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(Circulation. 1997;95:1886-1891.)
© 1997 American Heart Association, Inc.

Articles

₂-Antiplasmin Causes Thrombi to Resist Fibrinolysis Induced by Tissue Plasminogen Activator in Experimental Pulmonary Embolism

Anjum N. Butte, MB, BS; Aiilyan K. Houng, BS; Ik-Kyung Jang, MD, PhD; Guy L. Reed, MD

From the Cardiovascular Biology Laboratory, Harvard School of Public Health (A.K.H., G.L.R); Harvard Medical School (A.N.B., I.-K.J., G.L.R.); and Massachusetts General Hospital (A.N.B., I.-K.J., G.L.R.), Boston.

Correspondence to Guy L. Reed, MD, Harvard School of Public Health, II-127, 677 Huntington Ave, Boston, MA 02115. E-mail reed{at}cvlab.harvard.edu

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 ₂-antiplasmin (2AP) 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 2AP 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 2AP 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 2AP inhibition caused no consumption of fibrinogen.

Conclusions Inhibition of 2AP significantly amplified the lysis of experimental pulmonary emboli by rTPA without increasing fibrinogen consumption. These results suggest that 2AP may play an important role in thrombus resistance in patients with venous thromboembolism.

Key Words: 2-antiplasmin • fibrinolysis • embolism • plasminogen activators

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