Abstract 16486: Safely Removing the Brakes on Fibrinolysis: Inactivation of α2-Antiplasmin Dissolves Pulmonary Emboli Without Causing Bleeding

Abstract

Introduction: Venous thromboembolism affects millions of patients per year and pulmonary embolism (PE) is a leading cause of hospital mortality. PE activates the fibrinolytic system, but regulatory molecules such as α2-antiplasmin (a2AP) appear to prevent thrombus dissolution. Pharmacologic tissue plasminogen activator (tPA) dissolves pulmonary emboli, relieves right heart strain and improves mortality in high risk patients, but tPA has unacceptable bleeding risks. We examined whether inactivation of a2AP may prove to be a safer and more effective method for dissolving experimental pulmonary emboli. Methods: Pulmonary embolism was examined in a humanized model. Anesthetized, a2AP -/- mice, supplemented with physiological levels of a2AP, were infused with 125 I-labeled human thrombi via the jugular vein. Then mice were treated with tPA, no agent (control), a humanized chimeric monoclonal antibody inactivator of a2AP (a2AP-I) or the combination of low dose tPA and a2AP-I. Thrombus dissolution was determined by gamma counting and surgical bleeding was measured. Results: Clinical dose tPA dissolved pulmonary emboli more effectively than no therapy (control, p<0.001). However, mice treated with a2AP-I showed greater thrombus dissolution than tPA (p<0.001) or controls (p<0.001). Alone, low doses of tPA did not dissolve thrombi, but in combination with a2AP-I, low dose tPA increased thrombus dissolution more than clinical dose tPA alone (p<0.001) or a2AP-I alone (p<0.001). Clinical dose tPA therapy was associated with a significant increase in bleeding (p<0.01). Though more potent than tPA in dissolving pulmonary emboli, a2AP-I alone, or in combination with low dose tPA, did not increase bleeding risk vs. controls and caused less bleeding than tPA (p<0.01). Conclusion: In experimental pulmonary embolism a2AP plays a critical regulatory role in blocking fibrinolysis. Inactivation of a2AP was more potent than tPA in dissolving thrombi in PE, but unlike tPA, it did not cause bleeding. This suggests that a2AP inactivation may be a safer strategy for treating venous thromboembolism.