activator inhibitor (PAI)-resistant t-PA variant. Taken
together, these results confirm that platelet-released PAI-1 is a major
determinant of global lytic resistance. Next events occurring during
fibrinolysis in the unique microenvironment near the platelet surface were
monitored by scanning electron microscopy and quantitative fluorescence
microscopy. Scanning electron micrographs of the partially lysed model
thrombus in the presence of 200 mumol/L of D-RGDW showed no platelet
aggregates, and fibrin was attached by fewer strands to the platelets.
Quantitative fluorescence microscopy, using fluorescein- labeled fibrin,
showed that fibrin adherent to the surface of thrombin- stimulated
platelets lysed 20% to 50% more slowly than bulk fibrin (monitored in
parallel by laser light scattering). Furthermore, this microspectroscopic
technique showed that D-RGDW reduced the quantity of platelet-bound fibrin,
and accelerated lysis near the platelet surface with both native rt-PA and
the PAI-resistant variant. These observations suggest that the dense
network of fibrin bound to the platelet surface is protected from
fibrinolysis by tissue-type plasminogen activators. Further, uncoupling
fibrin from its platelet receptors uniquely hastens fibrinolysis at the
cell/fibrin interface.
Volume 83,
Issue 4,
pp. 982-993,
02/15/1994
Copyright © 1994 by The American Society of Hematology
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