tPA, but not uPA, significantly affects antithrombotic therapy by a glycoprotein IIb/IIIa antagonist, but not by a factor Xa inhibitor.
To define the interaction of fibrinolytic components with platelets or coagulation factors on thrombus formation, we investigated mouse deficient in tissue plasminogen activator (tPA -/-) or urokinase plasminogen activator (uPA -/-) and in their wild-type control (tPA +/+, uPA +/+). A thrombus was induced in the murine carotid artery using photochemical reaction. Blood flow was monitored and the time needed before the vessel became completely obstructed was within 12 min in all types of mice. When DX-9065a, a selective factor Xa inhibitor, or GR144053, a platelet glycoprotein (GP) complex IIb/IIIa antagonist was applied, the time required to occlusion was prolonged in a dose-dependent manner in all types of mice. When a factor Xa inhibitor was injected in tPA -/- mice, the estimated ED50 was not changed. However, when GR144053 was injected in tPA -/- mice, the most significant changes were observed: the estimated ED51 was 19.6 times higher than the one in tPA +/+ mice. Platelet aggregation, hemostasis 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. On the contrary, the inhibition of factor Xa shows a stable antithrombotic effect with or without tPA. Thus the lack of tPA, but not of uPA, significantly affects antithrombotic efficacy.
Nishida
M
M
Department of Pharmacology, Gifu University School of Medicine, Japan.
Matsuno
H
H
Kozawa
O
O
Ueshima
S
S
Matsuo
O
O
Collen
D
D
Uematsu
T
T
D000818:Animals; D001760:Bleeding Time; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007202:Indicators and Reagents; D051379:Mice; D009281:Naphthalenes / Q000494:pharmacology; D010314:Partial Thromboplastin Time; D010879:Piperazines / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D010960:Plasminogen Activators / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000037:antagonists & inhibitors*; D011422:Propionates / Q000494:pharmacology; D010959:Tissue Plasminogen Activator / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
C086910:(2S)-2-(4-(((3S)-1-acetimidoyl-3-pyrrolidinyl)oxy)phenyl)-3-(7-amidino-2-naphtyl)propanoic acid; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; C090662:GR 144053; D007202:Indicators and Reagents; D009281:Naphthalenes; D010879:Piperazines; D010880:Piperidines; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D011422:Propionates; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator