An inhibitor of activated thrombin-activatable fibrinolysis inhibitor potentiates tissue-type plasminogen activator-induced thrombolysis in a rabbit jugular vein thrombolysis model

When activated in vitro, thrombin-activatable fibrinolysis inhibitor (TAFI) slows clot lysis by cleaving the C-terminal lysine and arginine residues f rom partially degraded fibrin. An inhibitor of carboxypeptidase isolated fr om potato (CPI) reverses prolongation of clot lysis by inhibiting activated TAFI. We investigated in vivo effect of TAFI inhibition on tissue-type pla sminogen activator (t-PA)-induced clot lysis using CPI in a rabbit jugular vein thrombolysis model. It was found necessary to further purify the CPI p reparations from commercial sources by HPLC chromatography to remove endoto xin and anti-plasmin activity that would affect the endogenous fibrinolytic system. The effect of intravenous administration of the purified CPI with t-PA was determined by measuring thrombus weight at the end of 90 minutes i n six groups of animals. In the control group receiving saline, the median thrombus weight was 116 mg. In the group that received CPI only (0.5 mg/kg bolus injection followed by 0.3 mg/kg/h infusion), the median thrombus weig ht was 121 mg, In the group that received t-PA at a dose of 10 mu g/kg bolu s followed by 67 mu g/kg/h infusion, the median thrombus weight decreased t o 86 mg. When CPI was coadministered with the same regimen of t-PA, the med ian value further decreased to 58 mg. When animals were given three times h igher the dose of t-PA (30 mu g/kg bolus followed by 200 mu g/kg/h infusion ) in the absence or presence of CPI, median thrombus weights were 56 mg and 0 mg, respectively. Our results demonstrate that systemic coadministration of the purified CPI improves clot lysis induced by t-PA. (C) 2000 Elsevier Science Ltd. All rights reserved.