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Platelet activation and subsequent inhibition by plasmin and recombinant
tissue-type plasminogen activator
WF Penny and JA Ware
Charles A. Dana Research Institute, Beth Israel Hospital, Harvard Medical
School, Boston, MA.
The success of plasminogen activators in recanalizing occluded coronary
arteries may be influenced by their effect on blood platelets; however,
some previous studies have shown platelet activation by plasmin and
thrombolytic agents while others have shown an inhibitory effect. Moreover,
it has not been determined whether these effects reflect an alteration of
intracellular signal transduction, fibrinogenolysis, degradation of
adhesive protein receptors, or a combination of these events. To
distinguish among these possibilities, the increase of cytoplasmic [Ca2+]
[( Ca2+]i), which is an intracellular marker of platelet activation that
precedes fibrinogen binding to the surface of activated platelets, was
measured along with aggregation and release of 5-hydroxytryptamine (5-HT)
in washed human platelets incubated with plasmin or recombinant tissue-type
plasminogen activator (rt-PA). Plasmin (0.1 to 1.0 CU/mL) induced a prompt,
concentration-dependent [Ca2+]i increase when added to platelets, but
subsequently inhibited the [Ca2+]i increase in response to thrombin or the
endoperoxide analog U44069. Platelet aggregation accompanied the [Ca2+]i
increase if the platelets were stirred, while the aggregation of platelets
unstirred during plasmin incubation was inhibited upon agonist addition and
resumption of stirring. The release of 5-HT paralleled the [Ca2+]i increase
induced by plasmin and was also inhibited after the subsequent addition of
a second agonist. The effects of rt-PA, added with plasminogen (100
micrograms/mL), were similar to those of plasmin, and could be accounted
for by the concentration of plasmin generated. The ADP scavengers apyrase
and CP/CK each prevented the [Ca2+]i increase, and aggregation caused by
plasmin or rt-PA, and also prevented their inhibitory effects on
thrombin-induced activation. Thus, plasmin and rt- PA initially activate
platelets, inducing a [Ca2+]i increase, and, if the platelets are stirred,
aggregation. Such activation is followed by subsequent inhibition of
cellular activation by a second agonist; the inhibitory effect is in
proportion to the degree of initial activation, and ADP is an important
cofactor in both processes. These platelet effects occur at rt-PA
concentrations achievable clinically, and may affect the success of therapy
with thrombolytic and adjunctive agents.
Volume 79,
Issue 1,
pp. 91-98,
01/01/1992
Copyright © 1992 by The American Society of Hematology
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