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Inhibition of clot lysis and decreased binding of tissue-type plasminogen
activator as a consequence of clot retraction
S Kunitada, GA FitzGerald and DJ Fitzgerald
Division of Clinical Pharmacology, Vanderbilt University, Nashville, TN.
Tissue-type plasminogen activator (t-PA) is less active in vivo and in
vitro against clots that are enriched in platelets, even at therapeutic
concentrations. The release of radioactivity from 125I-fibrin-labeled clots
was decreased by 47% 6 hours after the addition of t-PA 400 U/mL when
formed in platelet-rich versus platelet-poor plasma. This difference was
not due to the release of plasminogen activator inhibitor-1 (PAI-1) by
platelets. Thus, the fibrinolytic activity of t- PA in the supernatant was
similar in the two preparations and fibrin autography demonstrated only a
minor degree of t-PA-PAI-1 complex formation. Furthermore, a similar
platelet-dependent reduction in clot lysis was seen with a t-PA mutant
resistant to inhibition by PAI-1. The reduction in t-PA activity correlated
with a decrease in t-PA binding to platelet-enriched clot (60% +/- 3% v
platelet-poor clot, n = 5). This reduction in binding was also shown using
t-PA treated with the chloromethylketone, D-Phe-Pro-Arg-CH2Cl (PPACK) (36%
+/- 13%, n = 3), and with S478A, a mutant t-PA in which the active site
serine at position 478 has been substituted by alanine (43% +/- 6%, n = 3).
In contrast, fixed platelets and platelet supernatants had no effect on the
binding or lytic activity of t-PA. Pretreatment with cytochalasin D 1
mumol/L, which inhibits clot retraction, also abolished the platelet-
induced inhibition of lysis and t-PA binding by platelets. These data
suggest that platelets inhibit clot lysis at therapeutic concentrations of
t-PA as a consequence of clot retraction and decreased access of
fibrinolytic proteins.
Volume 79,
Issue 6,
pp. 1420-1427,
03/15/1992
Copyright © 1992 by The American Society of Hematology
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