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

Anjum N. Butte, Aiilyan K. Houng, Ik Kyung Jang, Guy L. Reed

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1886-1891
Number of pages6
JournalCirculation
Volume95
Issue number7
DOIs
StatePublished - Apr 1 1997

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Antifibrinolytic Agents
Fibrinolysis
Tissue Plasminogen Activator
Pulmonary Embolism
Thrombosis
Ferrets
Monoclonal Antibodies
Embolism
Fibrinogen
Lung
Plasminogen Activators
Venous Thromboembolism
Heparin

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

α2-Antiplasmin causes thrombi to resist fibrinolysis induced by tissue plasminogen activator in experimental pulmonary embolism. / Butte, Anjum N.; Houng, Aiilyan K.; Jang, Ik Kyung; Reed, Guy L.

In: Circulation, Vol. 95, No. 7, 01.04.1997, p. 1886-1891.

Research output: Contribution to journalArticle

Butte, Anjum N. ; Houng, Aiilyan K. ; Jang, Ik Kyung ; Reed, Guy L. / α2-Antiplasmin causes thrombi to resist fibrinolysis induced by tissue plasminogen activator in experimental pulmonary embolism. In: Circulation. 1997 ; Vol. 95, No. 7. pp. 1886-1891.
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abstract = "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.",
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AU - Reed, Guy L.

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N2 - 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.

AB - 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.

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