Effects of low molecular weight heparin, alone or combined with antithrombin III, on mortality, fibrin deposits and hemostatic parameters in endotoxin-induced disseminated intravascular coagulation in rabbits

Abstract

The effect of low molecular weight heparin (LMWH) with or without antithrombin III (AT III) has been studied in a rabbit model of disseminated intravascular coagulation (DIC) induced by continuous infusion of 100 microg/kg/hr of Escherichia coli endotoxin for 6 hr. LMWH (5 and 10 IU/kg/hr/6 hr), alone or in combination with AT III (20 U/kg/hr/6 hr), or saline were administered simultaneously with endotoxin. Hemostatic markers at 0, 2, and 6 hr as well as kidney fibrin deposits and the mortality rate at 24 hr were determined. Rabbits receiving only endotoxin showed an impairment in hemostasis, as well as high kidney fibrin deposits and a high mortality rate. LMWH alone did not exert any effect. The simultaneous infusion of LMWH and AT III exerted a beneficial effect on the hemostatic markers and reduced the kidney fibrin deposits as well as the mortality rate in a LMWH dose-dependent manner. Fibrinogen and protein C consumption were significantly higher and renal fibrin deposits more intense in the rabbits that had died in the first 24 hr. There was also a significant positive correlation between kidney fibrin deposits and platelets, fibrinogen, and protein C consumption, taking the whole rabbit population. It is concluded that the simultaneous infusion of LMWH and AT III is useful in this DIC model and would make it possible to reduce significantly the AT III doses used when AT III is given alone.

Effects of pentoxifylline on coagulation profile and disseminated intravascular coagulation incidence in Egyptian septic neonates

“…interleukin‐1 (IL‐1), IL‐6, and tissue necrosis factor‐α (TNF‐α)]. One of the common complications of sepsis is disseminated intravascular coagulation (DIC) (4–6). DIC is an acquired disorder that induces the exhaustion of platelets, coagulation and fibrinolytic factors and causes multiple microvascular thrombi which contribute to the development of multiple organ failure.…”

Prevention of Renal Fibrin Deposition in Endotoxin-induced DIC through Inhibition of PAI-1

“…The significance of high levels of PAI-1 as a prothrombotic factor has been pointed out in several animal models of venous and arterial thrombosis in which the arrest of the inhibitor activity improved the endogenous thrombolysis and decreased the thrombus extension in the case of venous thrombosis (5)(6)(7), and facilitated the reperfusion and reduction of reocclusion in the case of arterial thrombosis (6)(7)(8). Although some models have dealt with endotoxemia (9), there have been no attempts so far to study the effect of the inhibition of PAI activity, which is dramatically increased after a continuous infusion of gram negative endotoxin [lipopolysaccharide (LPS)] at a dose sufficient to induce disseminated intravascular coagulation (DIC) (10)(11)(12)(13)(14)(15)(16). MA-33B8 is a PAI-1-neutralizing monoclonal antibody (Mo Ab) raised against human PAI-1 and crossreacting with, as well as exerting a strong neutralizing activity against, rabbit PAI-1 (17).…”

“…The PAI-1 neutralizing effect of MA-33B8 was shown to be associated with an accelerated conversion to the latent conformation (18,19). In this study we investigated the effect of MA-33B8 in a well defined model of LPS-induced DIC (14)(15)(16), in which the Mo Ab is administered to rabbits receiving a continuous intravenous infusion of E. coli LPS. As kidneys are a target organ for the formation of fibrin polymers in the microvasculature in DIC and previous studies have postulated a role for PAI-1 in the renal pathology and also in the generation of fibrin deposits (20,21), special attention is paid to the effect of treatment with MA-33B8 on PAI-1 activity in the renal microcirculation and its relationship with the formation of renal fibrin deposits.…”

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“…However, most experimental models describing coagulation abnormalities in mice as a consequence of sepsis are based on single dose endotoxemia or live E. coli models. Sustained endotoxin infusions are also regularly used as models for DIC, though predominantly in larger animals like rats and rabbits [ 19 , 20 ].…”