Introduction: DIC is a complication that occurs during serious infection with Gram-negative bacteria. Endotoxin is a component of the bacterial cell wall that elicits a cytokine-mediated cascade of tissue factor-dependent hypercoagulable reactions. The resulting hypercoagulable state may be inhibited by potent anticoagulation. Rivaroxaban is an oral, direct Factor Xa (FXa) inhibitor in advanced clinical development for the prevention and treatment of thromboembolic disorders. The aim of this study was to examine the effects of rivaroxaban in a rat model of endotoxin-induced DIC.

Methods: Rivaroxaban (0.1–10 mg/kg p.o.) or vehicle control (PEG400/H2O 60/40%, 5 mL/kg p.o.) were administered 30 minutes before endotoxin injection (lipopolysaccharide O55 B5 [LPS], 250 μg/kg i.v.) to conscious rats. Blood samples were withdrawn from anesthetized animals by heart puncture 4 hours after LPS injection and fibrinogen, platelet count, thrombin-antithrombin (TAT) complex levels and IL-6 were measured.

Results: The induction of DIC was indicated in the placebo + LPS group vs vehicle control by decreased fibrinogen (2.12±0.08 vs 2.69±0.10 g/L) and platelet count (571±28 vs 904±30×109/L) an increase in TAT (75±9 vs 2±1 μg/L) and IL-6 (8.6±1.23 μg/L vs 0.028±0.020 μg/L). Pretreatment with rivaroxaban (0.1–10 mg/kg p.o.) dose-dependently ameliorated the effects of LPS on fibrinogen, platelets and TAT. Rivaroxaban 10 mg/kg p.o. normalized fibrinogen (2.58±0.07 g/L) and TAT (5.6±1.2 μg/L) and increased platelet count (703±19×109/L) (Table). Rivaroxaban also slightly reduced the plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) (4.24±0.67 μg/L).

Conclusions: These results show that direct, selective inhibition of FXa by rivaroxaban effectively normalized the hypercoagulable reactions of endotoxemia with a slight modulating effect on the generation of pro-inflammatory active cytokines, such as IL-6, in the rat DIC model. Further research into the use of rivaroxaban in the management of DIC is therefore warranted.

Effects of rivaroxaban in an endotoxin-induced DIC model in rats 4 hours after LPS injection. Results show mean ± SEM.

Vehicle controlPlacebo + LPSRivaroxaban 1 mg/kg + LPSRivaroxaban 10 mg/kg + LPS
DIC, disseminated intravascular coagulation; IL-6, interleukin-6; LPS, lipopolysaccharide O55 B5; SEM, standard error of the mean; TAT, thrombin-antithrombin ## p<0.01 vs sham, ### p<0.001 vs sham, *p<0.05 vs LPS/placebo, ** p<0.01 vs LPS/placebo, *** p<0.001 vs LPS/placebo 
Fibrinogen (g/L) 2.69±0.10 n=5 2.12±0.08## n=14 2.41±0.09 n=14 2.58± 0.07** n=7 
Platelets (×109/l) 904±30 n=5 571±28### n=8 655±23 n=6 703±19* n=7 
TAT (μg/L) 1.8±0.8 n=5 75.2±9.4### n=14 65.3±8.0 n=14 5.6±1.2*** n=7 
IL-6 (μg/ml) 0.028±0.020 n=5 8.60±1.23### n=6 5.01±0.47 n=6 4.24±0.67 n=7 
Vehicle controlPlacebo + LPSRivaroxaban 1 mg/kg + LPSRivaroxaban 10 mg/kg + LPS
DIC, disseminated intravascular coagulation; IL-6, interleukin-6; LPS, lipopolysaccharide O55 B5; SEM, standard error of the mean; TAT, thrombin-antithrombin ## p<0.01 vs sham, ### p<0.001 vs sham, *p<0.05 vs LPS/placebo, ** p<0.01 vs LPS/placebo, *** p<0.001 vs LPS/placebo 
Fibrinogen (g/L) 2.69±0.10 n=5 2.12±0.08## n=14 2.41±0.09 n=14 2.58± 0.07** n=7 
Platelets (×109/l) 904±30 n=5 571±28### n=8 655±23 n=6 703±19* n=7 
TAT (μg/L) 1.8±0.8 n=5 75.2±9.4### n=14 65.3±8.0 n=14 5.6±1.2*** n=7 
IL-6 (μg/ml) 0.028±0.020 n=5 8.60±1.23### n=6 5.01±0.47 n=6 4.24±0.67 n=7 
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Topics:
disseminated intravascular coagulation, rats, rivaroxaban, interleukin-6, fibrinogen, endotoxins, cytokine, thrombophilia, antithrombin iii, antithrombins

Author notes

Disclosure:Employment: Employee of Bayer Healthcare. Ownership Interests:; Bayer stocks. Financial Information: Named as inventor on patents including rivaroxaban.

2007, The American Society of Hematology
2007
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