α₂-Antiplasmin causes thrombi to resist fibrinolysis induced by tissue plasminogen activator in experimental pulmonary embolism

Background: In patients with pulmonary embolism, thrombi resist fibrinolysis induced by plasminogen activators. Because the molecular basis of this thrombus resistance is poorly understood, we used a potent inhibitor to examine the potential role of α₂-antiplasmin (α2AP) in experimental pulmonary embolism. Methods and Results: Lysis of experimental pulmonary emboli was measured 4 hours after embolization in anesthetized ferrets. All animals received heparin (100 U/kg). Five experimental groups were studied: (1) no recombinant tissue plasminogen activator (rTPA); (2) rTPA at 1 mg/kg; (3) rTPA at 2 mg/kg; (4) rTPA at 1 mg/kg plus a control monoclonal antibody (MAb): and (5) rTPA at 1 mg/kg plus an α2AP inhibitor (MAb 77A3). In comparison with ferrets receiving no rTPA (15.6 ± 10.5% lysis, mean ± SD), rTPA-treated groups showed significantly greater lysis (P<.01). Animals treated with rTPA and α2AP inhibitor (56.2±4.7% lysis) showed significantly greater lysis than all other treatment groups, including ferrets treated with the same dose of rTPA alone (38.5±6.3%, P<.01), with twice the rTPA dose alone (45.0±6.5%, P<.05), or with a control MAb (35.2±4.6%, P<.01). The combination of rTPA treatment and α2AP inhibition caused no consumption of fibrinogen. Conclusion: Inhibition of α2AP significantly amplified the lysis of experimental pulmonary emboli by rTPA without increasing fibrinogen consumption. These results suggest that α2AP may play an important role in thrombus resistance in patients with venous thromboembolism.