Heparin cofactor II inhibits thrombus formation in a rat thrombosis model.
Heparin cofactor II is postulated to be an extravascular thrombin inhibitor that is physiologically stimulated by dermatan sulfate. However, the role of heparin cofactor II has not yet been clearly demonstrated in vivo. In this study, we estimated the antithrombotic effect of heparin cofactor II administered exogenously in a rat model of thrombosis. Thrombus was induced in the rat femoral artery by endothelial damage due to the photochemical reaction between systemically injected rose bengal and transillumination with green light. Pretreatment with heparin cofactor II significantly prolonged the time required to occlude the femoral artery (occlusion time) in a dose-dependent manner. At an effective dose in this thrombosis model, heparin cofactor II did not prolong the activated partial thromboplastin time and the prothrombin time in normal rats. Argatroban, a selective synthetic thrombin inhibitor, significantly prolonged the occlusion time. However, argatroban also prolonged the activated partial thromboplastin time and prothrombin time at an effective dose. These results suggest that the administration of heparin cofactor II in vivo effectively inhibited thrombus formation on the vessel walls whose endothelium is damaged without a prolongation of the coagulation time while heparin cofactor II may also inhibit the thrombin activity in the subendothelial tissue in vivo.
Yamanaga
K
K
Osaka Laboratories, Yoshitomi Pharmaceutical Industries, Ltd., 2-25-1 Shodai-Ohtani, Hirakata, Osaka, Japan. yamanaga@yoshitomi.co.jp
Yuuki
T
T
Tsukada
M
M
Koshiba
H
H
Nakajima
T
T
Takechi
K
K
Nakamura
N
N
D000818:Animals; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D015844:Heparin Cofactor II / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D051381:Rats; D017208:Rats, Wistar; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy*; D014914:Whole Blood Coagulation Time
D005343:Fibrinolytic Agents; D015842:Serine Proteinase Inhibitors; D015844:Heparin Cofactor II