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.

Effect of pentoxifylline on endotoxin-induced haemostatic disturbances in rabbits

“…The prolongation of APTT and PT after administration of LPS was significantly prevented by treatment with PTX. In harmony with earlier findings (Paloma et al, 1992;Munoz et al, 1999;Hermida et al, 1999;Montes et al, 2000), the injection of endotoxin into the rabbits caused a significant decrease in fibrinogen concentration at 6 h in the present investigation. Low fibrinogen level can be due to impaired fibrinogen synthesis as a result of hepatic tissue damage, increased consumption during DIC, loss into the extravascular spaces and massive haemorrhage.…”

“…Some authors have reported that low levels of AT-III are associated with a higher mortality in septic shock (Fourrier et al, 1993). LPS given alone reduced the AT-III activity, which is in agreement with previous reports (Scherer et al, 1995;Munoz et al, 1999;Hermida et al, 1999;Yamazaki et al, 1999;Asakura et al, 2001). The simultaneous administration of PTX to endotoxin-treated rabbits did not prevent the decrease in AT-III activity.…”

“…Earlier studies have shown that endotoxin injection chosen for coagulation activation induced DIC within 4-6 h in rabbits Munoz et al, 1999;Montes et al, 2000). Clinically, endotoxin, which is released from the cell membrane of Gram-negative bacteria continuously or intermittently in sepsis, is thought to play a role in the pathogenesis of DIC, which is accompanied by sepsis (Levi and ten Cate, 1999;Levi et al, 1997).…”

“…Despite the potent antimicrobial treatments and intensive supportive care introduced in the last decade, sepsis is still associated with a high mortality rate (60%; Munoz et al, 1999). Sepsis induced by Gram-negative bacteria is the leading cause of multiple organ failure and is commonly associated with disturbances of the haemostatic balance (Levi and ten Cate, 1999).…”

“…Endotoxin, a lipopolysaccharide component of the outer membrane of Gram-negative bacteria, is involved in the pathogenesis of DIC due to sepsis and plays a pivotal role in the initiation of the coagulopathy in sepsis (van der Poll et al, 1991;Munoz et al, 1999). The generation of thrombin in endotoxin-induced DIC was shown to be mediated by an extrinsic pathway of the coagulation system, involving tissue factor/factor VIIa system (van der Poll et al, 1990;Taylor et al, 1991;Levi et al, 1994;Dempfle et al, 1995).…”