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 sugge sts that the intravascular activation of platelets may limit the respo nse to this treatment. The aim of the present study was to investigate whether platelet-activating factor (PAF), an ether lipid mediator wit h 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 myoca rdial infarction treated or untreated with streptokinase (SK), and (2) since the endothelium/platelet interaction is thought to be at the ba sis of vascular reocclusion, we studied whether cultured human endothe lial cells synthesize PAF after stimulation with SK or plasmin. Method s and Results. PAF was extracted from blood samples immediately after acidification to destroy the acid-labile PAF-acetylhydrolase in 25 pat ients with acute myocardial infarction treated (group A, n=14) and unt reated (group B, n=11) with intravenous infusion of SK. PAF was detect ed in 10 of 14 patients of group A and none of group B. PAF began to b e detectable 60 to 90 minutes after SK infusion and disappeared from t he circulation within 120 to 180 minutes. Percent variation of platele t 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 minute s and persisted up to 30 minutes for SK and 2 hours for plasmin. PAF e xtracted from blood samples or from ECs was quantified by bioassay per formed after purification by thin-layer chromatography and high-perfor mance liquid chromatography (HPLC). PAF-bioactive material was charact erized as PAF with physicochemical and enzymatic treatments, HPLC-tand em mass spectrometry, and specific PAF-receptor antagonists. Conclusio ns. The observation that PAF was detectable in the blood of patients o f group A only after treatment with SK and was not detectable in patie nts with a comparable infarct not treated with SK (group B) suggested that SK stimulates the synthesis of this mediator either directly or v ia plasmin generation. Indeed, cultured human ECs synthesize PAF after stimulation with both SK and plasmin. PAF production by ECs may promo te platelet activation and interaction of these cells as well as of ci rculating leukocytes with endothelium. These events may limit the bene ficial effects of thrombolytic therapy.