All-trans retinoic acid is partially effective against lipopolysaccharide-induced but not against tissue-factor-induced disseminated intravascular coagulation in rat models.
All-trans retinoic acid (ATRA) has been introduced to the management of acute promyelocytic leukemia (APL) as a differentiation treatment. This drug not only causes complete remission, but also improves disseminated intravascular coagulation (DIC) without adding anticoagulants in APL. We have attempted to determine whether ATRA is effective against DIC in rat models induced by tissue factor (TF) or lipopolysaccharide (LPS), because the anticoagulant effect of ATRA has been considered to induce thrombomodulin upregulation and TF downregulation on endothelial cells as well as on APL cells. In male Wistar rats, DIC was induced by a 4-h infusion of thromboplastin (3.75 U/kg) or lipopolysaccharide (30 mg/kg). The rats were given ATRA orally each day at a dose of 100 mg/kg per day for 1 week before the injection of TF or LPS in ATRA treatment groups, or given low molecular weight heparin (LMWH) 10 min before the injection of TF or LPS (200 U/kg, bolus intravenously) in LMWH treatment groups. No significant changes in hemostatic parameters or markers of organ dysfunction were caused by the ATRA administration, while DIC was significantly improved by LMWH in the TF-induced model. DIC was significantly improved by both ATRA and LMWH in the LPS-induced model. These findings suggested that ATRA was useful for treating DIC only in the LPS-induced model, and that drug efficacy should be carefully assessed because the agents used to induce DIC considerably influenced the outcome.
Asakura
H
H
Department of Internal Medicine (III), Kanazawa University School of Medicine, Kanazawa, Ishikawa, Japan. hasakura@med3.m.kanazawa-u.ac.jp
Aoshima
K
K
Ichino
T
T
Suga
Y
Y
Saito
M
M
Morishita
E
E
Yamazaki
M
M
Ontachi
Y
Y
Mizutani
T
T
Kato
M
M
Miyamoto
K I
KI
Nakao
S
S
D000818:Animals; D004195:Disease Models, Animal; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000188:drug therapy*; D007641:Keratolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D008070:Lipopolysaccharides / Q000633:toxicity; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D013925:Thromboplastin / Q000633:toxicity; D014212:Tretinoin / Q000494:pharmacology / Q000627:therapeutic use*
D007641:Keratolytic Agents; D008070:Lipopolysaccharides; D014212:Tretinoin; D013925:Thromboplastin