Characteristic effects of activated human protein C on tissue thromboplastin-induced disseminated intravascular coagulation in rabbits.
Protein C (PC) is the zymogen of an anticoagulant serine protease and is converted to its active form (activated protein C: APC) by thrombin in the presence of thrombomodulin. APC plays an important role in regulating thrombosis and fibrinolysis by inhibiting not only blood coagulation factors Va and VIIIa but also type-1 plasminogen activator inhibitor (PAI-1). In the present study we examined the effects of human APC on tissue thromboplastin-induced disseminated intravascular coagulation (DIC) in rabbits and compared them with those of heparin. Both APC (300-3000 U/kg) and heparin (100-300 IU/kg) inhibited the decreases in platelet count and fibrinogen level equally. APC improved the prolonged bleeding time, but heparin aggravated bleeding with potent prolongation of activated partial thromboplastin time (APTT). Furthermore, in APC-treated animals, fibrin deposition in glomeruli was less than in heparin-treated animals. This result that APC accelerated local fibrinolysis by neutralizing PAI-1. From our findings, we concluded that APC can improve both coagulation and fibrinolysis in a DIC model and should be useful for the clinical remedy of DIC without having an adverse side effect like a bleeding tendency.
Katsuura
Y
Y
Pharmaceuticals Development Research Laboratories, Teijin Ltd., Tokyo, Japan.
Aoki
K
K
Tanabe
H
H
Kiyoki
M
M
Funatsu
A
A
D000818:Animals; D001760:Bleeding Time; D004211:Disseminated Intravascular Coagulation / Q000139:chemically induced / Q000188:drug therapy*; D004789:Enzyme Activation; D005337:Fibrin / Q000032:analysis; D005340:Fibrinogen / Q000032:analysis; D005342:Fibrinolysis / Q000187:drug effects*; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006493:Heparin / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007678:Kidney Glomerulus / Q000737:chemistry; D008297:Male; D010314:Partial Thromboplastin Time; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D010976:Platelet Count / Q000187:drug effects; D011486:Protein C / Q000494:pharmacology*; D011817:Rabbits; D015912:Thrombolytic Therapy; D013925:Thromboplastin / Q000633:toxicity*
D005343:Fibrinolytic Agents; D017395:Plasminogen Activator Inhibitor 1; D011486:Protein C; D005337:Fibrin; D005340:Fibrinogen; D006493:Heparin; D013925:Thromboplastin