Activated thrombin-activatable fibrinolysis inhibitor attenuates spontaneous fibrinolysis of batroxobin-induced fibrin deposition in rat lungs.
Studies have shown that inhibition of TAFI by small peptides enhances pharmacological effects of tPA in animal models of thrombosis, suggesting that TAFI modulates the fibrinolytic system. In this study, we investigated the effect of activated human TAFI (TAFIa) on endogenous fibrinolysis in a rat model of intravascular fibrin deposition. (125)I-labeled fibrinogen was injected intravenously followed by a bolus injection of batroxobin, a thrombin-like enzyme. Batroxobin cleaved fibrinogen to form insoluble fibrin that was deposited in tissues, including the lungs. This was shown by a decrease of radioactivity in the blood as a result of consumption of (125)I-labeled fibrinogen and an elevation of radioactivity in the lungs 5 min following batrox-obin administration. Endogenous fibrinolysis was detected by a gradual increase in radioactivity in the blood and a decrease in radioactivity in the lungs at 30 min, an indication of radiolabeled fibrin degradation products (FDPs) being released into the circulation from the tissues. Intravenous administration of human TAFIa dose-dependently attenuated the later phase reduction of radioactivity in the lungs. When the dose of TAFIa was 218 micro g/kg, giving a peak plasma level of TAFIa 0.9 +/- 0.05 micro g/ml, the spontaneous fibrinolysis was completely prevented. These results provide direct evidence that an increase in circulating TAFIa impairs endogenous clot lysis in a rat model of fibrin deposition.
Wu
Chengliang
C
Berlex Biosciences, Department of Pharmacology, P.O. Box: 4099, 2600 Hilltop Drive, Richmond, A 94804-0099, USA. bernd.binder@univie.ac.at
Dong
Ningzheng
N
da Cunha
Valdeci
V
Martin-McNulty
Baby
B
Tran
Katherine
K
Nagashima
Mariko
M
Wu
Qingyu
Q
Morser
John
J
Wang
Yi-Xin
YX
D000818:Animals; D012103:Batroxobin / Q000494:pharmacology*; D025901:Carboxypeptidase B2 / Q000097:blood / Q000494:pharmacology* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D005337:Fibrin / Q000378:metabolism*; D005340:Fibrinogen / Q000493:pharmacokinetics; D005342:Fibrinolysis / Q000187:drug effects*; D006801:Humans; D007275:Injections, Intravenous; D007457:Iodine Radioisotopes / Q000493:pharmacokinetics; D008171:Lung Diseases / Q000473:pathology*; D008297:Male; D051381:Rats; D013927:Thrombosis / Q000209:etiology
D007457:Iodine Radioisotopes; D005337:Fibrin; D005340:Fibrinogen; D025901:Carboxypeptidase B2; D012103:Batroxobin