title: Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli: Unique Effects of Plasminogen Activation and α2-Antiplasmin Inactivation.
abstract: BACKGROUND
  In patients with hemodynamically significant pulmonary embolism, physiological fibrinolysis fails to dissolve thrombi acutely and r-tPA (recombinant tissue-type plasminogen activator) therapy may be required, despite its bleeding risk. To examine potential mechanisms, we analyzed the expression of key fibrinolytic molecules in experimental pulmonary emboli, assessed the contribution of α2-antiplasmin to fibrinolytic failure, and compared the effects of plasminogen activation and α2-antiplasmin inactivation on experimental thrombus dissolution and bleeding.
  
  
  METHODS
  Pulmonary embolism was induced by jugular vein infusion of125I-fibrin or fluorescein isothiocyanate-fibrin labeled emboli in anesthetized mice. Thrombus site expression of key fibrinolytic molecules was determined by immunofluorescence staining. The effects of r-tPA and α2-antiplasmin inactivation on fibrinolysis and bleeding were examined in a humanized model of pulmonary embolism.
  
  
  RESULTS
  The plasminogen activation and plasmin inhibition system assembled at the site of acute pulmonary emboli in vivo. Thrombus dissolution was markedly accelerated in mice with normal α2-antiplasmin levels treated with an α2-antiplasmin-inactivating antibody (P<0.0001). Dissolution of pulmonary emboli by α2-antiplasmin inactivation alone was comparable to 3 mg/kg r-tPA. Low-dose r-tPA alone did not dissolve emboli, but was synergistic with α2-antiplasmin inactivation, causing more embolus dissolution than clinical-dose r-tPA alone (P<0.001) or α2-antiplasmin inactivation alone (P<0.001). Despite greater thrombus dissolution, α2-antiplasmin inactivation alone, or in combination with low-dose r-tPA, did not lead to fibrinogen degradation, did not cause bleeding (versus controls), and caused less bleeding than clinical-dose r-tPA (P<0.001).
  
  
  CONCLUSIONS
  Although the fibrinolytic system assembles at the site of pulmonary emboli, thrombus dissolution is halted by α2-antiplasmin. Inactivation of α2-antiplasmin was comparable to pharmacological r-tPA for dissolving thrombi. However, α2-antiplasmin inactivation showed a unique pattern of thrombus specificity, because unlike r-tPA, it did not degrade fibrinogen or enhance experimental bleeding. This suggests that modifying the activity of a key regulator of the fibrinolytic system, like α2-antiplasmin, may have unique therapeutic value in pulmonary embolism.
authors.affiliation: From Department of Medicine, University of Tennessee Health Science Center, Memphis.
authors.forename: Satish
authors.initials: S
authors.lastname: Singh
authors.affiliation: From Department of Medicine, University of Tennessee Health Science Center, Memphis.
authors.forename: Aiilyan
authors.initials: A
authors.lastname: Houng
authors.affiliation: From Department of Medicine, University of Tennessee Health Science Center, Memphis. glreed@uthsc.edu.
authors.forename: Guy L
authors.initials: GL
authors.lastname: Reed
mesh_terms: D000818:Animals; D000933:Antifibrinolytic Agents / Q000627:therapeutic use; D004195:Disease Models, Animal; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D005342:Fibrinolysis; D006454:Hemoglobins / Q000032:analysis; D006470:Hemorrhage; D006801:Humans; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008856:Microscopy, Fluorescence; D010958:Plasminogen / Q000378:metabolism*; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D011655:Pulmonary Embolism / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D000979:alpha-2-Antiplasmin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D000933:Antifibrinolytic Agents; D006454:Hemoglobins; D017395:Plasminogen Activator Inhibitor 1; D000979:alpha-2-Antiplasmin; D005340:Fibrinogen; D010958:Plasminogen; D010959:Tissue Plasminogen Activator
keywords: fibrinolysis; hemorrhage; pulmonary embolism; thrombosis; α2-antiplasmin