Lack of tPA significantly affects antithrombotic therapy by a GPIIb/IIIa antagonist, but not by a thrombin inhibitor in mice.
The interaction of fibrinolytic components with platelets or coagulation factors after endothelial injury, was investigated in mouse deficient in tissue type plasminogen activator (tPA -/-), or urokinase (uPA -/-) and in their wild type control (tPA +/+, uPA +/+). A thrombus was induced in the murine carotid artery using the photochemical reaction. Blood flow was continuously monitored and the time needed before the vessel became completely obstructed was within 11 min in all types of mice. When GR144053, a platelet glycoprotein IIb/IIIa antagonist, or argatroban, a thrombin inhibitor, was applied, the time required to occlusion was prolonged in a dose-dependent manner in all types of mice. However, when GR144053 was injected in tPA -/- mice, the most significant changes were observed: that is the estimated ED50 was 14.8 times higher than the one in tPA +/+ mice. On the other hand, when argatroban was injected in tPA -/- mice, the estimated ED50 was not changed. Platelet aggregation, haemostasis tests and bleeding times were not significantly different among the different types of mice. In conclusion, the antithrombotic effect of platelet inhibition by a GPIIb/IIIa antagonist, is severely affected by the absence or presence of tPA-production. Thus, the lack of tPA significantly reduces the antithrombotic efficacy.
Matsuno
H
H
Department of Pharmacology, Gifu University School of Medicine, Japan. leuven@cc.gifu-u.ac.jp
Kozawa
O
O
Ueshima
S
S
Matsuo
O
O
Collen
D
D
Uematsu
T
T
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D001760:Bleeding Time; D002341:Carotid Artery Thrombosis / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005343:Fibrinolytic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D018345:Mice, Knockout; D010875:Pipecolic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use*; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D013449:Sulfonamides; D013917:Thrombin / Q000037:antagonists & inhibitors*; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D014568:Urokinase-Type Plasminogen Activator / Q000172:deficiency / Q000235:genetics
D005343:Fibrinolytic Agents; C090662:GR 144053; D010875:Pipecolic Acids; D010879:Piperazines; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D013449:Sulfonamides; D001120:Arginine; D013917:Thrombin; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; C031942:argatroban