Nonradical excited oxygen species induce selective thrombolysis in vivo.
All the thrombolytic agents currently in clinical use act as plasminogen activators. In this study evidence is presented that also oxidants of the phagocyte type are of fibrinolytic efficiency in vivo. Activated phagocytes participate in physiologic fibrinolysis. The cells generate plasminogen activators and reactive oxidants of the nitrogen-chlorine type. Experimental mimicry of this oxidative inflammatory response induces selective thrombolysis in a rabbit jugular vein model. Intravenous bolus administration of sub-millimolar blood concentrations of chloramine-T resulted in thrombolysis after about 30 min without notable systemic toxicity; the coagulation parameters activated partial thromboplastin time (aPTT), thrombin time, fibrinogen, and alpha-2-antiplasmin were not influenced. Control experiments with 2000 IU of urokinase/kg induced thrombolysis after about 90 min with systemic changes of the hemostatic system. The fibrinolysis promoting effect of the oxidants of the phagocyte type could be inhibited by quenchers of singlet molecular oxygen and was not affected at all by inhibitors of oxygen radicals. The data gives evidence that nonradical excited oxygen species (NEOS) act as powerful pro-fibrinolytic and anti-coagulant agents in vivo. It might be suggested that NEOS could represent a novel class of regulators of the fibrinolytic system. The long lived and hydrophilic chloramine derivatives can either accumulate or diffuse far from their site of generation. Therefore, on the one hand oxidants in high (local) concentrations might be considered as direct pro-fibrinolytic agents due to their powerful protein modulating efficacy. On the other hand, oxidants at low concentrations may act as indirect pro-fibrinolytic compounds, i.e. as chemoattractants to concentrate phagocytes to the site of a thrombus. In this case the oxidants would play the role of signal elements faraway from the thrombus, a self amplifying mechanism possibly mediated by oxidation of blood arachidonat/lipid metabolites.
Stief
T W
TW
Univ. Dpt. of Hematology, General Hospital, Virgen del Rocío, Seville, Spain.
D000818:Animals; D002700:Chloramines / Q000494:pharmacology*; D005341:Fibrinolysin / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007700:Kinetics; D007958:Leukocyte Count / Q000187:drug effects; D010314:Partial Thromboplastin Time; D010960:Plasminogen Activators / Q000494:pharmacology*; D010976:Platelet Count / Q000187:drug effects; D011817:Rabbits; D012016:Reference Values; D013917:Thrombin / Q000494:pharmacology; D013918:Thrombin Time; D013927:Thrombosis / Q000097:blood*; D014105:Tosyl Compounds; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*; D000511:alpha-Macroglobulins / Q000032:analysis
D002700:Chloramines; D005343:Fibrinolytic Agents; D014105:Tosyl Compounds; D000511:alpha-Macroglobulins; C016300:chloramine-T; C024668:plasmin-alpha(2)-macroglobulin complex; D010960:Plasminogen Activators; D013917:Thrombin; D005341:Fibrinolysin; D014568:Urokinase-Type Plasminogen Activator