Attenuation of thrombolysis by release of plasminogen activator inhibitor type-1 from platelets.
Although platelets contain approximately 90% of the total amount of plasminogen activator inhibitor type-1 (PAI-1) present in blood, the functional significance of PAI-1 in platelets has been controversial. Most assessments of platelet PAI-1 have been performed with platelet lysates in which the PAI-1 derived from platelets may have been inactivated during the course of lysis. This study was performed to determine whether elaboration of PAI-1 from platelets activated physiologically by thrombolysis of pre-formed clots inhibits activation of plasminogen by tissue-type plasminogen activator (t-PA). Human whole blood clots were formed in Chandler tubes, and release of PAI-1 from platelets was quantified during and after clot formation. Subsequently, clots were placed in different Chandler tubes, and the effects of platelet PAI-1 on lysis induced by t-PA were characterized. Both the activity and concentrations of PAI-1 elaborated from platelets peaked approximately 15 min after induction of clotting. Induction of clot lysis with t-PA, 1,000 to 5,000 ng/ml, was inhibited by platelet-rich compared with platelet-poor plasma. Platelets inhibited lysis of preformed clots by t-PA and plasminogen in buffer solutions as well. Both the inhibition of clot lysis and accumulation of PAI-1 released from platelets were prevented by attenuation of thrombin-mediated activation of platelets with hirudin. Furthermore, the PAI-1 mediated inhibition was obviated by blockade of PAI-1 activity with a neutralizing monoclonal antibody to PAI-1. These results indicate that platelets inhibit clot lysis induced by t-PA by releasing functionally active PAI-1.
Torr-Brown
S R
SR
Cardiovascular Division, Washington University School of Medicine, St. Louis, MO 63110.
Sobel
B E
BE
D001792:Blood Platelets / Q000187:drug effects / Q000502:physiology*; D005342:Fibrinolysis / Q000187:drug effects / Q000502:physiology*; D006629:Hirudins / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D010958:Plasminogen / Q000378:metabolism; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism*; D015539:Platelet Activation / Q000187:drug effects / Q000502:physiology; D013917:Thrombin / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology
D006629:Hirudins; D017395:Plasminogen Activator Inhibitor 1; D010958:Plasminogen; D013917:Thrombin; D010959:Tissue Plasminogen Activator