Abstract 14994: Inactivation of α2-Antiplasmin Promotes Thrombus Dissolution in Humans: Preliminary Results of the Novel α2-Antiplasmin Inactivation for Lysis of Intravascular Thrombi (NAIL-IT) Trial

Introduction: The resistance of pathologic thrombi to dissolution contributes to death and disability in cardiovascular and cerebrovascular diseases. Plasminogen activator therapy overcomes thrombus resistance through massive plasmin generation causing coagulation factor depletion and increase propensity to bleeding. Alternatively, key regulatory molecules in the fibrinolytic pathway, such as α2-antiplasmin, the fast-acting inhibitor of plasmin, could be targeted. In experimental models of pulmonary embolism and ischemic stroke, monoclonal antibody inactivation of α2-antiplasmin enhances thrombus dissolution and improves survival, without causing bleeding. Therefore, we examined the effects of monoclonal antibody inactivation α2-antiplasmin on fibrinolysis and coagulation in humans. Methods and Results: The NAIL-IT study was a first-in-human study of an α2-antiplasmin inactivating antibody (TS23). Healthy male volunteers, ages 18-60, were administered TS23 intravenously in an ascending dose design and monitored for ten weeks. There was a significant, dose-related fall in blood α2-antiplasmin activity immediately after TS23 administration and α2-antiplasmin activity remained suppressed for hours to days, in a dose-related manner. Although all subjects had low or undetectable D-dimer levels at baseline, TS23 provoked significant, dose-related increases in D-dimer levels that were correlated with the degree of α2-antiplasmin inactivation. There were no significant bleeding episodes and no serious adverse events related to TS23. Conclusions: TS23 rapidly reduced α2-antiplasmin activity in humans and activated the fibrinolytic system. These findings support the central regulatory role of α2-antiplasmin in the fibrinolytic pathway and suggest that inactivation of α2-antiplasmin may prove useful in the treatment of thrombotic vascular diseases.