Rivaroxaban Has Protective Effects in a Model of Disseminated Intravascular Coagulation (DIC) in Rats.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 935-935 ◽  
Author(s):  
Elisabeth Perzborn ◽  
Claudia Hirth-Dietrich ◽  
Elke Fischer ◽  
Martin Groth ◽  
Elke Hartmann ◽  
...  
Keyword(s):  
Platelet Count ◽  
Disseminated Intravascular Coagulation ◽  
Interleukin 6 ◽  
Factor Xa ◽  
Selective Inhibition ◽  
Vehicle Control ◽  
Protective Effects ◽  
Intravascular Coagulation ◽  
Serious Infection ◽  
Fxa Inhibitor

Abstract 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 Blood samples were withdrawn from anesthetized animals by heart puncture 4 hours after LPS injection and fibrinogen, platelet count, thrombin-antithrombin (TAT) complex levels and IL-6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 control Placebo + LPS Rivaroxaban 1 mg/kg + LPS Rivaroxaban 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

Effects of DX-9065a, an Orally Active, Newly Synthesized and Specific Inhibitor of Factor Xa, against Experimental Disseminated Intravascular Coagulation in Rats

1994 ◽  
Vol 72 (03) ◽  
pp. 393-396 ◽  
Author(s):  
Masahide Yamazaki ◽  
Hidesaku Asakura ◽  
Keiji Aoshima ◽  
Masanori Saito ◽  
Hiroshi Jokaji ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Degradation Products ◽  
Specific Inhibitor ◽  
Factor Xa ◽  
Dose Finding ◽  
Protective Effects ◽  
Intravascular Coagulation ◽  
Safety Studies ◽  
Orally Active ◽  
Fibrin Thrombi

SummaryWe investigated the protective effects of DX-9065a, an orally active, newly synthesized and specific inhibitor of factor Xa, against two kinds of experimental disseminated intravascular coagulation (DIC) in rats. Endotoxin-induced experimental DIC was induced by a 4-h sustained infusion of endotoxin at a dose of 100 mg/kg. Thromboplastin-induced experimental DIC was induced by a bolus injection of thromboplastin at a dose of 150 mg/kg. The rats were orally administered DX-9065a at 10, 30 or 100 mg/kg 30 min before endotoxin or thromboplastin injection.In both DIC models, DX-9065a showed a protective effect against DIC, at all doses and in all parameters, including fibrin/fibrinogen degradation products (FDP), fibrinogen level, prothrombin time, activated partial thromboplastin time, platelet count and the number of renal glomeruli with fibrin thrombi.When DX-9065a was orally administrated at 100 mg/kg without endotoxin or thromboplastin, no significant changes were seen in hemostatic parameters except PT and APTT, and no fibrin thrombi or abnormal bleeding were seen in renal specimens.These findings suggest that the new oral anti-Xa drug, DX-9065a, has an effect in reducing the severity of DIC. However, further dose-finding and safety studies of this drug have still to be assessed.

Inhibitory Effect Of Gabexate Mesilate On Experimental Disseminated Intravascular Coagulation

1981 ◽  
Author(s):  
H Ohno ◽  
S W Chang ◽  
J Kambayashi ◽  
S Imaoka ◽  
G Kōsaki
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Factor Xa ◽  
Inhibitory Effect ◽  
Rat Plasma ◽  
Gabexate Mesilate ◽  
Antithrombotic Agent ◽  
Continuous Administration ◽  
Intravascular Coagulation ◽  
Relevant Compound

Gabexate mesilate:[Ethyl p-(6-guanidinohexanoyloxy)benzoate]methanesulfonate, which is clinically used as a potent trypsin inhibitor in Japan, inhibits competitively the hydrolytic reactions with synthetic substrates by thrombin and factor Xa. However, its virtual anticoagulant effect in vivo remains to be evaluated, because of its short halflife due to the presence of plasma esterase. In the present study, the inhibitory effect of gabexate mesilate on experimental disseminated intravascular coagulation was investigated in comparison with those of heparin and aprotinin. 125I-Fibrinogen was injected into rats along with t-AMCHA to prevent lysis of fibrin formed. Five minutes after a infusion of gabexate mesilate, heparin, aprotinin or saline, intravascular cogulation was triggered by a continuous infusion of thrombin or tissue thromboplstin. The deposition of fibrin in kidney was continuously monitored by scintillation detector. Platelet count and 125I-fibrinogen in blood were determined. The formation of fibrin induced by thrombin and tissue thromboplastin was completely inhibited by continuous administration of 120 μmol gabexate mesilate/kg/h or 200 U heparin/kg/h. On the other hand, aprotinin failed to prevent the deposition of fibrin even at dose of 50,000 U/kg/h. Also, other parameters corroborated the same aspect. The naturally occuring lysis of the microthrombi previously formed by thrombin was not blocked by the infusion of 120 μmol gabexate mesilate/kg/h or 200 U heparin/kg/h. However, aprotinin, at 5,000 U/kg/h, completely blocked the lysis. Using clotting assay, the biological half life of gabexate mesilate in human plasma was found to be ten times longer than that in rat plasma, suggesting that much lower dose would be effective in human. In conclusion, gabexate mesilate is a relevant compound as an antithrombotic agent.

Disseminated Intravascular Coagulation: A Clinical/Laboratory Correlation In 48 Patients

1981 ◽  
Author(s):  
R L Bick
Keyword(s):  
Platelet Count ◽  
Disseminated Intravascular Coagulation ◽  
Clinical Laboratory ◽  
Fibrinogen Level ◽  
Degradation Products ◽  
Severe Bleeding ◽  
Thrombin Time ◽  
Intravascular Coagulation ◽  
At Iii ◽  
Pre Treatment

Disseminated intravascular coagulation (DIC) is a frequent clinical entity spanning from a moderately severe bleeding disorder to a catastrophic, fulminant, and often fatal form usually associated with hemorrhage or, less commonly,as diffuse thromboses. The clinical and laboratory features of DIC remain confusing and controversial. To critically evaluate the usefulness of coagulation tests in aiding in the diagnosis and monitoring of therapy in DIC the clinical and laboratory findings were summarized in 48 patients with DIC. All patients were subjected to a prothrombin time (PT), activated partial thromboplastin time (PTT), reptilase time (RT), thrombin time (TT), fibrin(ogen) degradation products (FDP), platelet count, protamine sulfate test (PSO4), fibrinogen determination, and biological antithrombin-III (AT-III) level at the time of diagnosis. In addition, these same laboratory modalities were used to monitor patients during and after therapy. In this series of 48 patients, 38 patients had acute DIC and 10 patients had chronic DIC. In those patients with acute DIC, 100% of patients presented with hemorrhage and 53% of patients had thrombosis; 26% of patients died of their DIC type syndrome. In those patients with chronic DIC, 100% presented with hemorrhage, 80% presented with thrombosis, and none died of their intravascular clotting process. The probability of a pre-treatment abnormality in acute DIC was: FDP > AT-III = platelet count PS04 > TT > PT > fibrinogen level > PTT > RT. The probability of pre-treatment abnormalties in chronic DIC was: FDP > PSO4 = PT > AT-III = RT platelet count fibrinogen level = TT. These studies suggest the FDP level, the AT-III level, PSO4, and fibrinogen level to be reliable for aiding in the diagnosis of acute DIC. In chronic DIC the fibrinogen level, PS04, PTT, and AT-III level appear to be the most reliable indicies.

Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an oral, direct factor Xa inhibitor

2007 ◽  
Vol 97 (03) ◽  
pp. 471-477 ◽  
Author(s):  
Elisabeth Perzborn ◽  
Philip Friederich ◽  
Marcel Levi ◽  
Ulf Buetehorn ◽  
Harry Büller ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Factor Xa ◽  
Vehicle Control ◽  
Venous Stasis ◽  
Treatment Model ◽  
Direct Factor ◽  
Experimental Thrombosis ◽  
Prevention And Treatment ◽  
Prevention Model ◽  
Fxa Inhibitor

SummaryCurrent anticoagulant therapies for the prevention and treatment of thromboembolic disorders have many drawbacks: vitamin K antagonists interact with food and drugs and require frequent laboratory monitoring, and heparins require parenteral administration. Oral rivaroxaban (BAY 597939) is a new, highly selective and potent direct factor-Xa (FXa) inhibitor with a predictable pharmacodynamic and pharmacokinetic profile and could therefore be an attractive antithrombotic drug. It was the objective of this study to investigate the antithrombotic efficacy of oral rivaroxaban in two rabbit models of experimental venous thrombosis. In the venous stasis (prevention) model, animals were randomized to receive oral rivaroxaban 0.3, 1.0, 3.0 or 10.0 mg/kg or vehicle control. Thrombosis was induced by jugular vein stasis and injection of thromboplastin into the ear vein. In the venous thrombosis (treatment) model, intravenous (1.0 and 3.0 mg/kg) and oral (3.0 mg/kg) rivaroxaban was compared with intravenous nadroparin (40 U bolus and 20 U/h), fon-daparinux (42 Mg/kg) and vehicle control. Thrombus growth was assessed by measuring the accretion of radiolabeled fibrinogen into preformed clots in the jugular veins. Bleeding was assessed using an ear bleeding model. In the prevention model, rivaroxaban reduced thrombus formation dose-dependently (calculated ED50 1.3 mg/kg). In the treatment model, oral rivaroxaban (3.0 mg/kg) reduced thrombus growth to a similar extent to intravenous rivaroxaban (1.0 mg/kg), nadroparin and fondapari-nux. Oral rivaroxaban did not prolong bleeding time. In conclusion, the orally available selective, direct FXa inhibitor rivaroxaban is effective in the prevention and treatment of venous thrombosis in two well-established models of experimental thrombosis.

scholarly journals Associations Among Coagulation-Related Variables, Resolution of Disseminated Intravascular Coagulation (DIC), and Mortality in Patients with Sepsis-Induced DIC Treated with Recombinant Human Soluble Thrombomodulin: A Retrospective Observational Study

2021 ◽  
Author(s):  
Chieko Mitaka ◽  
Izumi Kawagoe ◽  
Daizoh Satoh ◽  
Masakazu Hayashida
Keyword(s):  
Platelet Count ◽  
Observational Study ◽  
Disseminated Intravascular Coagulation ◽  
Early Phase ◽  
Degradation Products ◽  
International Normalized Ratio ◽  
Soluble Thrombomodulin ◽  
Intravascular Coagulation ◽  
Before And After ◽  
Recombinant Human Soluble Thrombomodulin

Abstract Background: We evaluated associations among coagulation-related variables, resolution of disseminated intravascular coagulation (DIC), and mortality in patients with sepsis-induced DIC treated with recombinant human soluble thrombomodulin (rTM). Methods: We retrospectively investigated patients with sepsis-induced DIC treated with rTM. Changes in coagulation-related variables before and after treatment with rTM were examined. Further, associations between coagulation-related variables and DIC resolution were evaluated. Results: A total of 123 patients were included. The platelet count, prothrombin international normalized ratio (PT-INR), and fibrin/fibrinogen degradation products (FDP) significantly (p < 0.001) improved after rTM administration in survivors (n = 98), but not in nonsurvivors (n = 25). However, the DIC score significantly (p < 0.001) reduced not only in survivors but also in nonsurvivors. PT-INR before rTM was significantly (p = 0.0029) lower in patients attaining than not attaining DIC resolution (n = 87 and 36, respectively). The 28-day mortality was significantly lower in patients attaining than not attaining DIC resolution (11.5% vs. 41.7 %, p = 0.0001).Conclusions: The DIC score significantly reduced after rTM in both survivors and nonsurvivors. rTM might play an important role in improving DIC, especially when treatment with rTM is initiated in the early phase of DIC.

Effect of Vitamin E on Endotoxin-Induced Disseminated Intravascular Coagulation in Rats

1982 ◽  
Vol 48 (02) ◽  
pp. 235-237 ◽  
Author(s):  
T Yoshikawa ◽  
Y Furukawa ◽  
M Murakami ◽  
K Watanabe ◽  
M Kondo
Keyword(s):  
Platelet Count ◽  
Vitamin E ◽  
Disseminated Intravascular Coagulation ◽  
Fibrinogen Level ◽  
Degradation Products ◽  
Tocopheryl Acetate ◽  
Preventive Effect ◽  
Intravascular Coagulation ◽  
Fibrin Degradation Products ◽  
Fibrin Thrombi

SummaryExperimental disseminated intravascular coagulation (DIC) can be induced by 4 hr sustained infusion of endotoxin in a dose of 100 mg/kg in rats. The experimental model of DIC in rats was used to study the preventive effect of vitamin E, α-tocopheryl acetate, against DIC. Before the infusion of endotoxin, 0.01, 0.1, 1.0 or 10.0 mg/kg/day of α-tocopheryl acetate was injected intraperitoneally for 4 successive days. The preventive effect against DIC was noted in all the parameters, such as fibrinogen and fibrin degradation products, fibrinogen level, prothrombin time, partial thromboplastin time, platelet count, and the number of renal glomeruli with fibrin thrombi, in rats treated with 1.0 or 10.0 mg/kg of α-tocopheryl acetate. From these results, it was shown that vitamin E, α-tocopheryl acetate, inhibited endotoxin-induced experimental DIC in rats.

Effects of Ticlopidine and Aspirin on Endotoxin-Induced Disseminated Intravascular Coagulation in Rats

1983 ◽  
Vol 49 (03) ◽  
pp. 190-192 ◽  
Author(s):  
T Yoshikawa ◽  
M Murakami ◽  
Y Furukawa ◽  
S Takemura ◽  
M Kondo
Keyword(s):  
Platelet Count ◽  
Continuous Infusion ◽  
Disseminated Intravascular Coagulation ◽  
Partial Thromboplastin Time ◽  
Fibrinogen Level ◽  
Degradation Products ◽  
Preventive Effect ◽  
Intravascular Coagulation ◽  
Fibrin Degradation Products ◽  
Fibrin Thrombi

SummaryThe effects of ticlopidine and aspirin on endotoxin-induced experimental disseminated intravascular coagulation (DIC) were studied in rats. Experimental DIC was induced by a 4 hr sustained infusion of endotoxin at a dose of 100 mg/kg. The rats were intraperitoneally injected with ticlopidine at 2.0, 20.0, 50.0, 100.0 or 200.0 mg/kg, or aspirin at 0.03, 0.3, 3.0 or 30.0 mg/kg, followed by the continuous infusion of 100 mg/kg/4 hr of endotoxin. A preventive effect against DIC was noted in all the parameters, such as fibrinogen and fibrin degradation products (FDP), fibrinogen level, prothrombin time, partial thromboplastin time (PTT), platelet count and the number of renal glomeruli with fibrin thrombi, in the rats treated with 20.0, 50.0, 100.0 or mg/kg of ticlopidine. Although a preventive effect was also noted in FDP, PTT, platelet count and the number of glomeruli with thrombi in rats treated with 0.03 or 0.3 mg/kg of aspirin, this agent was less effective than ticlopidine.

Sign in / Sign up

Export Citation Format

Share Document