Abstract TP66: Quantitative Proteomic Profile of Tissue Plasminogen Activator (tPA) Responders
Background: The utilization of IV tPA continues to be low after more than a decade of FDA approval. We aim to widen the therapeutic window for tPA by understanding clinical thrombolysis response. Besides its intended role in clot lysis, tPA is also a pleiotrophic signaling protease in the blood, whose efficacy may potentially be monitored by proteomic profiles directly in stroke patients.
Method/Results: To study thrombolysis response, we mapped quantitative profiles of all proteins pre and post IV tPA administration in plasma of stroke patients with good clinical outcome at 3 months. Plasma was sampled from stroke patients immediately before and 6-12hrs after tPA administration (n=28). Quantitative changes of proteins pre and post tPA were mapped by isotopic methods and analyzed on LC-MS. While both intra- and extracellular proteins were found, most were known plasma proteins, as seen on IPA analysis (Figure). Of 191 proteins found, 48 changed significantly post tPA (fold ratio in parenthesis). Compared to pre-tPA levels, we found significantly increased post-tPA levels of thrombolysis-related proteins such as fibrinogen gamma chain (↑11x), α-2-antiplasmin (↑4x), and a decrease in factor X (↓7x) etc. Changes were also found in factors outside of standard thrombolytic pathways, such as α-2-macroglobulin (↑2.3x); CD14 (↓2x) and GPX3 glutathione peroxidase 3 (↓2x) etc.
Conclusion: In order to study thrombolysis response and monitor thrombolysis efficacy at the bedside, we mapped quantitative protein fold changes of IV tPA responders and found a coordinated change not only in reported thrombolysis pathways, but also in other enzymatic pathways in patient plasma. These early results are a step toward attempts to monitor clinical thrombolysis response in acute stroke patients in real time. Further studies are under way to compare plasma profiles of tPA-treated stroke patients with respect to different clinical outcome and imaging findings of reperfusion.
- © 2012 by American Heart Association, Inc.