A combination of a thrombin inhibitor and dexamethasone prevents the development of experimental disseminated intravascular coagulation in rats.
BACKGROUND
Disseminated intravascular coagulation (DIC) is a serious and potentially lethal complication of severe sepsis. DIC is characterised primarily by widespread platelet aggregation and fibrin deposition, followed by consumption of platelets, coagulation factors, and inhibitors. The aim of the study was to evaluate the efficacy of the active-site thrombin inhibitor melagatran, the active form of the oral direct thrombin inhibitor ximelagatran, in reducing fibrinogen and platelet consumption in blood and fibrin deposition in organs, in an experimental endotoxinaemia rat model.


METHODS
In this model, DIC was induced by an intravenous injection of endotoxin (1 mg/kg). Melagatran was compared with unfractionated heparin and the synthetic glucocorticoid analogue dexamethasone. Animals were divided into 16 treatment groups in which high and low doses of each agent were tested alone and in combination with melagatran.


RESULTS
Fibrinogen consumption was reduced by melagatran, dexamethasone, and heparin, and was completely prevented by melagatran in combination with dexamethasone. Platelet consumption was partially reduced by melagatran, unfractionated heparin, and dexamethasone, but complete protection was observed only with melagatran in combination with dexamethasone. Melagatran in combination with dexamethasone or heparin protected the liver and spleen from fibrin deposition.


CONCLUSIONS
In this experimental DIC rat model, the direct thrombin inhibitor melagatran given together with dexamethasone protected against the consequences of activated haemostasis.
Elg
Margareta
M
Department of Integrative Pharmacology, AstraZeneca R&D Mölndal, Mölndal, Sweden. Margareta.Elg@astrazeneca.com
Gustafsson
David
D
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000008:administration & dosage; D000925:Anticoagulants / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D001384:Azetidines / Q000008:administration & dosage*; D001596:Benzylamines / Q000008:administration & dosage*; D001777:Blood Coagulation / Q000187:drug effects*; D003907:Dexamethasone / Q000008:administration & dosage*; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000175:diagnosis* / Q000517:prevention & control*; D006801:Humans; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley; D013917:Thrombin / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome
D000893:Anti-Inflammatory Agents; D000925:Anticoagulants; D001384:Azetidines; D001596:Benzylamines; C109573:melagatran; D003907:Dexamethasone; D013917:Thrombin