No Fibrinolytic Benefit of Adjunctive Anticoagulation during Arterial Thrombolysis Induced by tPA Combined with TAFIa Inhibitor in a Rabbit Arterial Thrombosis Model.

Abstract Introduction: In a previous study, we reported that inhibition of activated TAFI (TAFIa) with potato carboxypeptidase inhibitor (PCI) enhanced tPA-induced clot lysis in a rabbit aortic thrombosis model. Building on these results, this study used the same model to determine whether the addition of anticoagulants to PCI would further enhance tPA-induced clot lysis. Methods: After balloon injury and creation of a critical stenosis, a radiolabelled thrombus of known mass was generated in the distal aorta. Rabbits were then given tPA (0.25 mg/kg bolus followed by 0.25 mg/kg infusion over 60 min) in conjunction with PCI (30 μg/kg bolus followed by 30 μg/kg/hr) or saline (SAL, 1ml/kg bolus followed by 1 ml/kg/hr). Rabbits treated with tPA/PCI were also supplemented with hirudin (HIR, 0.2 mg/kg bolus followed by 0.2 mg/kg/hr) or heparin (H, 50 U/kg bolus followed by 50 U/kg/hr) or pentasaccharide (PENTA,1 mg/kg iv bolus) or SAL. To assess safety, standardized ear incisions were made 15 min after starting tPA and cumulative blood loss was measured over a 30 min period. This time point was chosen because both tPA and anticoagulant levels are at their peak. To assess efficacy, clot lysis was measured at 90 min by subtracting the radioactivity of the residual thrombus from that of the initial thrombus and expresing this value as a percentage of initial radioactivity. Results: As illustrated in the table, PCI increases tPA-induced clot lysis from 71.3 to 89.2 % with a minimal effect on bleeding. The addition of anticoagulants produced no further increase in clot lysis, but all 3 of the anticoagulants tested increased blood loss. Conclusions: These preliminary data support the concept that PCI enhances tPA-induced clot lysis to an extent where concomitant administration of anticoagulants provides no additional benefit and compromises safety. Thrombolytic efficacy/safety profile of various treatments. Treatment Clot lysis (%) Blood loss (μL) Values are expressed in Mean ± SEM, four rabbits per treatment group SAL 19.7 ± 2.2 15.6 ± 5.3 tPA 71.3 ± 7.1 66.8 ± 14.0 tPA + PCI 89.2 ± 3.3 104.2 ± 42.7 tPA + PCI + H 90.3 ± 5.5 134.0 ± 60.9 tPA + PCI + PENTA 90.6 ± 3.2 215.6 ± 41.5 tPA + PCI + HIR 92.0 ± 5.7 680.3 ± 536.6

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