Effects of argatroban and heparin on thrombus formation and tissue plasminogen activator-induced thrombolysis in a microvascular thrombosis model.
Effects of (2R,4R)-4-methyl-1-[N(2)-(3-methyl-1,2,3,4-tetrahydro-8-quinolinesulfonyl)-L-arginyl]-2-piperidine-carboxylic acid monohydrate (argatroban) and unfractionated heparin (UFH) were compared with respect to thrombus formation and tissue-type plasminogen activator (t-PA)-induced thrombolysis in a microvasculature thrombosis model. The antithrombotic activities of anticoagulants were evaluated with respect to the time required for the initiation of thrombus formation (T(i)) and the time required for the thrombus to stop blood flow (T(s)). The effects of anticoagulants administered with t-PA were evaluated by percent stenosis of the vessel and percent area of the thrombus. Argatroban (1-3 mg/kg/bolus) significantly prolonged T(i) and T(s) in a dose-dependent fashion compared to control. Argatroban (3 mg/kg/bolus) significantly prolonged both the T(i) and T(s) more effectively than UFH (100 anti-XaU (a-XaU)/kg/bolus), despite equivalent prolongation of the activated partial thromboplastin time (aPTT). Higher doses of UFH (300-500 a-XaU/kg) were required to significantly prolong T(i) and T(s), but at these doses, UFH caused over-prolongation of aPTT (>180 s), which might consequently cause bleeding complications. Argatroban (0.1-0.3 mg/kg/h) significantly accelerated thrombolysis by t-PA in both a dose- and time-dependent fashion. Although argatroban (0.1-0.2 mg/kg/h) did not significantly prolong the aPTT and bleeding time (BT) as compared with control, it significantly accelerated thrombolysis by t-PA at these doses of lower bleeding risk. Argatroban (0.3 mg/kg/h) significantly enhanced thrombolysis by t-PA, while UFH (12.5 anti-XaU/kg/h) attenuated it again, despite equivalent prolongation of the aPTT and BT. We conclude that argatroban seems to be a more efficient and safer anticoagulant than UFH for the prevention of thrombus formation and acceleration of t-PA-induced thrombolysis.
Yamada
Keizo
K
Second Department of Medicine, Kyoto Prefectural University of Medicine, 465 Kajii-cho Hirokoji Kawaramachi, Kamigyo-ku, Kyoto 602-8566, Japan.
Tsuji
Hajime
H
Kimura
Shinzo
S
Kato
Hisato
H
Yano
Shingo
S
Ukimura
Naoki
N
Yamada
Yuka
Y
Nakagawa
Katsumi
K
Nakagawa
Masao
M
D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives; D006224:Cricetinae; D004195:Disease Models, Animal; D004347:Drug Interactions; D005343:Fibrinolytic Agents / Q000494:pharmacology; D006493:Heparin / Q000008:administration & dosage / Q000494:pharmacology*; D008647:Mesocricetus; D008833:Microcirculation / Q000473:pathology; D010314:Partial Thromboplastin Time; D010875:Pipecolic Acids / Q000008:administration & dosage / Q000494:pharmacology*; D013449:Sulfonamides; D015912:Thrombolytic Therapy / Q000379:methods* / Q000592:standards; D013927:Thrombosis / Q000188:drug therapy*; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000494:pharmacology*
D005343:Fibrinolytic Agents; D010875:Pipecolic Acids; D013449:Sulfonamides; D006493:Heparin; D001120:Arginine; D010959:Tissue Plasminogen Activator; C031942:argatroban