Fibrin-specific lysis of microthrombosis in endotoxemic rats by saruplase.
The dissolution by the fibrinolytic agent saruplase of microthrombi due to disseminated intravascular coagulation (DIC) has been studied in anesthetized rats. The intravenous infusion of E. coli lipopolysaccharide (endotoxin) for 4 hours (total dose: 25 mg/kg) induced marked thrombocytopenia and hypofibrinogenemia. DIC-related microthrombosis, detected as increased deposition of 125I-labelled human fibrin, was found in the liver and the kidneys, but not in the lungs, the heart, the mesenterium, the spleen and the M. rectus abdominis of endotoxemic rats. Treatment with 1-20 micrograms/kg.min saruplase, that was infused concomitantly with endotoxin, dose-dependently and significantly reduced endotoxin-induced microthrombosis in the liver and the kidneys by 85 resp. 88%. When saruplase (20 micrograms/kg.min) was administered only during the last two hours of endotoxin infusion, liver microthrombosis was still significantly dissolved by 69%, whereas renal microthrombosis was insignificantly reduced by 34%. The inhibition of endotoxin-induced microthrombosis took place in the same dosage range as the shortening of the euglobulin clot lysis time in normal rats by saruplase as a measure of its fibrinolytic activity. Saruplase did not modify thrombocytopenia and hypofibrinogenemia in endotoxemic rats. Saruplase per se did not affect plasma fibrinogen levels. Thus, in a fibrin-selective dose range saruplase is able to dissolve microthrombosis associated with DIC in endotoxemic rats.
Schneider
J
J
Grünenthal GmbH, Center of Research, Aachen, FRG.
D000818:Animals; D004211:Disseminated Intravascular Coagulation / Q000188:drug therapy* / Q000209:etiology; D004731:Endotoxins / Q000633:toxicity; D005337:Fibrin / Q000032:analysis / Q000187:drug effects*; D005340:Fibrinogen / Q000378:metabolism / Q000493:pharmacokinetics; D008297:Male; D009928:Organ Specificity; D010976:Platelet Count; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000627:therapeutic use; D012772:Shock, Septic / Q000150:complications*; D013047:Specific Pathogen-Free Organisms; D015912:Thrombolytic Therapy; D014018:Tissue Distribution; D014568:Urokinase-Type Plasminogen Activator / Q000627:therapeutic use*
D004731:Endotoxins; D011994:Recombinant Proteins; C044101:endotoxin, Escherichia coli; D005337:Fibrin; D005340:Fibrinogen; D014568:Urokinase-Type Plasminogen Activator; C067551:saruplase