Effects of gabexate mesilate on coagulopathy and organ dysfunction in rats with endotoxemia: a potential use of thrombelastography in endotoxin-induced sepsis.
Sepsis and its associated multiple organ failure are related to high mortality in critical patients. Several studies have reported that gabexate mesilate, a synthetic inhibitor of trypsin-like serine protease, protects tissues/organs against injury in the models of endotoxemia. The aim of this study was to examine whether gabexate mesilate could attenuate coagulopathy and organ dysfunction in lipopolysaccharide (LPS)-induced sepsis model by using thrombelastography (TEG). LPS (7.5  mg/kg/h, intravenouly for 4  h) was administered to male adult Wistar rats. Some of the LPS rats received a continuous infusion of gabexate mesilate (10  mg/kg/h, intravenously for 8.5  h) for 30  min before the LPS administration. Variable parameters of hemodynamics, biochemistry, hemostasis and inflammatory response were measured for 6  h after the LPS infusion. TEG variables (R-time, K-time, α-angle, and maximal amplitude) were also measured. The pretreatment of LPS rats with gabexate mesilate significantly attenuated the lung, liver and kidney dysfunction, consumptive coagulopathy, the increases in serum tumor necrosis factor-α, interleukin-6, plasma thrombin-antithrombin complex and plasminogen activator inhibitor-1, and neutrophils infiltration score in lung, liver and kidney, compared with the LPS alone group. In addition, TEG parameters correlated with tissue and liver injury in the late phase of endotoxemia. In particular, a strong negative correlation between maximal amplitude at 4  h and Ln (lactate dehydrogenase) at 6  h after LPS infusion was noted (r = -0.752, P < 0.001, R = 0.566). These results indicate that beneficial effects of anticoagulants (e.g. gabexate mesilate) in endotoxemia could be monitored by TEG per se.
aDepartment of Pharmacology, National Defense Medical Center bDepartment of Anesthesiology, Mackay Memorial Hospital, Taipei, Taiwan cCenter of Coronary Heart Disease, Fu Wai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China dDepartment of Anesthesiology, Taipei Veterans General Hospital and National Yang-Ming University eDepartment of Anesthesiology fGraduate Institute of Aerospace and Undersea Medicine, National Defense Medical Center, Taipei gDepartment of Anesthesiology, Tungs' Taichung MetroHarbor Hospital, Taichung hDepartment of Pharmacology, Taipei Medical University, Taipei, Taiwan *Wen-Jinn Liaw and Chin-Chen Wu contributed equally to this study.
Hsin-Jung
HJ
Tsai
Chen
C
Ding
Cheng-Ming
CM
Tsao
Mei-Hui
MH
Liao
Shuk-Man
SM
Ka
Wen-Jinn
WJ
Liaw
Chin-Chen
CC
Wu
D000818:Animals; D000925:Anticoagulants / Q000494:pharmacology*; D001778:Blood Coagulation Disorders / Q000188:drug therapy; D019446:Endotoxemia / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D016670:Gabexate / Q000494:pharmacology*; D008070:Lipopolysaccharides; D008297:Male; D009102:Multiple Organ Failure / Q000097:blood* / Q000188:drug therapy* / Q000503:physiopathology; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D013916:Thrombelastography / Q000379:methods*
D000925:Anticoagulants; D008070:Lipopolysaccharides; D016670:Gabexate