Effect of the administration of recombinant hirudin and/or tissue-plasminogen activator (t-PA) on endotoxin-induced disseminated intravascular coagulation model in rabbits

Abstract

Summary.We evaluated the effect of r-hirudin and/or tissueplasminogen activator (t-PA) in a model of DIC in rabbits induced by i.v. infusion of 100 mg/kg/h/6 h endotoxin. Rabbits were treated with saline (endotoxin control group), r-hirudin at 0·3 mg/kg/h/6 h, t-PA at 0·3 mg/kg for 90 min and r-hirudin plus t-PA at the doses described above. The best results were achieved when r-hirudin and t-PA were infused together. This treatment reduced the consumption of platelets and protein C and attenuated the increase of PAI-1 more efficiently than r-hirudin or t-PA alone. r-Hirudin plus t-PA also resulted in the lowest formation of fibrin deposits in the kidneys. Finally, mortality at 24 h dropped from 70% in the endotoxin control group to 40%, 10% and 0% in the t-PA, r-hirudin and rhirudin plus t-PA groups respectively. None of the t-PA-infused rabbits which had died by 24 h showed macroscopic signs of haemorrhage. r-Hirudin alone was better than t-PA alone, as was shown by fibrin deposits and mortality. We conclude that r-hirudin and t-PA given simultaneously were more efficient than either given alone in this model of DIC. Effective thrombin inhibition, which could influence other pathophysiological mechanisms apart from coagulation, together with the improvement in fibrinolysis, would explain these results.

Role of Lipopolysaccharide and Cecal Ligation and Puncture on Blood Coagulation and Inflammation in Sensitive and Resistant Mice Models

“…26 The role of anticoagulant treatments in mortality associated with sepsis is controversial. Some reports suggest that hirudin decreases mortality, especially in LPS-induced sepsis, 27,28 but others find no effect, 29,30 or even an increased mortality, especially in bacterial peritonitis (because anticoagulant treatments may enhance the spread of bacteria by preventing localization of the septic focus). 31 Blockade of thrombin formation (by using anti-factor Xa drugs) also achieved similar results: they attenuate endotoxininduced coagulopathy, but do not alter endotoxin-induced changes in the fibrinolytic system, cytokine levels, activation of leukocytes, cellular infiltration, and do not increase survival.…”

Plasminogen Activators in Inflammation and Sepsis

“…Circulation and metabolism, after a hyperdynamic phase, enter a more prolonged hypodynamic phase. Initial hyperfibrinolysis is followed by protracted hypofibrinolysis ( 2, 8, 15, 65, 122, 173, 184 ). Most of our patients actually are immunocompromised ( 22, 121, 182, 183 ).…”

“…A vigorous inflammatory stimulus, such as endotoxin, is followed by a bimodal response of overall fibrinolytic activity. Plasminogen activators and overall fibrinolytic activity markedly increase for a few hours, followed by prolonged suppression of fibrinolytic activity, paralleled by sustained increase in PAI (2, 8, 15, 65, 122, 173, 184). Fibrinolytic activity, expressed as PAP level, is especially low in sepsis with multiorgan failure (9).…”

“…In endotoxin‐challenged animals, tPA, streptokinase and urokinase markedly improved survival, blunted protein C consumption and PAI increase, reduced fibrin deposits and ex vivo clot formation, correlating with dose. No animal bled (122, 144, 170).…”

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“…A newer anticoagulant agent with direct thombin inhibitory activity, recombinant hirudin (r-hirudin) [ 67 , 68 ], was recently shown to be effective in treating DIC in animal studies, although a study of the effect of this thrombin inhibitor in a sheep model of lethal endotoxemia showed no benefit [ 69 ]. Preliminary experimental human studies proved that this drug attenuated endotoxin-induced coagulation activation [ 70 ].…”