Endotoxin-induced disseminated intravascular coagulation in rabbits: Effect of recombinant hirudin on hemostatic parameters, fibrin deposits, and mortality

Hermida, José; Montes, Ramón; Paramo, J.A.; Rocha, Eduardo

doi:10.1016/s0022-2143(98)90080-4

“…As in experiments previously performed by our group (Gómez et al, 1989;Paloma et al, 1992Paloma et al, , 1995Hermida et al, 1998), a significant impairment in the haemostatic parameters as well as an intense kidney fibrin deposition and a high mortality rate were assessed following LPS infusion in rabbits. Haemostatic parameters at 2 and 6 h in the LPS group and all treatment groups.…”

Section: Discussionmentioning

confidence: 99%

“…r-Hirudin, whose efficacy in venous and arterial thrombosis has been widely studied (Ten-Cate, 1996), could be an attractive therapeutic agent in LPS-induced DIC, as is suggested by previous work in several experimental models (Ishikawa et al, 1980;Hoffmann et al, 1990;Zawilska et al, 1993;Hermida et al, 1998). On the other hand, fibrinolytic activators have been found to be useful in different animal models of thrombosis and DIC (Matsuo et al, 1981;Korninger et al, 1982;Collen et al, 1983;Agnelli et al, 1985;Schneider, 1993;Paloma et al, 1995;Hardaway et al, 1996).…”

mentioning

confidence: 98%

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

Muñóz

¹

,

Sánchez

²

,

Hermida

³

et al. 1999

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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.

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“…The effect of the simultaneous administration of r‐hirudin and t‐PA to rabbits given LPS to induce DIC was compared with the effect of the infusion of r‐hirudin or t‐PA alone. As in experiments previously performed by our group (Gómez et al , 1989; Paloma et al , 1992, 1995; Hermida et al , 1998), a significant impairment in the haemostatic parameters as well as an intense kidney fibrin deposition and a high mortality rate were assessed following LPS infusion in rabbits.…”

Section: Discussionmentioning

confidence: 99%

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

Muñoz

¹

,

Montes

²

,

Hermida

³

et al. 1999

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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.

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“…10 In endotoxemic rabbits, selective inhibition of thrombin with hirudin decreased fibrin deposition and decreased mortality. 14 Moreover, endotoxemicAT-III + / − and PC + / − heterozygous mice exhibited increased fibrin deposition and mortality compared with wild-type (WT) controls, presumably due to reduced levels of the anticoagulants. 15,16 In a lethal baboon model of Escherichia coli-induced sepsis, inhibition of the TF-factor VIIa (FVIIa) complex with either an inhibitory anti-TF monoclonal antibody, active siteinhibited FVIIa (FVIIai), or TFPI-1 decreased coagulation and prevented death.…”

Section: Introductionmentioning

confidence: 99%

Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia

Pawliński

¹

,

Pedersen

²

,

Schabbauer

³

et al. 2004

Blood

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Sepsis is associated with a systemic activation of coagulation and an excessive inflammatory response. Anticoagulants have been shown to inhibit both coagulation and inflammation in sepsis. In this study, we used both genetic and pharmacologic approaches to analyze the role of tissue factor and protease-activated receptors in coagulation and inflammation in a mouse endotoxemia model. We used mice expressing low levels of the procoagulant molecule, tissue factor (TF), to analyze the effects of TF deficiency either in all tissues or selectively in hematopoietic cells. Low TF mice had reduced coagulation, inflammation, and mortality compared with control mice. Similarly, a deficiency of TF expression by hematopoietic cells reduced lipopolysaccharide (LPS)-induced coagulation, inflammation, and mortality. Inhibition of the downstream coagulation protease, thrombin, reduced fibrin deposition and prolonged survival without affecting inflammation. Deficiency of either protease activated receptor-1 (PAR-1) or protease activated receptor-2 (PAR-2) alone did not affect inflammation or survival. However, a combination of thrombin inhibition and PAR-2 deficiency reduced inflammation and mortality. These data demonstrate that hematopoietic cells are the major pathologic site of TF expression during endotoxemia and suggest that multiple protease-activated receptors mediate crosstalk between coagulation and inflammation.

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Endotoxin-induced disseminated intravascular coagulation in rabbits: Effect of recombinant hirudin on hemostatic parameters, fibrin deposits, and mortality

Cited by 36 publications

References 39 publications

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

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

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

Role of tissue factor and protease-activated receptors in a mouse model of endotoxemia

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