Streptokinase induces intravascular release of platelet-activating factor in patients with acute myocardial infarction and stimulates its synthesis by cultured human endothelial cells.
BACKGROUND Reocclusion of a successfully recanalized infarct-related artery may account for failure of thrombolytic therapy. Evidence suggests that the intravascular activation of platelets may limit the response to this treatment. The aim of the present study was to investigate whether platelet-activating factor (PAF), an ether lipid mediator with multiple potent biological activities, is synthesized during therapy with thrombolytic agents. Two sets of experiments were performed: (1) we extracted and quantified PAF in blood of patients with acute myocardial infarction treated or untreated with streptokinase (SK), and (2) since the endothelium/platelet interaction is thought to be at the basis of vascular reocclusion, we studied whether cultured human endothelial cells synthesize PAF after stimulation with SK or plasmin.
METHODS AND RESULTS PAF was extracted from blood samples immediately after acidification to destroy the acid-labile PAF-acetylhydrolase in 25 patients with acute myocardial infarction treated (group A, n = 14) and untreated (group B, n = 11) with intravenous infusion of SK. PAF was detected in 10 of 14 patients of group A and none of group B. PAF began to be detectable 60 to 90 minutes after SK infusion and disappeared from the circulation within 120 to 180 minutes. Percent variation of platelet count over basal values correlated negatively with the amount of PAF present in the circulation at 90 minutes (r = -.719; P < .001) and at 120 minutes (r = -.652; P < .001). Cultured human umbilical cord vein-derived endothelial cells (ECs) synthesized PAF in a dose-dependent manner in response to SK and plasmin, with a synthesis that peaked at 15 minutes and persisted up to 30 minutes for SK and 2 hours for plasmin. PAF extracted from blood samples or from ECs was quantified by bioassay performed after purification by thin-layer chromatography and high-performance liquid chromatography (HPLC). PAF-bioactive material was characterized as PAF with physicochemical and enzymatic treatments, HPLC-tandem mass spectrometry, and specific PAF-receptor antagonists.
CONCLUSIONS The observation that PAF was detectable in the blood of patients of group A only after treatment with SK and was not detectable in patients with a comparable infarct not treated with SK (group B) suggested that SK stimulates the synthesis of this mediator either directly or via plasmin generation. Indeed, cultured human ECs synthesize PAF after stimulation with both SK and plasmin. PAF production by ECs may promote platelet activation and interaction of these cells as well as of circulating leukocytes with endothelium. These events may limit the beneficial effects of thrombolytic therapy.
- Copyright © 1993 by American Heart Association