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Platelets inhibit fibrinolysis in vitro by both plasminogen activator
inhibitor-1-dependent and -independent mechanisms
WP Fay, DT Eitzman, AD Shapiro, EL Madison and D Ginsburg
Ann Arbor Veterans Affairs Hospital, Research Service, MI.
Platelet-rich thrombi are resistant to lysis by tissue-type plasminogen
activator (t-PA). Although platelet alpha-granules contain plasminogen
activator inhibitor-1 (PAI-1), a fast-acting inhibitor of t-PA, the
contribution of PAI-1 to the antifibrinolytic effect of platelets has
remained a subject of controversy. We recently reported a patient with a
homozygous mutation within the PAI-1 gene that results in complete loss of
PAI-1 expression. Platelets from this individual constitute a unique
reagent with which to probe the role of platelet PAI-1 in the regulation of
fibrinolysis. The effects of PAI-1-deficient platelets were compared with
those of normal platelets in an in vitro clot lysis assay. Although the
incorporation of PAI-1-deficient platelets into clots resulted in a
moderate inhibition of t-PA-mediated fibrinolysis, normal platelets
markedly inhibited clot lysis under the same conditions. However, no
difference between PAI-1-deficient platelets and platelets with normal
PAI-1 content was observed when streptokinase or a PAI-1-resistant t-PA
mutant were used to initiate fibrinolysis. In addition, PAI-1-resistant
t-PA was significantly more efficient in lysing clots containing normal
platelets than wild-type t-PA. We conclude that platelets inhibit
t-PA-mediated fibrinolysis by both PAI- 1-dependent and PAI-1-independent
mechanisms. These results have important implications for the role of PAI-1
in the resistance of platelet-rich thrombi to lysis in vivo.
Volume 83,
Issue 2,
pp. 351-356,
01/15/1994
Copyright © 1994 by The American Society of Hematology
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