Alpha 2-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 alpha 2-antiplasmin (alpha 2AP) in experimental pulmonary embolism.


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 alpha 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 alpha 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 alpha 2AP inhibition caused no consumption of fibrinogen.


CONCLUSIONS
Inhibition of alpha 2AP significantly amplified the lysis of experimental pulmonary emboli by rTPA without increasing fibrinogen consumption. These results suggest that alpha 2AP may play an important role in thrombus resistance in patients with venous thromboembolism.
Butte
A N
AN
Harvard Medical School, Boston, MA, USA.
Houng
A K
AK
Jang
I K
IK
Reed
G L
GL
D000818:Animals; D004351:Drug Resistance; D005289:Ferrets; D005342:Fibrinolysis / Q000187:drug effects*; D006493:Heparin / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010960:Plasminogen Activators / Q000494:pharmacology* / Q000627:therapeutic use; D011655:Pulmonary Embolism / Q000188:drug therapy / Q000503:physiopathology*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000494:pharmacology* / Q000627:therapeutic use; D000979:alpha-2-Antiplasmin / Q000494:pharmacology*
D011994:Recombinant Proteins; D000979:alpha-2-Antiplasmin; D006493:Heparin; D010960:Plasminogen Activators; D010959:Tissue Plasminogen Activator