| First Author | Singh S | Year | 2017 |
| Journal | Circulation | Volume | 135 |
| Issue | 11 | Pages | 1011-1020 |
| PubMed ID | 28028005 | Mgi Jnum | J:256585 |
| Mgi Id | MGI:6116166 | Doi | 10.1161/CIRCULATIONAHA.116.024421 |
| Citation | Singh S, et al. (2017) Releasing the Brakes on the Fibrinolytic System in Pulmonary Emboli: Unique Effects of Plasminogen Activation and alpha2-Antiplasmin Inactivation. Circulation 135(11):1011-1020 |
| abstractText | 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 alpha2-antiplasmin to fibrinolytic failure, and compared the effects of plasminogen activation and alpha2-antiplasmin inactivation on experimental thrombus dissolution and bleeding. METHODS: Pulmonary embolism was induced by jugular vein infusion of (125)I-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 alpha2-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 alpha2-antiplasmin levels treated with an alpha2-antiplasmin-inactivating antibody (P<0.0001). Dissolution of pulmonary emboli by alpha2-antiplasmin inactivation alone was comparable to 3 mg/kg r-tPA. Low-dose r-tPA alone did not dissolve emboli, but was synergistic with alpha2-antiplasmin inactivation, causing more embolus dissolution than clinical-dose r-tPA alone (P<0.001) or alpha2-antiplasmin inactivation alone (P<0.001). Despite greater thrombus dissolution, alpha2-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 alpha2-antiplasmin. Inactivation of alpha2-antiplasmin was comparable to pharmacological r-tPA for dissolving thrombi. However, alpha2-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 alpha2-antiplasmin, may have unique therapeutic value in pulmonary embolism. |
