Antithrombin ameliorates endotoxin-induced organ dysfunction more efficiently when combined with danaparoid sodium than with unfractionated heparin.
OBJECTIVE
This study investigated the potential benefits of combination therapy using antithrombin (AT) with danaparoid sodium (DA) compared with the use of AT with unfractionated heparin (UFH) in the treatment of sepsis.


METHODS
Rats infused with lipopolysaccharide were treated with either DA alone, AT alone, AT plus DA, AT plus UFH, or human serum albumin as controls. AT (125 U/kg) was injected into the AT group immediately after lipopolysaccharide infusion. The AT/DA and AT/UFH groups received the same dose of AT in conjunction with either DA (400 U/kg) or UFH (400 U/kg). The status of the mesenteric microcirculation was examined by intra-vital microscopy and the laboratory indices of coagulation, inflammation, and organ dysfunction were measured.


RESULTS
The coagulation markers were improved following the administration of DA or UFH. The decreases in the WBC counts were significantly suppressed in the AT/DA group. The elevation of IL-6 decreased in the AT, DA, and AT/DA groups (all p<0.01) but not in the AT/UFH group. The prostaglandin I2 levels were significantly elevated only in the AT/DA group (p<0.05). The WBC adhesion was significantly suppressed in the DA, AT/UFH, and AT/DA groups (p<0.05), and the RBC velocity was best maintained in the AT/DA group with no associated increase in capillary hemorrhage. The elevation of ALT and BUN significantly improved only in the AT/DA group. ONCLUSION: Organ dysfunction can thus be alleviated by even moderate doses of AT replacement when co-administered with DA.
Department of Surgery, Juntendo University School of Medicine, Juntendo Urayasu Hospital, 2-1-1 Tomioka, 279-0021 Urayasu, Chiba, Japan. iba-jun@umin.ac.jp
Toshiaki
T
Iba
Akio
A
Kidokoro
Masaki
M
Fukunaga
Kunihiko
K
Nagakari
Masaru
M
Suda
Seiichiro
S
Yoshikawa
Yukiko
Y
Ida
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D000991:Antithrombins / Q000627:therapeutic use*; D001806:Blood Urea Nitrogen; D002809:Chondroitin Sulfates / Q000627:therapeutic use*; D003871:Dermatan Sulfate / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D005343:Fibrinolytic Agents / Q000627:therapeutic use; D006493:Heparin / Q000627:therapeutic use; D006497:Heparan Sulfate / Q000627:therapeutic use*; D015850:Interleukin-6 / Q000097:blood; D007958:Leukocyte Count; D008070:Lipopolysaccharides / Q000633:toxicity; D009102:Multiple Organ Failure / Q000139:chemically induced / Q000188:drug therapy*; D010976:Platelet Count; D051381:Rats; D017208:Rats, Wistar
D015121:6-Ketoprostaglandin F1 alpha; D000410:Alanine Transaminase; D000925:Anticoagulants; D000991:Antithrombins; D002809:Chondroitin Sulfates; D003871:Dermatan Sulfate; D005343:Fibrinolytic Agents; D006493:Heparin; D006497:Heparan Sulfate; D015850:Interleukin-6; D008070:Lipopolysaccharides; C035838:danaparoid